A meta-analysis of the effect of stent design on clinical and radiologic outcomes of carotid artery stenting.
Procedural characteristics, including stent design, may influence the outcome of carotid artery stenting (CAS). A thorough comparison of the effect of stent design on outcome of CAS is thus warranted to allow for optimal evidence-based clinical decision making. This study sought to evaluate the effect of stent design on clinical and radiologic outcomes of CAS. A systematic search was conducted in MEDLINE, Embase, and Cochrane databases in May 2018. Included were articles reporting on the occurrence of clinical short- and intermediate-term major adverse events (MAEs; any stroke or death) or radiologic adverse events (new ischemic lesions on postprocedural magnetic resonance diffusion-weighted imaging [MR-DWI], restenosis, or stent fracture) in different stent designs used to treat carotid artery stenosis. Random effects models were used to calculate combined overall effect sizes. Metaregression was performed to identify the effect of specific stents on MAE rates. From 2654 unique identified articles, two randomized, controlled trials and 66 cohort studies were eligible for analysis (including 46,728 procedures). Short-term clinical MAE rates were similar for patients treated with open cell vs closed cell or hybrid stents. Use of an Acculink stent was associated with a higher risk of short-term MAE compared with a Wallstent (risk ratio [RR], 1.51; P = .03), as was true for use of Precise stent vs Xact stent (RR, 1.55; P < .001). Intermediate-term clinical MAE rates were similar for open vs closed cell stents. Use of open cell stents predisposed to a 25% higher chance (RR, 1.25; P = .03) of developing postprocedural new ischemic lesions on MR-DWI. No differences were observed in the incidence of restenosis, stent fracture, or intraprocedural hemodynamic depression with respect to different stent design. Stent design is not associated with short- or intermediate-term clinical MAE rates in patients undergoing CAS. Furthermore, the division in open and closed cell stent design might conceal true differences in single stent efficacy. Nevertheless, open cell stenting resulted in a significantly higher number of subclinical postprocedural new ischemic lesions detected on MR-DWI compared with closed cell stenting. An individualized patient data meta-analysis, including future studies with prospective homogenous study design, is required to adequately correct for known risk factors and to provide definite conclusions with respect to carotid stent design for specific subgroups.


Community health workers in low-, middle-, and high-income countries: an overview of their history, recent evolution, and current effectiveness.
Over the past half-century, community health workers (CHWs) have been a growing force for extending health care and improving the health of populations. Following their introduction in the 1970s, many large-scale CHW programs declined during the 1980s, but CHW programs throughout the world more recently have seen marked growth. Research and evaluations conducted predominantly during the past two decades offer compelling evidence that CHWs are critical for helping health systems achieve their potential, regardless of a country's level of development. In low-income countries, CHWs can make major improvements in health priority areas, including reducing childhood undernutrition, improving maternal and child health, expanding access to family-planning services, and contributing to the control of HIV, malaria, and tuberculosis infections. In many middle-income countries, most notably Brazil, CHWs are key members of the health team and essential for the provision of primary health care and health promotion. In the United States, evidence indicates that CHWs can contribute to reducing the disease burden by participating in the management of hypertension, in the reduction of cardiovascular risk factors, in diabetes control, in the management of HIV infection, and in cancer screening, particularly with hard-to-reach subpopulations. This review highlights the history of CHW programs around the world and their growing importance in achieving health for all.


Pressure-dependent contribution of Rho kinase-mediated calcium sensitization in serotonin-evoked vasoconstriction of rat cerebral arteries.
Our understanding of the cellular signalling mechanisms contributing to agonist-induced constriction is almost exclusively based on the study of conduit arteries. Resistance arteries/arterioles have received less attention as standard biochemical approaches lack the necessary sensitivity to permit quantification of phosphoprotein levels in these small vessels. Here, we have employed a novel, highly sensitive Western blotting method to assess: (1) the contribution of Ca(2+) sensitization mediated by phosphorylation of myosin light chain phosphatase targeting subunit 1 (MYPT1) and the 17 kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17) to serotonin (5-HT)-induced constriction of rat middle cerebral arteries, and (2) whether there is any interplay between pressure-induced myogenic and agonist-induced mechanisms of vasoconstriction. Arterial diameter and levels of MYPT1 (T697 and T855), CPI-17 and 20 kDa myosin light chain subunit (LC(20)) phosphorylation were determined following treatment with 5-HT (1 micromol l(1)) at 10 or 60 mmHg in the absence and presence of H1152 or GF109203X to suppress the activity of Rho-associated kinase (ROK) and protein kinase C (PKC), respectively. Although H1152 and GF109203X suppressed 5-HT-induced constriction and reduced phospho-LC(20) content at 10 mmHg, we failed to detect any increase in MYPT1 or CPI-17 phosphorylation. In contrast, an increase in MYPT1-T697 and MYPT1-T855 phosphorylation, but not phospho-CPI-17 content, was apparent at 60 mmHg following exposure to 5-HT, and the phosphorylation of both MYPT1 sites was sensitive to H1152 inhibition of ROK. The involvement of MYPT1 phosphorylation in the response to 5-HT at 60 mmHg was not dependent on force generation per se, as inhibition of cross-bridge cycling with blebbistatin (10 micromol l(1)) did not affect phosphoprotein content. Taken together, the data indicate that Ca(2+) sensitization owing to ROK-mediated phosphorylation of MYPT1 contributes to 5-HT-evoked vasoconstriction only in the presence of pressure-induced myogenic activation. These findings provide novel evidence of an interplay between myogenic- and agonist-induced vasoconstriction in cerebral resistance arteries.


Bioluminescence imaging of mitochondrial Ca2+ dynamics in soma and neurites of individual adult mouse sympathetic neurons.
Changes in the cytosolic Ca(2+) concentration ([Ca(2+)](c)) are essential for triggering neurotransmitter release from presynaptic nerve terminals. Calcium-induced Ca(2+) release (CICR) from the endoplasmic reticulum (ER) may amplify the [Ca(2+)](c) signals and facilitate neurotransmitter release in sympathetic neurons. In adrenal chromaffin cells, functional triads are formed by voltage-operated Ca(2+) channels (VOCCs), CICR sites and mitochondria. In fact, mitochondria take up most of the Ca(2+) load entering the cells and are essential for shaping [Ca(2+)](c) signals and exocytosis. Here we have investigated the existence of such functional triads in sympathetic neurons. The mitochondrial Ca(2+) concentration ([Ca(2+)](m)) in soma and neurites of individual mouse superior cervical ganglion (SCG) neurons was monitored by bioluminescence imaging of targeted aequorins. In soma, Ca(2+) entry through VOCCs evoked rapid, near millimolar [Ca(2+)](m) increases in a subpopulation of mitochondria containing about 40% of the aequorin. Caffeine evoked a similar [Ca(2+)](m) increase in a mitochondrial pool containing about 30% of the aequorin and overlapping with the VOCC-sensitive pool. These observations suggest the existence of functional triads similar to the ones described in chromaffin cells. In neurites, mitochondria were able to buffer [Ca(2+)](c) increases resulting from activation of VOCCs but not those mediated by caffeine-induced Ca(2+) release from the ER. The weaker Ca(2+) buffering by mitochondria in neurites could contribute to facilitate Ca(2+)-induced exocytosis at the presynaptic sites.


The chemosensitivity of nodal metastases in recurrent epithelial ovarian cancer.
In this study, we compared second-line chemotherapy effects of nodal metastases with other metastases sites. The medical records of 44 women with recurrent ovarian cancer who received second-line chemotherapy were retrospectively reviewed. Median age at the time of second-line chemotherapy was 55 years (range: 31-74). Recurrent sites were as follows: 29 patients had a solitary site (abdominal cavity: 8; lymph node: 3; pelvic cavity: 10; liver: 4; lung: 4) and 15 patients had multiple sites In total, the response rate was 30% (CR: 8, PR: 5). The response rate in sensitive cases was higher than in refractory/resistant cases (50% vs 5% p = 0.002). However, age, chemotherapy regimen, histologic type and number of diseases were not related with chemotherapy effect. In all diseases, response rate tended to be higher in lymph node disease than in the others (44% vs 27%). In both sensitive and refractory/resistant cases, response rate tended to be higher in lymph node disease. The response rate for lymph node diseases tended to be relatively high. Further study analyzing survival will be required to conclude the chemotherapy effect.


Cholecystokinin-induced protection against gastric injury is independent of endogenous somatostatin.
Cholecystokinin (CCK) prevents macroscopic injury to the stomach from luminal irritants by an unknown mechanism. The present study was undertaken in conscious rats to ascertain what role gastric mucosal blood flow, sensory neurons, and endogenous somatostatin play in CCK-induced gastric protection. Subcutaneous administration of CCK (10-100 micrograms/kg) significantly reduced macroscopic injury to the acid-secreting portion of the stomach caused by 1 ml of orally administered acidified ethanol (150 mM HCl, 50% ethanol) and augmented gastric mucosal blood flow (fluorescent microspheres) in a dose-dependent fashion. However, although the protective response to CCK (100 micrograms/kg) was still present at 2 h, the blood flow response had returned to baseline by 45 min. Ablation of capsaicin-sensitive afferent neurons with capsaicin (125 mg/kg sc) did not negate CCK-induced protection. Pretreatment with exogenous somatostatin (1 pmol-1 nmol/kg sc) failed to prevent the damaging effects of acidified ethanol to gastric mucosa. Immunoneutralization of endogenous somatostatin with somatostatin monoclonal antibody (2 mg ip) did not reverse the protective actions of CCK. Thus the data suggest that although CCK may prepare the gastric mucosa to withstand a damaging insult by augmenting gastric mucosal blood flow, its protective mechanism is independent of intact sensory neurons and endogenous somatostatin.


Improving bowel preparation for colonoscopy in a cost effective manner.
Colonoscopy is a key investigation used to exclude large bowel pathologies including surveillance for CRC (Colorectal cancer) Poor bowel preparation (bowel prep) is one of the most important factors affecting its diagnostic yield. Different formulations of bowel prep are currently in use depending upon patient tolerance, indication & co-morbidities. In University Hospital Llandough we retrospectively reviewed the outcome of colonoscopies performed over period of 3 months, in relation to the type and outcome of bowel preparations used. We implemented a change of patient instruction and pre-assessment of bowel preparation prescribed. We repeated the same measurements over 3 different cycles on 3 different occasions and compared the outcome. We noticed that quality of bowel preparation noticeably improved from 80% to almost 93% if patients were given appropriate advice in a written format, prior to procedure. In addition to improvement in the quality of assessment & reducing the number of repeat procedures, by changing the bowel preparation product and postage methods we estimated savings of almost £150,000 for the trust in a year.


c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo.
c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycER(TAM) mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through two distinct pathways.


Spatial learning and memory in male mice with altered growth hormone action.
Growth hormone (GH) has a significant influence on cognitive performance in humans and other mammals. To understand the influence of altered GH action on cognition, we assessed spatial learning and memory using a Barnes maze (BM) comparing twelve-month old, male, bovine GH (bGH) and GH receptor antagonist (GHA) transgenic mice and their corresponding wild type (WT) littermates. During the acquisition training period in the BM, bGH mice showed increased latency, traveled longer path lengths and made more errors to reach the target than WT mice, indicating significantly poorer learning. Short-term memory (STM) and long-term memory (LTM) trials showed significantly suppressed memory retention in bGH mice when compared to the WT group. Conversely, GHA mice showed significantly better learning parameters (latency, path length and errors) and increased use of an efficient search strategy than WT mice. Our study indicates a negative impact of GH excess and a beneficial effect of the inhibition of GH action on spatial learning and memory and, therefore, cognitive performance in male mice. Further research to elucidate GH's role in brain function will facilitate identifying therapeutic applications of GH or GHA for neuropathological and neurodegenerative conditions.


Effect of different 5-HT1A receptor antagonists in combination with paroxetine on expression of the immediate-early gene Arc in rat brain.
Selective 5-HT(1A) receptor antagonists enhance the effect of selective serotonin reuptake inhibitors (SSRIs) on presynaptic 5-HT function, and have potential as antidepressant augmentation therapies. The present study tested the effect of different selective 5-HT(1A) receptor antagonists (WAY 100635, NAD-299, p-MPPI and LY 426965) in combination with a SSRI (paroxetine), on postsynaptic 5-HT function measured by increased expression of the immediate early gene, Arc. Paroxetine (5 mg/kg s.c.) combined with WAY 100635 (0.3 mg/kg s.c.) increased Arc mRNA in frontal, parietal and piriform cortices, and caudate putamen. Paroxetine (5 mg/kg s.c.) plus NAD-299 (1 or 5 mg/kg s.c.) had a similar effect. None of these drugs increased Arc mRNA when administered alone. Paroxetine (5 mg/kg s.c.) plus p-MPPI (8.5 mg/kg s.c.) also increased Arc mRNA but p-MPPI itself elevated Arc mRNA in many regions. Whilst LY 426965 (3 or 10 mg/kg s.c.) had no effect alone, when combined with paroxetine (5 mg/kg s.c.), the drug increased Arc mRNA in caudate putamen but not cortical regions.In conclusion, this study demonstrates that four 5-HT(1A) receptor antagonists augment the effect of an SSRI on Arc mRNA expression, which is suggestive of increased postsynaptic 5-HT function. However, the data reveal certain differences in the 5-HT(1A) receptor antagonists not recognised in models of presynaptic 5-HT function.


Titanium dioxide (TiO2) nanoparticles induce JB6 cell apoptosis through activation of the caspase-8/Bid and mitochondrial pathways.
Titanium dioxide (TiO(2)), a commercially important material, is used in a wide variety of products. Although TiO(2) is generally regarded as nontoxic, the cytotoxicity, pathogenicity, and carcinogenicity of TiO(2) nanoparticles have been recently recognized. The present study investigated TiO(2) nanoparticle-induced cell apoptosis and molecular mechanisms involved in this process in a mouse epidermal (JB6) cell line. Using the 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, TiO(2) nanoparticles were found to exhibit higher cytotoxicity than fine particles. YO-PRO-1 iodide (YP) staining demonstrated that both TiO(2) nanoparticles and fine particles induced cell death through apoptosis. The signaling pathways involved in TiO(2) particle-induced apoptosis were investigated. Western-blot analysis showed an activation of caspase-8, Bid, BAX, and caspase-3 and a decrease of Bcl-2 in JB6 cells treated with TiO(2) particles. Time-dependent poly(ADP)ribose polymerase (PARP) cleavage induced by TiO(2) nanoparticles was observed. TiO(2) particles also induced cytochrome c release from mitochondria to cytosol. Further studies demonstrated that TiO(2) nanoparticles induced significant changes in mitochondrial membrane permeability, suggesting the involvement of mitochondria in the apoptotic process. In conclusion, evidence indicated that TiO(2) nanoparticles exhibit higher cytotoxicity and apoptotic induction compared to fine particles in JB6 cells. Caspase-8/Bid and mitochondrial signaling may play a major role in TiO(2) nanoparticle-induced apoptosis involving the intrinsic mitochondrial pathway. Unraveling the complex mechanisms associated with these events may provide further insights into TiO(2) nanoparticle-induced pathogenicity and potential to induce carcinogenicity.


Abnormal Elevated CA 19-9 in the Dermoid Cyst: A Sign of the Ovarian Torsion?
Dermoid cyst is the most common germ cell tumor of the ovary containing various tissue elements. Ovarian torsion is a common complication of which ultrasonographic diagnosis is confusing. We report here a 14-year-old adolescent with painless torsion of the ovary including dermoid cyst and with abnormal elevated CA 19-9 serum levels. Elevated CA 19-9 level may be related to ovarian torsion and may predict the extent of tissue necrosis.


Soliton fiber laser with a hybrid saturable absorber.
We present an experimental study of a picosecond fiber soliton laser in which mode locking is achieved by the combined action of a multiple-quantum-well saturable absorber and a nonlinear amplifying loop mirror. In this configuration the multiple-quantum-well sample acts not only as a saturable absorber but also as a passive phase modulator, while the inclusion of a nonlinear amplifying loop mirror fixes the energy of the generated pulses. The laser stably operates at a repetition rate of 250 MHz with a timing jitter below 10 ps.


The turning point: identifying end-of-life care in everyday health care practice.
There is a broad consensus among international policy statements that care provided at end-of-life should be different from care provided during other periods of life which assumes a turning point which reflects the onset of the dying process and the associated care reorientation. Few studies derived from empirical data have described this turning point from a clinical perspective. With the purpose to increase the clinical understanding about the nature of such turning points this study explores this phenomenon as determined from health-care records of a representative sample of adults who accessed the public health care system, and who died in the County of Västra Götaland, Sweden, during 2001 (n=229). Record entries reflecting a turning point, that is recognition of the patients as being at the end-of-life and a message about a switch from curative, life-extending or rehabilitative care to an emphasis on palliation, were found in slightly less than 70% of the records while slightly more than 30% lacked such descriptions. The record entries were analyzed with content analysis. As a whole, the descriptions were largely relying on a biomedical discourse and typically put in terms of signs of declining processes, undefined serious condition, prognostications of fatal outcome or justifications of given up active treatments. The procedures which followed the recognition of a turning point revealed that nurses and physicians typically emphasize procedures directed to the patients' families, on re-orientation of treatments and on approaches to further care. The picture of the patients' last time of life as reflected from these record entries is that end-of-life is described in biomedical and factual-oriented terms. The end-of-life care was broadly described in vague terms with lack of concrete care plans. Holistic and good end-of-life care as revealed in this study is indistinguishable, highly embedded in a medical model of care and, hence, an abstract and unknown territory without specific content.


Successful Resuscitation in a Model of Asphyxia and Hemorrhage to Test Different Volume Resuscitation Strategies. A Study in Newborn Piglets After Transition.
Background: Evidence for recommendations on the use of volume expansion during cardiopulmonary resuscitation in newborn infants is limited. Objectives: To develop a newborn piglet model with asphyxia, hemorrhage, and cardiac arrest to test different volume resuscitation on return of spontaneous circulation (ROSC). We hypothesized that immediate red cell transfusion reduces time to ROSC as compared to the use of an isotonic crystalloid fluid. Methods: Forty-four anaesthetized and intubated newborn piglets [age 32 h (12-44 h), weight 1,220 g (1,060-1,495g), Median (IQR)] were exposed to hypoxia and blood loss until asystole occurred. At this point they were randomized into two groups: (1) Crystalloid group: receiving isotonic sodium chloride (n = 22). (2) Early transfusion group: receiving blood transfusion (n = 22). In all other ways the piglets were resuscitated according to ILCOR 2015 guidelines [including respiratory support, chest compressions (CC) and epinephrine use]. One hour after ROSC piglets from the crystalloid group were randomized in two sub-groups: late blood transfusion and infusion of isotonic sodium chloride to investigate the effects of a late transfusion on hemodynamic parameters. Results: All animals achieved ROSC. Comparing the crystalloid to early blood transfusion group blood loss was 30.7 ml/kg (22.3-39.6 ml/kg) vs. 34.6 ml/kg (25.2-44.7 ml/kg), Median (IQR). Eleven subjects did not receive volume expansion as ROSC occurred rapidly. Thirty-three animals received volume expansion (16 vs. 17 in the crystalloid vs. early transfusion group). 14.1% vs. 10.5% of previously extracted blood volume in the crystalloid vs. early transfusion group was infused before ROSC. There was no significant difference in time to ROSC between groups [crystalloid group: 164 s (129-198 s), early transfusion group: 163 s (162-199 s), Median (IQR)] with no difference in epinephrine use. Conclusions: Early blood transfusion compared to crystalloid did not reduce time to ROSC, although our model included only a moderate degree of hemorrhage and ROSC occurred early in 11 subjects before any volume resuscitation occurred.


Phylogenetic relationships of †Luisiella feruglioi (Bordas) and the recognition of a new clade of freshwater teleosts from the Jurassic of Gondwana.
Teleosts constitute more than 99 % of living actinopterygian fishes and fossil teleosts have been studied for about two centuries. However, a general consensus on the definition of Teleostei and the relationships among the major teleostean clades has not been achieved. Our current ideas on the origin and early diversification of teleosts are mainly based on well-known Mesozoic marine taxa, whereas the taxonomy and phylogenetic relationships of many Jurassic continental teleosts are still poorly understood despite their importance to shed light on the early evolutionary history of this group. Here, we explore the phylogenetic relationships of the Late Jurassic (Oxfordian - Tithonian) freshwater †Luisiella feruglioi from Patagonia, in a comprehensive parsimony analysis after a thorough revision of characters from previous phylogenetic studies on Mesozoic teleosts. We retrieved †Luisiella feruglioi as the sister taxon of the Late Jurassic †Cavenderichthys talbragarensis, both taxa in turn forming a monophyletic group with the Early Cretaceous †Leptolepis koonwarri. This new so far exclusively Gondwanan freshwater teleost clade, named †Luisiellidae fam. nov. herein, is placed outside crown Teleostei, as a member of the stem-group immediately above the level of †Leptolepis coryphaenoides. In addition, we did not retrieve the Late Jurassic †Varasichthyidae as a member of †Crossognathiformes. The position of †Crossognathiformes within Teleocephala is confirmed whereas †Varasichthyidae is placed on the stem. The general morphology of luisiellids is that of basal, stem Teleocephala; however, most of their synapomorphies have evolved independently in teleocephalans. Similarly, the resemblance between varasichthyids and crossognathiforms might be due to parallel evolution. In accordance to most teleostean phylogenies, our analysis shows that a major morphological change occurred along the stem line and are currently recorded at the level of †Leptolepis coryphaenoides. A stem-based total clade Teleostei has been accepted for this work.


Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet.
Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension.


Ultrasonographic examination of the liver in sheep.
The purpose of the study reported here was to get detailed information about the normal size and texture of the liver in sheep by means of ultrasonographic examinations. Structure, location, and shape of the liver, gallbladder, portal vein, and caudal vena cava were examined ultrasonographically in 100 sheep. Furthermore, 10 sheep were scanned 10 times within 2 weeks to determine reproducibility of findings. Examinations were performed on the right side of the abdomen in the seventh through twelfth intercostal spaces. In each intercostal space, the dimensions of the liver, and, if visible, the location and diameter of the caudal vena cava and portal vein were determined. The angle of the liver, and location and size of the gallbladder also were determined. Ultrasonographic measurements of liver size and location in healthy sheep can be used as references for changes in liver size attributable to illness.


Seroprevalence of Toxoplasma gondii infection in feral cats in Qatar.
Cats are essential in the life cycle of Toxoplasma gondii as they can shed the environmentally resistant oocysts after acquiring infection. Human populations living in cities with high densities of feral cats are therefore likely to be at risk of infection. The current study is the first to estimate the seroprevalence of T. gondii in the feral cat population in Qatar. We investigated the seroprevalence of T. gondii among 495 adult cats from urban and suburban districts in Qatar. Using results from the Modified Agglutination Test, we fitted statistical models with host sex, area and season as explanatory factors and seropositivity as the outcome. The analysis revealed an overall seroprevalence of 82%. Seroprevalence was significantly higher in the summer season (P = 0.006). No significant difference was detected (P > 0.05) between seroprevalence in female and male cats and in cats from urban and suburban districts of Qatar. Despite the seasonal difference, the observed seroprevalence of T. gondii suggests high environmental contamination throughout the year, with some female cats generating more intense responses compared to males. Both findings merit further investigations.


The Gut Microbiota and Autism Spectrum Disorders.
Gastrointestinal (GI) symptoms are a common comorbidity in patients with autism spectrum disorder (ASD), but the underlying mechanisms are unknown. Many studies have shown alterations in the composition of the fecal flora and metabolic products of the gut microbiome in patients with ASD. The gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune and autonomic nervous systems. In addition, an abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease (IBD), ASD and mood disorders. Here, we review the bidirectional interactions between the central nervous system and the gastrointestinal tract (brain-gut axis) and the role of the gut microbiota in the central nervous system (CNS) and ASD. Microbiome-mediated therapies might be a safe and effective treatment for ASD.


Agrobacterium ParA/MinD-like VirC1 spatially coordinates early conjugative DNA transfer reactions.
Agrobacterium tumefaciens translocates T-DNA through a polar VirB/D4 type IV secretion (T4S) system. VirC1, a factor required for efficient T-DNA transfer, bears a deviant Walker A and other sequence motifs characteristic of ParA and MinD ATPases. Here, we show that VirC1 promotes conjugative T-DNA transfer by stimulating generation of multiple copies per cell of the T-DNA substrate (T-complex) through pairwise interactions with the processing factors VirD2 relaxase, VirC2, and VirD1. VirC1 also associates with the polar membrane and recruits T-complexes to cell poles, the site of VirB/D4 T4S machine assembly. VirC1 Walker A mutations abrogate T-complex generation and polar recruitment, whereas the native protein recruits T-complexes to cell poles independently of other polar processing factors (VirC2, VirD1) or T4S components (VirD4 substrate receptor, VirB channel subunits). We propose that A. tumefaciens has appropriated a progenitor ParA/MinD-like ATPase to promote conjugative DNA transfer by: (i) nucleating relaxosome assembly at oriT-like T-DNA border sequences and (ii) spatially positioning the transfer intermediate at the cell pole to coordinate substrate-T4S channel docking.


Leading by design.
Leaders have the responsibility to develop leadership in their departmental members. Leadership capacity is needed so that health information professionals will be able to successfully respond to the constant changes in the healthcare environment. This article demonstrates how leadership can be modeled and developed through the redesign of jobs in departments of health information services.


WITHDRAWN--a resource for withdrawn and discontinued drugs.
Post-marketing drug withdrawals can be associated with various events, ranging from safety issues such as reported deaths or severe side-effects, to a multitude of non-safety problems including lack of efficacy, manufacturing, regulatory or business issues. During the last century, the majority of drugs voluntarily withdrawn from the market or prohibited by regulatory agencies was reported to be related to adverse drug reactions. Understanding the underlying mechanisms of toxicity is of utmost importance for current and future drug discovery. Here, we present WITHDRAWN, a resource for withdrawn and discontinued drugs publicly accessible at http://cheminfo.charite.de/withdrawn. Today, the database comprises 578 withdrawn or discontinued drugs, their structures, important physico-chemical properties, protein targets and relevant signaling pathways. A special focus of the database lies on the drugs withdrawn due to adverse reactions and toxic effects. For approximately one half of the drugs in the database, safety issues were identified as the main reason for withdrawal. Withdrawal reasons were extracted from the literature and manually classified into toxicity types representing adverse effects on different organs. A special feature of the database is the presence of multiple search options which will allow systematic analyses of withdrawn drugs and their mechanisms of toxicity.


Exposure to violence in childhood is associated with higher body mass index in adolescence.
To determine whether different types of childhood adversity are associated with body mass index (BMI) in adolescence, we studied 147 adolescents aged 13-17 years, 41% of whom reported exposure to at least one adversity (maltreatment, abuse, peer victimization, or witness to community or domestic violence). We examined associations between adversity type and age- and sex-specific BMI z-scores using linear regression and overweight and obese status using logistic regression. We adjusted for potential socio-demographic, behavioral, and psychological confounders and tested for effect modification by gender. Adolescents with a history of sexual abuse, emotional abuse, or peer victimization did not have significantly different BMI z-scores than those without exposure (p>0.05 for all comparisons). BMI z-scores were higher in adolescents who had experienced physical abuse (β=0.50, 95% CI 0.12-0.91) or witnessed domestic violence (β=0.85, 95% CI 0.30-1.40). Participants who witnessed domestic violence had almost 6 times the odds of being overweight or obese (95% CI: 1.09-30.7), even after adjustment for potential confounders. No gender-by-adversity interactions were found. Exposure to violence in childhood is associated with higher adolescent BMI. This finding highlights the importance of screening for violence in pediatric practice and providing obesity prevention counseling for youth.


Intraperitoneal mesenchymal stem cell administration ameliorates allergic rhinitis in the murine model.
Previous studies showed that bone marrow-derived mesenchymal stem cells (BMSCs) could ameliorate a variety of immune-mediated and inflammatory diseases due to their immunomodulatory and anti-inflammatory effects. In this study, we developed a mouse model of ovalbumin (OVA) induced allergic inflammation in the upper airways and evaluated the effects of the intraperitoneal administration of BMSCs on allergic inflammation. Twenty-five BALB/c mice were divided into five groups; group I (control group), group II (sensitized and challenged with OVA and treated with saline-placebo group), group III (sensitized and challenged with OVA and treated with 1 × 106 BMSCs), group IV (sensitized and challenged with OVA and treated with 2 × 106 BMSCs), and group V (sensitized and challenged with phosphate buffered saline (PBS) and treated with 1 × 106 BMSCs). Histopathological features (number of goblet cells, eosinophils and mast cells, basement membrane, epithelium thickness, and subepithelial smooth muscle thickness) of the upper and lower airways and BMSCs migration to nasal and lung tissue were evaluated using light and confocal microscopes. Levels of cytokines in the nasal lavage fluid and lung tissue supernatants were measured using enzyme-linked immunosorbent assay (ELISA). Confocal microscopic analysis showed that there was no significant amount of BMSCs in the nasal and lung tissues of group V. However, significant amount of BMSCs were observed in group III and IV. In OVA-induced AR groups (group II, III, and IV), histopathological findings of chronic asthma, such as elevated subepithelial smooth muscle thickness, epithelium thickness, and number of goblet and mast cells, were determined. Furthermore, the number of nasal goblet and eosinophil cells, histopathological findings of chronic asthma, and IL-4, IL-5, IL-13, and NO levels was significantly lower in both BMSCs-treated groups compared to the placebo group. Our findings indicated that histopathological findings of chronic asthma were also observed in mice upon AR induction. BMSCs migrated to the nasal and lung tissues following intraperitoneal delivery and ameliorated to the airway remodeling and airway inflammation both in the upper and lower airways via the inhibition of T helper (Th) 2 immune response in the murine model of AR.


Increased 18F-FDG uptake in degenerative disease of the spine: Characterization with 18F-FDG PET/CT.
We determined the prevalence of abnormal spinal 18F-FDG uptake and assessed the relationship between the severity of findings on 18F-FDG PET and the severity of degenerative spinal disease (DSD) on CT. PET/CT scans of 150 patients >18 y old, referred for whole-body 18F-FDG PET/CT for evaluation of known or suspected malignancy from June to July 2002, were analyzed retrospectively for the presence of increased 18F-FDG uptake in the spine and for anatomic correlates. Initially, PET images were examined and foci of 18F-FDG uptake in the spine were graded on a 0-4 scale based on intensity of 18F-FDG uptake (0 = definitely normal, 1 = probably normal, 2 = equivocal, 3 = probably abnormal, 4 = definitely abnormal). From PET alone, an impression as to whether lesions were most likely metastases or degenerative, as well the level of the spine involved, was also recorded. CT images of all 150 patients were reviewed independently by a musculoskeletal radiologist, who was unaware of patient identification, history, and findings of other imaging modalities, with the location recorded and severity graded on a 4-point-scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe for both degenerative disk and facet disease). The relationship between PET and CT findings was then determined. Of the 150 patients, 63 (42.0%) had no abnormal findings in the spine on PET (grade 0), 27 (18.0%) had grade 1, 25 (16.7%) had grade 2, 17 (11.3%) had grade 3, and 16 patients (10.7%) had grade 4 18F-FDG uptake for DSD. Two additional patients had apparent spinal metastases with no degenerative changes. Five patients had metastases and DSD (included above). Of the patients who had abnormal spinal findings graded as probable or definite for DSD on CT (grades 3-4), 11 had abnormal findings in the cervical spine, 16 in the thoracic spine, and 23 patients in the lumbosacral spine. Seven patients (4.7%) had PET findings suggestive of spinal metastases. For patients with a maximum regional DSD score of 3, the mean 18F-FDG uptake for that spinal level was 1.4 +/- 1.5, whereas for patients with a maximum regional DSD score of 0, the mean PET grade was significantly lower at 0.4 +/- 0.9 (P = 0.0001). Incidental findings on PET suggestive of DSD are common (22% of patients), most common in the lumbosacral spine, and can be recognized on CT. The severity of PET findings correlates with the severity of degenerative disk and facet disease as graded by CT, likely due to the fact that the inflammatory process that accompanies DSD is evident on PET. Increased 18F-FDG uptake in DSD should not be confused with metastatic disease.


Statistical traces of long-term memories stored in strengths and patterns of synaptic connections.
Learning and long-term memory rely on plasticity of neural circuits. In adult cerebral cortex, plasticity can result from potentiation and depression of synaptic strengths and structural reorganization of circuits through growth and retraction of dendritic spines. By analyzing 166 distributions of spine head volumes and spine lengths from mouse, rat, monkey, and human brains, we determine the "generalized cost" of dendritic spines. This cost universally depends on spine shape, i.e., the dependence is the same in all the analyzed systems. We show that, in adult, synaptic strength and structural synaptic plasticity mechanisms are in statistical equilibrium, the numbers of dendritic spines in different cortical areas are nearly optimally chosen for memory storage, and the distributions of spine lengths and head volumes are governed by a single parameter--the effective temperature. We suggest that the effective temperature may be viewed as a measure of circuit stability or longevity of stored memories.


Soil Carbon Dynamics in Soybean Cropland and Forests in Mato Grosso, Brazil.
Climate and land use models predict that tropical deforestation and conversion to cropland will produce a large flux of soil carbon (C) to the atmosphere from accelerated decomposition of soil organic matter (SOM). However, the C flux from the deep tropical soils on which most intensive crop agriculture is now expanding remains poorly constrained. To quantify the effect of intensive agriculture on tropical soil C, we compared C stocks, radiocarbon, and stable C isotopes to 2 m depth from forests and soybean cropland created from former pasture in Mato Grosso, Brazil. We hypothesized that soil disturbance, higher soil temperatures (+2°C), and lower OM inputs from soybeans would increase soil C turnover and deplete C stocks relative to nearby forest soils. However, we found reduced C concentrations and stocks only in surface soils (0-10 cm) of soybean cropland compared with forests, and these differences could be explained by soil mixing during plowing. The amount and Δ14C of respired CO2 to 50 cm depth were significantly lower from soybean soils, yet CO2 production at 2 m deep was low in both forest and soybean soils. Mean surface soil δ13C decreased by 0.5‰ between 2009 and 2013 in soybean cropland, suggesting low OM inputs from soybeans. Together these findings suggest the following: (1) soil C is relatively resistant to changes in land use and (2) conversion to cropland caused a small, measurable reduction in the fast-cycling C pool through reduced OM inputs, mobilization of older C from soil mixing, and/or destabilization of SOM in surface soils.


Negative psychological aspects and survival in lung cancer patients.
We conducted a prospective cohort study in Japan to investigate associations between negative psychological aspects and cancer survival. Between July 1999 and July 2004, a total of 1178 lung cancer patients were enrolled. The questionnaire asked about socioeconomic variables, smoking status, clinical symptoms, and psychological aspects after diagnosis. Negative psychological aspects were assessed for the subscales of helplessness/hopelessness and depression. Clinical stage, performance status (PS), and histologic type were obtained from medical charts. The subjects were followed up until December 2004, and 686 had died. A Cox regression model was used to estimate the hazards ratio (HR) of all-cause mortality. After adjustment for socioeconomic variables and smoking status in addition to sex, age, and histologic type, both helplessness/hopelessness and depression subscales showed significant linear positive associations with the risk of mortality (p for trend<0.001 for both). However, after adjustment for clinical state variables in addition to sex, age, and histologic type, these significant linear positive associations were no longer observed (p for trend=0.41 and 0.26, respectively). Our data supported the hypothesis that the association between helplessness/hopelessness and depression and the risk of mortality among lung cancer patients was largely confounded by clinical state variables including clinical stage, PS, and clinical symptoms.


Preservation of endothelial function by the HMG-CoA reductase inhibitor fluvastatin through its lipid-lowering independent antioxidant properties in atherosclerotic rabbits.
Recent evidence suggests that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on entothelial function and cardiovascular ischemic events may be attributed not only to their lipid-lowering effects but also to cholesterol-lowering independent (direct) effects on the atherosclerotic vessel wall. This study was designed to test the hypothesis that fluvastatin (Flu) preserves the endothelial function by its cholesterol-lowering independent actions. Rabbits were fed a 0.5% high-cholesterol (HC) diet for 12 weeks (progression phase) and then fed the HC diet either containing or not containing Flu 2 mg/kg/day for an additional 8 weeks (treatment phase). Rabbits fed a normal diet were used as controls. Plasma total and low-density lipoprotein cholesterol concentrations did not differ during the treatment phase: Endothelium-dependent/NO-mediated relaxation (acetylcholine and A23187) was impaired in the HC diet group, whereas it was preserved in the HC plus Flu treatment group. The endothelium-independent relaxation (sodium nitroprusside) was similar between the three groups. Interestingly, aortic oxidative stress (lipid peroxides and isoprostane F(2alpha)-III contents) and NADPH oxidase component (p22phox and gp91phox) mRNA expression were increased in the HC group but not in the HC plus Flu group. The A23187-induced nitric oxide production from the aorta was increased in both HC and HC plus Flu groups. There was no significant difference in tissue endothelial-type nitric oxide synthase mRNA expression. Plaque area and intimal thickening of the aorta were significantly lowered in the HC plus Flu group. Flu treatment preserved the endothelial function associated with the decrease in markers of oxidative stress in this experiment. These beneficial endothelial effects of Flu are likely to occur independently of plasma lipid concentrations and to be mediated by its antioxidant action.


The dystrophin complex controls bk channel localization and muscle activity in Caenorhabditis elegans.
Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle.


The importance of therapy motivation for patients with substance use disorders.
The present study aimed to examine whether patients' pretherapy motivation was related to other patient characteristics and whether it predicted retention in psychotherapy. Data were collected within a naturalistic outcome study of various forms of psychotherapy for patients (N = 172) with substance use disorders (SUD). Therapy motivation was measured using the Client Motivation for Therapy Scale (CMOTS), including the variables autonomous motivation, controlled motivation, and amotivation. Female patients had higher levels of autonomous motivation (d = .53), lower levels of controlled motivation (d = -.32), and lower levels of amotivation (d = -.62). Level of symptoms and impairment was significantly positively correlated with controlled motivation (r = .31). Autonomous motivation was positively correlated with four expectation subscales associated with constructive therapeutic work, whereas amotivation was negatively correlated with three of these subscales. Controlled motivation was positively correlated with the subscales external orientation, defensiveness, and support. In a logistic regression, amotivation stood out as a negative predictor of retention, in terms of starting in psychotherapy after assessment or not. Quite surprisingly, autonomous motivation was not a significant predictor of retention. The present study indicates that amotivation is a risk factor for early dropout among SUD patients. More efforts should be directed at preparing patients for psychotherapy through strengthening motivation.


Parental smoking during pregnancy and ADHD in children: the Danish national birth cohort.
Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.


Evaluating arcuate fasciculus laterality measurements across dataset and tractography pipelines.
The arcuate fasciculi are white-matter pathways that connect frontal and temporal lobes in each hemisphere. The arcuate plays a key role in the language network and is believed to be left-lateralized, in line with left hemisphere dominance for language. Measuring the arcuate in vivo requires diffusion magnetic resonance imaging-based tractography, but asymmetry of the in vivo arcuate is not always reliably detected in previous studies. It is unknown how the choice of tractography algorithm, with each method's freedoms, constraints, and vulnerabilities to false-positive and -negative errors, impacts findings of arcuate asymmetry. Here, we identify the arcuate in two independent datasets using a number of tractography strategies and methodological constraints, and assess their impact on estimates of arcuate laterality. We test three tractography methods: a deterministic, a probabilistic, and a tractography-evaluation (LiFE) algorithm. We extract the arcuate from the whole-brain tractogram, and compare it to an arcuate bundle constrained even further by selecting only those streamlines that connect to anatomically relevant cortical regions. We test arcuate macrostructure laterality, and also evaluate microstructure profiles for properties such as fractional anisotropy and quantitative R1. We find that both tractography choice and implementing the cortical constraints substantially impact estimates of all indices of arcuate laterality. Together, these results emphasize the effect of the tractography pipeline on estimates of arcuate laterality in both macrostructure and microstructure.


Volume reduction in the caudate nucleus following stereotactic placement of lesions in the anterior cingulate cortex in humans: a morphometric magnetic resonance imaging study.
The goal of this study was to test hypotheses regarding changes in volume in subcortical structures following anterior cingulotomy. Morphometric magnetic resonance (MR) imaging methods were used to assess volume reductions in subcortical regions following anterior cingulate lesioning in nine patients. Magnetic resonance imaging data obtained before and 9 +/- 6 months following anterior cingulotomy were subjected to segmentation and subcortical parcellation. Significant volume reductions were predicted and found bilaterally within the caudate nucleus, but not in the amygdala, thalamus, lenticular nuclei, or hippocampus. Subcortical parcellation revealed that the volume reduction in the caudate nucleus was principally referrable to the body, rather than the head. Furthermore, the magnitude of volume reduction in the caudate body was significantly correlated with total lesion volume. Taken together, these findings implicate significant connectivity between a region of anterior cingulate cortex (ACC) lesioned during cingulotomy and the caudate body. This unique data set complements published findings in nonhuman primates, and advances our knowledge regarding patterns of cortical-subcortical connectivity involving the ACC in humans. Moreover, these findings indicate changes distant from the site of anterior cingulotomy lesions that may play a role in the clinical response to this neurosurgical procedure.


Solar UV radiation in a changing world: roles of cryosphere-land-water-atmosphere interfaces in global biogeochemical cycles.
Global change influences biogeochemical cycles within and between environmental compartments (i.e., the cryosphere, terrestrial and aquatic ecosystems, and the atmosphere). A major effect of global change on carbon cycling is altered exposure of natural organic matter (NOM) to solar radiation, particularly solar UV radiation. In terrestrial and aquatic ecosystems, NOM is degraded by UV and visible radiation, resulting in the emission of carbon dioxide (CO2) and carbon monoxide, as well as a range of products that can be more easily degraded by microbes (photofacilitation). On land, droughts and land-use change can reduce plant cover causing an increase in exposure of plant litter to solar radiation. The altered transport of soil organic matter from terrestrial to aquatic ecosystems also can enhance exposure of NOM to solar radiation. An increase in emission of CO2 from terrestrial and aquatic ecosystems due to the effects of global warming, such as droughts and thawing of permafrost soils, fuels a positive feedback on global warming. This is also the case for greenhouse gases other than CO2, including methane and nitrous oxide, that are emitted from terrestrial and aquatic ecosystems. These trace gases also have indirect or direct impacts on stratospheric ozone concentrations. The interactive effects of UV radiation and climate change greatly alter the fate of synthetic and biological contaminants. Contaminants are degraded or inactivated by direct and indirect photochemical reactions. The balance between direct and indirect photodegradation or photoinactivation of contaminants is likely to change with future changes in stratospheric ozone, and with changes in runoff of coloured dissolved organic matter due to climate and land-use changes.


Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrin-β1/ERK/caspase-9 phosphorylation cascade.
Early reperfusion after myocardial ischemia that is essential for tissue salvage also causes myocardial and vascular injury. Cardioprotection during reperfusion therapy is an essential aspect of treating myocardial infarction. Angiopoietin-1 is an endothelial-specific angiogenic factor. The potential effects of angiopoietin-1 on cardiomyocytes and vascular cells undergoing reperfusion have not been investigated. We propose a protective mechanism whereby angiopoietin-1 increases the integrity of the endothelial lining and exerts a direct survival effect on cardiomyocytes under myocardial ischemia followed by reperfusion. First, we found that angiopoietin-1 prevents vascular leakage through regulating vascular endothelial (VE)-cadherin phosphorylation. The membrane expression of VE-cadherin was markedly decreased on hypoxia/reoxygenation but was restored by angiopoietin-1 treatment. Interestingly, these effects were mediated by the facilitated binding between SH2 domain-containing tyrosine phosphatase (SHP2) or receptor protein tyrosine phosphatase μ (PTPμ) and VE-cadherin, leading to dephosphorylation of VE-cadherin. siRNA against SHP2 or PTPμ abolished the effect of angiopoietin-1 on VE-cadherin dephosphorylation and thereby decreased levels of membrane-localized VE-cadherin. Second, we found that angiopoietin-1 prevented cardiomyocyte death, although cardiomyocytes lack the angiopoietin-1 receptor Tie2. Angiopoietin-1 increased cardiomyocyte survival through integrin-β1-mediated extracellular signal-regulated kinase (ERK) phosphorylation, which inhibited caspase-9 through phosphorylation at Thr¹²⁵ and subsequently reduced active caspase-3. Neutralizing antibody against integrin-β1 blocked these protective effects. In a mouse myocardial ischemia/reperfusion model, angiopoietin-1 enhanced cardiac function and reduction in left ventricular-end systolic dimension (LV-ESD) and left ventricular-end diastolic dimension (LV-EDD) with an increase in ejection fraction (EF) and fractional shortening (FS). Our findings suggest the novel cardioprotective mechanisms of angiopoietin-1 that are achieved by reducing both vascular leakage and cardiomyocyte death after ischemia/reperfusion injury.


Potential KPC-2 carbapenemase reservoir of environmental Aeromonas hydrophila and Aeromonas caviae isolates from the effluent of an urban wastewater treatment plant in Japan.
Aeromonas hydrophila and Aeromonas caviae adapt to saline water environments and are the most predominant Aeromonas species isolated from estuaries. Here, we isolated antimicrobial-resistant (AMR) Aeromonas strains (A. hydrophila GSH8-2 and A. caviae GSH8M-1) carrying the carabapenemase blaKPC-2 gene from a wastewater treatment plant (WWTP) effluent in Tokyo Bay (Japan) and determined their complete genome sequences. GSH8-2 and GSH8M-1 were classified as newly assigned sequence types ST558 and ST13, suggesting no supportive evidence of clonal dissemination. The strains appear to have acquired blaKPC-2 -positive IncP-6-relative plasmids (pGSH8-2 and pGSH8M-1-2) that share a common backbone with plasmids in Aeromonas sp. ASNIH3 isolated from hospital wastewater in the United States, A. hydrophila WCHAH045096 isolated from sewage in China, other clinical isolates (Klebsiella, Enterobacter and Escherichia coli), and wastewater isolates (Citrobacter, Pseudomonas and other Aeromonas spp.). In addition to blaKPC-2 , pGSH8M-1-2 carries an IS26-mediated composite transposon including a macrolide resistance gene, mph(A). Although Aeromonas species are opportunistic pathogens, they could serve as potential environmental reservoir bacteria for carbapenemase and AMR genes. AMR monitoring from WWTP effluents will contribute to the detection of ongoing AMR dissemination in the environment and might provide an early warning of potential dissemination in clinical settings and communities.


Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.


Intracerebral depth electrode monitoring in partial epilepsy: the morbidity and efficacy of placement using magnetic resonance image-guided stereotactic surgery.
To determine the indications for, efficacy of, and safety of depth electrode placement using magnetic resonance imaging (MRI)-guided stereotactic surgery in patients with intractable epilepsy. We analyzed retrospectively the results of depth electrode usage in 50 consecutive patients at the University of Michigan Hospitals studied in the years 1991 through 1994, using MRI-guided stereotactic implantation, in conjunction with simultaneous subdural strip electrode recordings. There were no deaths, no infections, and no new neurological deficits. One small subdural hematoma adjacent to a subdural strip electrode was evacuated to prevent interference with ictal recording. Two cylindrical subdural electrodes were found to be intraparenchymal, as revealed by postoperative MRI, and were removed. One patient was unintentionally left alone briefly, and he pulled out the electrodes while confused postictally, requiring a subsequent operation for replacement. Ictal onset zones were successfully localized in 47 patients. We have found intracerebral electrode placement to be as safe as subdural strip electrode placement and have found combined depth and strip electrode monitoring to be highly effective in localizing the onset zones of complex partial seizures. Intracranial monitoring was particularly useful in the detection of a single ictal onset zone in the absence of neuroimaging abnormality and in the definitive diagnosis of bilateral independent ictal onset zones in the temporal lobe epilepsy syndrome. The specific technical aspects of the procedure that contribute to a successful outcome are reviewed. A comparison with earlier reported series suggests that MRI-guided stereotaxy and pial inspection may reduce complications of depth electrode placement.


Ca(2+) signals, NAADP and two-pore channels: role in cellular differentiation.
Ca(2+) signals regulate a wide range of physiological processes. Intracellular Ca(2+) stores can be mobilized in response to extracellular stimuli via a range of signal transduction mechanisms, often involving recruitment of diffusible second messenger molecules. The Ca(2+) -mobilizing messengers InsP3 and cADPR release Ca(2+) from the endoplasmic reticulum via the InsP3 and ryanodine receptors, respectively, while a third messenger, NAADP, releases Ca(2+) from acidic endosomes and lysosomes. Bidirectional communication between the endoplasmic reticulum (ER) and acidic organelles may have functional relevance for endolysosomal function as well as for the generation of Ca(2+) signals. The two-pore channels (TPCs) are currently strong candidates for being key components of NAADP-regulated Ca(2+) channels. Ca(2+) signals have been shown to play important roles in differentiation; however, much remains to be established about the exact signalling mechanisms involved. The investigation of the role of NAADP and TPCs in differentiation is still at an early stage, but recent studies have suggested that they are important mediators of differentiation of neurones, skeletal muscle cells and osteoclasts. NAADP signals and TPCs have also been implicated in autophagy, an important process in differentiation. Further studies will be required to identify the precise mechanism of TPC action and their link with NAADP signalling, as well as relating this to their roles in differentiation and other key processes in the cell and organism.


3D Printing Bioceramic Porous Scaffolds with Good Mechanical Property and Cell Affinity.
Artificial bone grafting is widely used in current orthopedic surgery for bone defect problems. Unfortunately, surgeons remain unsatisfied with the current commercially available products. One of the major complaints is that these products cannot provide sufficient mechanical strength to support the human skeletal structure. In this study, we aimed to develop a bone scaffold with better mechanical property and good cell affinity by 3D printing (3DP) techniques. A self-developed 3D printer with laser-aided gelling (LAG) process was used to fabricate bioceramic scaffolds with inter-porous structures. To improve the mechanical property of the bioceramic parts after heating, CaCO3 was added to the silica ceramic slurry. CaCO3 was blended into a homogenous SiO2-sol dispersion at weight ratios varying from 0/100 to 5/95 to 9/91 (w/w). Bi-component CaCO3/SiO2-sol was prepared as a biocomposite for the 3DP scaffold. The well-mixed biocomposite was used to fabricate the bioceramic green part using the LAG method. The varied scaffolds were sintered at different temperatures ranging from 900 to 1500°C, and the mechanical property was subsequently analyzed. The scaffolds showed good property with the composite ratio of 5:95 CaCO3:SiO2 at a sintering temperature of 1300°C. The compressive strength was 47 MPa, and the porosity was 34%. The topography of the sintered 3DP bioceramic scaffold was examined by SEM, EDS and XRD. The silica bioceramic presented no cytotoxicity and good MG-63 osteoblast-like cell affinity, demonstrating good biocompatibility. Therefore, the new silica biocomposite is viable for fabricating 3DP bone bioceramics with improved mechanical property and good cell affinity.


Enzyme activities of aerobic lignocellulolytic bacteria isolated from wet tropical forest soils.
Lignocellulolytic bacteria have promised to be a fruitful source of new enzymes for next-generation lignocellulosic biofuel production. Puerto Rican tropical forest soils were targeted because the resident microbes decompose biomass quickly and to near-completion. Isolates were initially screened based on growth on cellulose or lignin in minimal media. 75 Isolates were further tested for the following lignocellulolytic enzyme activities: phenol oxidase, peroxidase, β-d-glucosidase, cellobiohydrolase, β-xylopyranosidase, chitinase, CMCase, and xylanase. Cellulose-derived isolates possessed elevated β-d-glucosidase, CMCase, and cellobiohydrolase activity but depressed phenol oxidase and peroxidase activity, while the contrary was true of lignin isolates, suggesting that these bacteria are specialized to subsist on cellulose or lignin. Cellobiohydrolase and phenol oxidase activity rates could classify lignin and cellulose isolates with 61% accuracy, which demonstrates the utility of model degradation assays. Based on 16S rRNA gene sequencing, all isolates belonged to phyla dominant in the Puerto Rican soils, Proteobacteria, Firmicutes, and Actinobacteria, suggesting that many dominant taxa are capable of the rapid lignocellulose degradation characteristic of these soils. The isolated genera Aquitalea, Bacillus, Burkholderia, Cupriavidus, Gordonia, and Paenibacillus represent rarely or never before studied lignolytic or cellulolytic species and were undetected by metagenomic analysis of the soils. The study revealed a relationship between phylogeny and lignocellulose-degrading potential, supported by Kruskal-Wallis statistics which showed that enzyme activities of cultivated phyla and genera were different enough to be considered representatives of distinct populations. This can better inform future experiments and enzyme discovery efforts.


Fluorescence Detection of DNA Based on Non-covalent π-π Stacking Interaction between 1-Pyrenebutanoic Acid and Hypericin.
Herein, we applied hypericin (Hyp) for the detection of DNA on streptavidin-functionalized magnetic beads (SA-MB) through non-covalent π-π stacking interaction between 1-pyrenebutanoic acid (PBA) and Hyp. Briefly, the target DNA (tDNA) was hybridized to morpholino oligonucleotide (MO) that was immobilized on the surface of SA-MB. PBA was incorporated to the backbone of tDNA by means of phosphate-zirconium-carboxylate coordination reaction. Then, fluorescent Hyp was linked to PBA via π-π stacking interaction. Under the optimal conditions, this biosensor displayed a good linear relationship between the fluorescence intensity and the tDNA concentrations in the range from 1 to 100 nM with a low detection limit of 2.9 nM. The mismatch type in a specific DNA sequence can also be efficiently discriminated. Compared with some other reports, this method is more convenient, and has great potential for practical applications.


Transcriptome sequencing in an ecologically important tree species: assembly, annotation, and marker discovery.
Massively parallel sequencing of cDNA is now an efficient route for generating enormous sequence collections that represent expressed genes. This approach provides a valuable starting point for characterizing functional genetic variation in non-model organisms, especially where whole genome sequencing efforts are currently cost and time prohibitive. The large and complex genomes of pines (Pinus spp.) have hindered the development of genomic resources, despite the ecological and economical importance of the group. While most genomic studies have focused on a single species (P. taeda), genomic level resources for other pines are insufficiently developed to facilitate ecological genomic research. Lodgepole pine (P. contorta) is an ecologically important foundation species of montane forest ecosystems and exhibits substantial adaptive variation across its range in western North America. Here we describe a sequencing study of expressed genes from P. contorta, including their assembly and annotation, and their potential for molecular marker development to support population and association genetic studies. We obtained 586,732 sequencing reads from a 454 GS XLR70 Titanium pyrosequencer (mean length: 306 base pairs). A combination of reference-based and de novo assemblies yielded 63,657 contigs, with 239,793 reads remaining as singletons. Based on sequence similarity with known proteins, these sequences represent approximately 17,000 unique genes, many of which are well covered by contig sequences. This sequence collection also included a surprisingly large number of retrotransposon sequences, suggesting that they are highly transcriptionally active in the tissues we sampled. We located and characterized thousands of simple sequence repeats and single nucleotide polymorphisms as potential molecular markers in our assembled and annotated sequences. High quality PCR primers were designed for a substantial number of the SSR loci, and a large number of these were amplified successfully in initial screening. This sequence collection represents a major genomic resource for P. contorta, and the large number of genetic markers characterized should contribute to future research in this and other pines. Our results illustrate the utility of next generation sequencing as a basis for marker development and population genomics in non-model species.


[Evaluation of risk factors of falls in early postmenopausal women].
It was to evaluate the frequency and the risk factors of falls in early postmenopausal women. A cross-sectional study was conducted on 358 women (age: 45-65 years and amenorrhea >12 months) with time since menopause <10 years. Exclusion criteria were: neurological or musculoskeletal disorders, vestibulopathies, uncorrected visual deficit, uncontrolled hypertension and postural hypotension, or drug use (sedative and hypnotic agents). A fall was identified as an unexpected unintentional change in position which causes an individual to remain in a lower level in relation to the initial position. The history of self-reported falls during the previous 24 months, and clinical and anthropometric data (body mass index (BMI) and waist circumference (WC)) and bone densitometric measures were analyzed. For statistical analysis, c² trend test and the logistic regression method (odds ratio (OR)) were used for the comparison between groups of women with and without falls. Of the 358 women, 48.0% (172/358) had a history of falls and 17.4% (30/172) had fractures. The fall occurred indoors (at home) in 58.7% (101/172). The mean age was 53.7 ± 6.5 years, time since menopause 5.8 ± 3.5 years, BMI 28.3 ± 4.6 kg/m² and WC 89.0 ± 11.4 cm. There were differences as the occurrence of smoking and diabetes, with greater frequency among fallers vs. non-fallers, 25.6 versus 16.1% and 12.8 versus 5.9%, respectively (p<0.05). By evaluating the risk of falls in the presence of influential variables, it was observed that risk increased with current smoking status (OR 1.93; 95%CI 1.01-3.71), whereas other clinical and anthropometric variables did not influence this risk. In early postmenopausal women there was higher frequency of falls. Current smoking was clinical indicators of risk for falls. With the recognition of factors for falling, preventive measures become important, as the orientation of abolishing smoking.


Virulence Diversity in the Population of Bipolaris sorokiniana.
Spot blotch, caused by Bipolaris sorokiniana, is a damaging disease of barley in Canada, especially in the prairie region (Manitoba, Saskatchewan, and Alberta) where most of Canadian crops are produced. Considerable interaction between isolates of the pathogen and barley genotypes necessitates the evaluation of the virulence diversity in the B. sorokiniana population in order to deploy effective resistance against the pathogen. The virulence diversity of 127 B. sorokiniana isolates from Canada and other countries was evaluated on 12 barley genotypes. Different virulence patterns were detected across B. sorokiniana isolates and eight virulence groups were identified using qualitative analysis of the virulence data. Results indicate broader virulence diversity in the pathogen population in the eastern prairie region of Canada, especially in Manitoba, compared with that previously reported. One group of isolates collected from Manitoba displayed a virulence pattern which had not been reported previously. This group was moderately virulent on most differential lines, including American six-rowed barley genotypes considered to possess durable resistance against B. sorokiniana. Although the classical method of pathotype identification can be exploited to analyze interactions in the barley-B. sorokiniana pathosystem, the continuous range of infection phenotypes found suggests that a quantitative analysis of the complex interactions occurring may be warranted.


Retrograde neural circuit specification by target-derived neurotrophins and growth factors.
Neural circuit assembly during development involves a series of highly regulated steps. While genetically pre-determined programs play key roles in the early steps including neurogenesis, migration, and initial growth and guidance of axons; increasing evidence indicates that as the axons reach their targets, the late steps of neuronal differentiation and connectivity formation may be influenced or even specified by target-derived signals. Here we attempt to provide a brief synthesized review on the roles of retrograde neurotrophin and growth factor signaling in regulating the final stages of neural circuit specificity such as axonal projection, dendritic patterning, neurotransmitter phenotype acquisition, and synapse formation.


Chronic fatigue of the small enterprise workers participating in an occupational health checkup center in southern Taiwan.
There has been increasing interest in the occupational health of workers in small enterprises, especially in developing countries. This study examines the association between psychosocial job characteristics and fatigue, and attempts to identify risk factors for fatigue among workers of small enterprises in southern Taiwan. A structured questionnaire was administered to workers receiving regular health examinations between August 2005 and January 2006. The questionnaire collected demographic information and data on working conditions, personal health status and life styles. It also collected information on psychosocial job characteristics, fatigue and psychological distress using three instruments. A total of 647 workers with mean age of 43.7 were completed. Probable fatigue was found in 34.6% of the sample. Fatigue was found by multiple logistic regressions to be associated with the lack of exercise, working in shifts, depression score and lack of social support at workplace. This study found associations between life style, psychosocial job characteristics and fatigue. Because the high prevalence of probable fatigue was found in such small enterprises, the authors suggest that a short interview with some quick questionnaires in health checkup for these small enterprise workers are helpful to early detect psychosocial and fatigue problems.


Robust classification of EEG signal for brain-computer interface.
We report the implementation of a text input application (speller) based on the P300 event related potential. We obtain high accuracies by using an SVM classifier and a novel feature. These techniques enable us to maintain fast performance without sacrificing the accuracy, thus making the speller usable in an online mode. In order to further improve the usability, we perform various studies on the data with a view to minimizing the training time required. We present data collected from nine healthy subjects, along with the high accuracies (of the order of 95% or more) measured online. We show that the training time can be further reduced by a factor of two from its current value of about 20 min. High accuracy, fast learning, and online performance make this P300 speller a potential communication tool for severely disabled individuals, who have lost all other means of communication and are otherwise cut off from the world, provided their disability does not interfere with the performance of the speller.


Validation of a mathematical approach to estimate dynamic scapular orientation.
The goal of this study was to develop and validate a non-invasive approach to estimate scapular kinematics in individual patients. We hypothesized that individualized mathematical algorithms can be developed using motion capture data to accurately estimate dynamic scapula orientation based on measured humeral orientations and acromion process positions. The accuracy of the mathematical algorithms was evaluated against a gold standard of biplane fluoroscopy using a 2D to 3D fluoroscopy/model matching process. Individualized linear models were developed for nine healthy adult shoulders. These models were used to predict scapulothoracic kinematics, and the predicted kinematics were compared to kinematics obtained using biplane fluoroscopy to determine the accuracy of the algorithms. Results showed strong correlations between mathematically predicted kinematics and validation kinematics. Estimated kinematics were within 8° of validation kinematics. We concluded that individualized linear models show promise for providing accurate, non-invasive measurements of scapulothoracic kinematics in a clinical environment.


Epidemiology of antibiotic resistance in Pseudomonas aeruginosa. Implications for empiric and definitive therapy.
Pseudomonas aeruginosa is one of the major pathogens causing hospital-acquired infections. It can easily develop antibiotic resistance through chromosomal mutations or by horizontal acquisition of resistant determinants. The increasing prevalence of multi-drug-resistant (MDR) or extensively-drug-resistant (XDR) P. aeruginosa isolates is associated with the dissemination of the so-called high-risk-clones, such as ST175. Infections caused by MDR/XDR are a cause of concern as they compromise the selection of appropriate empiric and definitive antimicrobial treatments. Introduction of new antibiotics with potent activity against MDR/XDR P. aeruginosa opens new horizons in the treatment of these infections.


Mutations affecting donor preference during mating type interconversion in Saccharomyces cerevisiae.
Homothallic strains of Saccharomyces cerevisiae can convert mating type from a to alpha or alpha to a as often as every generation, by replacing genetic information specifying one mating type at the expressor locus, MAT, with information specifying the opposite mating type. The cryptic mating type information that is copied and inserted at MAT is contained in either of two loci, HML or HMR. The particular locus selected as donor during mating type interconversion is regulated by the allele expressed at MAT. MATa cells usually select HML, and MAT alpha cells usually select HMR, a process referred to as donor preference. To identify factors required for donor preference, we isolated and characterized a number of mutants that frequently selected the nonpreferred donor locus during mating type interconversion. Many of these mutants were found to harbor chromosome rearrangements or mutations at MAT or HML that interfered with the switching process. However, one mutant carried a recessive allele of CHL1, a gene previously shown to be required for efficient chromosome segregation during mitosis. Homothallic strains of yeast containing a null allele of CHL1 exhibited almost random selection of the donor locus in a MATa background but were normal in their ability to select HMR in a MAT alpha background. Our results indicate that Chl1p participates in the process of donor selection and are consistent with a model in which Chl1p helps establish an intrinsic bias in donor preference.


Comparison of Clinical Efficacy and Anatomical Investigation between Retrolaminar Block and Erector Spinae Plane Block.
Retrolaminar block (RLB) and erector spinae plane block (ESPB) are alternative approaches to paravertebral block (PVB) and are advantageous in that they are easier and safer techniques compared with the traditional PVB. Many clinical reports of these blocks have described their efficacy for ipsilateral thoracic analgesia. The local anesthetic injection points of RLB and ESPB are the lamina and transverse process, respectively. Despite the similarity of the puncture sites, there have been no clinical studies comparing RLB and ESPB. In addition, the underlying mechanism of these blocks has not been clarified. Recent anatomical investigations indicated that the injectate was distributed in the paravertebral space and spread laterally into the intercostal spaces. The limited distribution into the paravertebral space indicated that compared to PVB, RLB and ESPB exert their effects via a different mechanism. In this review, we describe the features of and differences between RLB and ESPB based on current clinical and anatomical reports. We also propose the clinical indication and discuss the differences, clinical outcomes, and anatomical mechanisms of the techniques.


Prevalence of low bone mineral density in inpatients with traumatic brain injury receiving neurobehavioural rehabilitation: a postoperative, observational study.
Osteoporosis is characterised by low bone mineral density (BMD) leading to an increased risk of fracture. Patients who have sustained a significant traumatic brain injury may have an increased risk of secondary reduced BMD as a result of immobility and other factors. To describe BMD in a cohort of patients recovering from traumatic brain injury, and to discuss the implications of the findings for physiotherapy practice. Prospective, observational. Specialist, residential unit providing care for individuals with brain injury, many with a history of severe challenging behaviour. Current inpatients (n=51, 80% male) with the capacity to provide consent, as judged by their responsible clinician. The median age was 41 years (range 20 to 60 years), and the median time since the brain injury was sustained was 22 years (range 4 to 54 years). Participants' BMD was measured at the radius and tibia using quantitative ultrasound. Various clinical and demographic details were collected. Participants had suboptimal BMD measurements that were generally low for their age and gender. Nine (18%) participants met the criteria for osteopenia measured at the radius, and 26 (51%) participants met criteria for osteoporosis or osteopenia measured at the tibia. Some participants had reduced BMD, putting them at risk of fracture or of developing such risk in the future. This group is at particular risk because they frequently display challenging aggressive behaviours that may be met with responses including proportionate use of manual restraint. Physiotherapists should bear this increased risk in mind when devising exercise programmes assessing risk in neurobehavioural rehabilitation settings.


Receipt of best care according to current quality of care measures and outcomes in men with prostate cancer.
We evaluated whether patients with prostate cancer who received best care according to a set of 5 nationally endorsed quality measures had decreased treatment related morbidity and improved cancer control. In this retrospective cohort study we included 38,055 men from the SEER (Surveillance, Epidemiology and End Results)-Medicare database treated for localized prostate cancer between 2004 and 2010. We determined whether each patient received best care, defined as care adherent to all applicable measures. We measured associations of best care with the need for interventions, addressing treatment related morbidity, and with the need for secondary cancer therapy using Cox proportional hazards models. Only 3,412 men (9.0%) received best care. Five years after treatment these men and men who did not receive best care had a similar likelihood of undergoing procedures for urinary morbidity (prostatectomy subset 10.7% vs 12.9%, p = 0.338) and secondary cancer therapy (prostatectomy for high risk prostate cancer subset 40.9% vs 37.3%, p = 0.522). However, they were more likely to be treated with a procedure for sexual morbidity (prostatectomy 17.3% vs 10.8%, p <0.001). Similar trends were observed in men treated with radiotherapy. Overall men who received best care did not fare better in regard to treatment related morbidity or cancer control. Collectively our findings suggest that the current process of care measures are not tightly linked to outcomes and further research is needed to identify better measures that are meaningful and important to patients.


Spermine and arcaine block and permeate N-methyl-D-aspartate receptor channels.
Polyamines such as spermine are thought to be endogenous regulators of NMDA (N-methyl-D-aspartate)-type glutamate receptors. Polyamine block of NMDA receptors was studied in excised outside-out patches from rat hippocampal neurons and Xenopus oocytes expressing recombinant receptors. Extracellular spermine and arcaine reduced NMDA single-channel conductance in a voltage-dependent manner, with partial relief of block evident at large inside negative membrane potentials. Reducing extracellular Na+ concentration increased the apparent affinities for spermine and arcaine, indicating strong interaction between spermine and permeant ions. Internal spermine also blocked NMDA channels in a voltage-dependent manner, with relief of block evident at large inside positive potentials. The Woodhull model of channel block by an impermeant ion adequately described the actions of external spermine from -60 to +60 mV, but failed for more negative potentials. Eyring rate theory for a permeable blocker with two barriers and one binding site adequately described the voltage-dependent block and relief from block by both external and internal spermine over the range of -120 to +60 mV. These findings indicate that polyamines block and permeate neuronal NMDA receptor channels from the extracellular and intracellular sides, although sensitivity to internal spermine is probably too low to be physiologically relevant.


Sexually transmitted infection trends among gay or bisexual men from a clinic-based sentinel surveillance system in British Columbia, Canada.
We described trends for sexually transmitted infections (STI) among gay/bisexual men in British Columbia, Canada, using a sentinel site surveillance approach. Using data from an electronic charting system, we included gay/bisexual men who visited high-volume STI clinics from 2000 to 2013. Diagnosis rates and incidence density were calculated for chlamydia, gonorrhea, syphilis, HIV, hepatitis C, genital herpes, and genital warts. Incidence density was estimated among repeat testers who converted from a negative to positive test result. We also conducted Poisson regression analysis to determine factors that were associated with increased incidence rates. A total of 47,170 visits were identified for gay/bisexual men during our time frame. The median age was 34 years (interquartile range, 27-43 years), and most clients were seen in Vancouver. Although trends for most STI were stable, diagnoses of gonorrhea and syphilis have risen steadily in recent years. Coinfection with HIV was associated with higher gonorrhea and syphilis rates in the Poisson regression model. In addition, visiting a Vancouver clinic and younger age were associated with increased incidence. Our clinic-based sentinel surveillance system found increasing trends for gonorrhea and syphilis among gay/bisexual men but not for other STI in British Columbia. Further investigation is required to explore the syndemic effects of syphilis, gonorrhea, and HIV. This new platform will be a valuable tool for ongoing monitoring of STI and targeting prevention efforts.


Continuing education--a new approach.
Many teachers of general practice in this country and abroad have called upon colleagues in practice to take upon themselves a larger share of continuing education within this branch of the profession.One response to this call, reported in this article, was a five-day intensive course for 29 established general practitioners, held at the Eastbourne Postgraduate Medical Centre, 1980. The course was planned entirely by a team of seven general practitioners who had gained their teaching experience as vocational training course organizers. The course and its evaluation are described. We offer it as a new approach to continuing education which some of our general practitioner colleagues may prefer to conventional courses, but we do not suggest that our approach should replace well-tried and successful methods.


Perinaphthenone phototransformation in a model of leaf epicuticular waxes.
Perinaphthenone (1H-phenalen-1-one, PN) is a reference photosensitizer producing singlet oxygen with a quantum yield close to one in a large variety of solvents. It is also the basic structure of a class of phototoxic phytoalexins. In this work, the PN photoreactivity was studied for the first time in a paraffinic wax, used as model of leaf epicuticular waxes. The PN photodegradation was monitored by UV-Vis spectroscopy. The triplet excited state, singlet oxygen and the hydroxyperinaphthenyl radical were detected by diffuse reflectance laser flash photolysis, near infrared phosphorescence and by EPR spectroscopy, respectively. The PN phototransformation was found to be fivefold faster in the wax than in n-heptane under steady-state irradiation. The hydroxyperinaphthenyl radical formation was observed in aerated irradiated paraffin wax while in n-heptane solution the radical was observed only in the absence of oxygen. These results show that under continuous irradiation, PN is much more easily phototransformed in a solid environment than in solution. Several photoproducts were identified, in particular phenalanone, PN dimers, and oxidized PN-alkanes adducts. Finally, when pyrethrum extract is added into the wax along with PN, the hydroxyperinaphthenyl radical concentration was increased by a factor of 2.4. Such photochemical reactions may occur when systemic pesticides enter the plant cuticle.


Structural encoding of body and face in human infants and adults.
Most studies on visual perception of human beings have focused on perception of faces. However, bodies are another important visual element, which help us to identify a member of our species in the visual scene. In order to study whether similar configural information processing is used in body and face perception, we recorded high-density even-related potentials (ERPs) to normal and distorted faces and bodies in adults and 3-month-old infants. In adults, the N1 responses evoked by bodies and faces were similar in amplitude but differed slightly in latency. The voltage topography of N1 also differed in concordance with fMRI data showing that two distinct areas are involved in face and body perception. Distortion affected ERPs to faces and bodies similarly from N1 on, although the effect was significant earlier for bodies than for faces. These results suggest that fast processing of configural information is not specific to faces but it also occurs for bodies. In 3-month-old infants, distortion decreased the amplitude of P400 around 450 msec, showing no interaction with image category. This result demonstrates that infants are not only able to recognize the normal configuration of faces, but also that of bodies. This could either be related to an innate knowledge of this particular type of biological object, or to fast learning through intense exposure during the first months of life.


Longitudinal Effects of Gendered Harassment Perpetration and Victimization on Mental Health Outcomes in Adolescence.
Gendered harassment, including sexual harassment and homophobic name-calling, is prevalent in adolescents and is linked to negative outcomes including depression, anxiety, suicidality, substance abuse, and personal distress. However, much of the extant literature is cross-sectional and rarely are perpetrators of these behaviors included in studies of outcomes. Therefore, the current study examined the effects of longitudinal changes in gendered harassment perpetration and victimization on changes in mental health outcomes among a large sample of early adolescents. Given that these behaviors commonly occur in the context of a patriarchal society (males hold power), we also investigated the impact of gender on gendered harassment. Participants included 3,549 students from four Midwestern middle schools (50.4% female, 49% African American, 34% White) at two time points (13 and 17 years old). Results indicated that increases from age 13 to 17 years in sexual harassment perpetration and victimization and homophobic name-calling perpetration and victimization predicted increases in depression symptoms and substance use. Gender did not moderate these pathways. These findings highlight that negative outcomes are associated with changes in gendered harassment among adolescents and emphasize the importance of prevention efforts. Implications for school interventions are discussed.