Adipose derived mesenchymal stem cells seeded onto a decellularized nerve allograft enhances angiogenesis in a rat sciatic nerve defect model.
Adipose derived mesenchymal stem cells (MSCs) are hypothesized to supplement tissues with growth factors essential for regeneration and neovascularization. The purpose of this study was to determine the effect of MSCs with respect to neoangiogenesis when seeded onto a decellularized nerve allograft in a rat sciatic nerve defect model. Allograft nerves were harvested from Sprague-Dawley rats and decellularized. MSCs were obtained from Lewis rats. 10 mm sciatic nerve defects in Lewis rats were reconstructed with reversed autograft nerves, decellularized allografts, decellularized allografts seeded with undifferentiated MSC or decellularized allografts seeded with differentiated MSCs. At 16 weeks, the vascular surface area and volume were evaluated. The vascular surface area in normal nerves (34.9 ± 5.7%), autografts (29.5 ± 8.7%), allografts seeded with differentiated (38.9 ± 7.0%) and undifferentiated MSCs (29.2 ± 3.4%) did not significantly differ from each other. Unseeded allografts (21.2 ± 6.2%) had a significantly lower vascular surface area percentage than normal nonoperated nerves (13.7%, p = .001) and allografts seeded with differentiated MSCs (17.8%, p = .001). Although the vascular surface area was significantly correlated to the vascular volume (r = .416; p = .008), no significant differences were found between groups concerning vascular volumes. The vascularization pattern in allografts seeded with MSCs consisted of an extensive nonaligned network of microvessels with a centripetal pattern, while the vessels in autografts and normal nerves were more longitudinally aligned with longitudinal inosculation patterns. Neoangiogenesis of decellularized allograft nerves was enhanced by stem cell seeding, in particular by differentiated MSCs. The pattern of vascularization was different between decellularized allograft nerves seeded with MSCs compared to autograft nerves.


Different CD40-mediated signaling events require distinct CD40 structural features.
Signals delivered to B cells through CD40 are critical to the development of humoral immune responses. In this study we characterize regions of the 62-amino acid cytoplasmic domain of human CD40 (hCD40) that are essential for signal transduction and examine the functional consequences of mutations in these regions. A panel of mutant hCD40 molecules was stably expressed in mouse B cell lines and tested for its ability to stimulate Ab secretion, homotypic adhesion, and increased surface expression of B7, Fas, CD23, LFA-1, and intracellular adhesion molecule-1. Our results indicate that CD40 contains at least two major signaling determinants in the cytoplasmic domain: one disrupted by a truncation of 22 amino acids, and a second disrupted by the removal of 10 additional amino acids. The second determinant includes threonine 234, a residue previously shown to be important in CD40 signal transduction. Our functional analysis of alanine and serine substitutions at position 234 indicates that phosphorylation of this residue may be important for full CD40 signaling activity.


Genital human papillomavirus infections: current and prospective therapies.
Infection with human papillomaviruses (HPVs) is very common and associated with benign and malignant epithelial proliferations of skin and internal squamous mucosae. A subset of the mucosal HPVs are oncogenic and associated with 5 % of all cancers in men and women. There are two licensed prophylactic vaccines, both target HPV 16 and 18, the two most pathogenic, oncogenic types and one, additionally, targets HPV 6 and 11 the cause of genital warts. The approach of deliberate immunization with oncogenic HPV E6 and/or E7 proteins and the generation of antigen-specific cytotoxic T-cells as an immunotherapy for HPV-associated cancer and their high-grade pre-cancers has been tested with a wide array of potential vaccine delivery systems in Phase I/II trials with varying success. Understanding local viral and tumour immune evasion strategies is a prerequisite for the rational design of therapeutic vaccines for HPV-associated infection and disease, progress in this is discussed. There are no antiviral drugs for the treatment of HPV infection and disease. Current therapies are not targeted antiviral therapies, but either attempt physical removal of the lesion or induce inflammation and a bystander immune response. There has been recent progress in the identification and characterization of molecular targets for small molecule antagonists of the HPV proteins E1, E2 and E6 or their interactions with their cellular targets. Lead compounds that could disrupt E1-E2 protein-protein interactions have been discovered as have inhibitors of E6-E6-AP-binding interactions. Some of these compounds showed nanomolar affinities and high specificities and demonstrate the feasibility of this approach for HPV infections. These studies are, however, at an early phase and it is unlikely that any specific anti-HPV chemotherapeutic will be in the clinic within the next 10-20 years.


WITHDRAWN: Reduction versus abrupt cessation in smokers who want to quit.
The standard way to stop smoking is to quit abruptly on a designated quit day. A number of smokers have tried unsuccessfully to quit this way. Reducing smoking before quitting could be an alternative approach to cessation. Before this method is adopted it is important to determine whether it is at least as successful as abrupt quitting. 1. To compare the success of reducing smoking to quit and abrupt quitting interventions. 2. To compare adverse events between arms in studies that used pharmacotherapy to aid reduction. We searched the Cochrane Tobacco Addiction Review Group specialised register using topic specific terms. The register contains reports of trials of tobacco addiction interventions identified from searches of MEDLINE, EMBASE and PsycInfo. We also searched reference lists of relevant papers and contacted authors of ongoing trials. Date of most recent search: July 2012. We included randomized controlled trials (RCTs) that recruited adults who wanted to quit smoking. Studies included at least one condition which instructed participants to reduce their smoking and then quit and one condition which instructed participants to quit abruptly. The outcome measure was abstinence from smoking after at least six months follow-up. We pooled the included trials using a Mantel-Haenszel fixed-effect model. Trials were split for two sub-group analyses: pharmacotherapy vs no pharmacotherapy, self help therapy vs behavioural support. Adverse events were summarised as a narrative. It was not possible to compare them quantitatively as there was variation in the nature and depth of reporting across studies. Ten studies were relevant for inclusion, with a total of 3760 participants included in the meta-analysis. Three of these studies used pharmacotherapy as part of the interventions. Five studies included behavioural support in the intervention, four included self-help therapy, and the remaining study had arms which included behavioural support and arms which included self-help therapy. Neither reduction or abrupt quitting had superior abstinence rates when all the studies were combined in the main analysis (RR= 0.94, 95% CI= 0.79 to 1.13), whether pharmacotherapy was used (RR= 0.87, 95% CI= 0.65 to 1.22), or not (RR= 0.97, 95% CI= 0.78 to 1.21), whether studies included behavioural support (RR= 0.87, 95% CI= 0.64 to 1.17) or self-help therapy (RR= 0.98, 95% CI= 0.78 to1.23). We were unable to draw conclusions about the difference in adverse events between interventions, however recent studies suggest that pre-quit NRT does not increase adverse events. Reducing cigarettes smoked before quit day and quitting abruptly, with no prior reduction, produced comparable quit rates, therefore patients can be given the choice to quit in either of these ways. Reduction interventions can be carried out using self-help materials or aided by behavioural support, and can be carried out with the aid of pre-quit NRT. Further research needs to investigate which method of reduction before quitting is the most effective, and which categories of smokers benefit the most from each method, to inform future policy and intervention development.


Depletion of CpG Dinucleotides in Papillomaviruses and Polyomaviruses: A Role for Divergent Evolutionary Pressures.
Papillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses. We studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses. All papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses. The extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our results highlight the existence of divergent evolutionary pressures leading to CpG dinucleotide depletion among small ds-DNA viruses infecting vertebrate hosts.


Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction.
Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.


Effects of cortisone on rat liver mitochondria.
Experiments were designed to determine the effects of parenteral administration of cortisone on mitochondrial numbers of rat liver cells. Observations were made in three ways: (1) after osmic acid fixation and appropriate stain, (2) by phase microscopy on intact cells, (3) by actual enumeration of mitochondria and nuclei to provide data on mitochondria per cell. The results of the experiments indicate that the mitochondria per cell are significantly reduced under the conditions used. Each experimental approach provided similar data, and each tended to support the results obtained from the others.


Relationship between QRS duration and left ventricular mass and volume in patients at high cardiovascular risk.
Longer QRS duration on the ECG is associated with increased cardiovascular (CV) mortality. To evaluate potential mechanisms, we examined in this study the relationship between QRS duration and left ventricular (LV) mass and LV end systolic and end diastolic volume in patients with known CV disease or high-risk diabetes. In a substudy of the ONTARGET/TRANSCEND (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) clinical trials, 368 patients had a cardiac magnetic resonance scan to measure LV mass, LV end systolic volume, LV end diastolic volume and LV ejection fraction at baseline and after 2 years of follow-up. Relationships between QRS duration on the 12-lead ECG and LV mass and volumes were evaluated at both assessments. Each 10-ms increase in QRS duration both within and above the normal reference range was associated with an 8.3% (95% CI 6.7% to 9.9%) increase in LV mass, a 9.2% (95% CI 7.4% to 10%) increase in LV end diastolic volume and a 7.8% (95% CI 6.4% to 9.3%) increase in LV end systolic volume. QRS duration increased with body size, but associations with LV mass and volumes remained strong after indexing measurements to height(2.7) (p<0.001 for all) and were similar for subjects with an otherwise normal and abnormal ECG. A longer QRS duration both within and above the normal reference range is associated with a greater LV mass and larger LV end systolic and end diastolic volumes. This may explain the known association of longer QRS duration with increased CV mortality.


Group-Schematherapy for Adolescents: Results from a Naturalistic Multiple Case Study.
Personality disorders are complex mental health problems, associated with chronic dysfunction in several life domains. Adolescents suffer from these disorders as well. The present study is a naturalistic case study, investigating whether group schematherapy (GST) can be applied to adolescents with personality disorders or personality disorder traits. Four clinically referred patients were included and completed questionnaires on quality of life, symptoms of psychopathology, schema modes, early maladaptive schemas, and schema coping styles. Patients participated in weekly GST sessions complemented by weekly or 2-weekly individual sessions. The parents of the adolescents participated in a separate parent group. From pre- to post-treatment, results demonstrated improvements for some patients in quality of life and symptoms of psychopathology. Changes in a number of modes and schemas were observed in all patients from pre- to post-therapy. In addition to assessing changes from pre- to post-treatment, the current study investigated the temporal changes in modes during therapy as well. Results demonstrated that maladaptive modes decreased, whereas healthy modes increased for all patients across the course of therapy. The present study provides preliminary support for the applicability of GST for adolescents as well as the effectiveness of GST. It is a starting point for further research on this intervention.


The transferrin receptor: a key function in iron metabolism.
Iron is essential to cell proliferation. Its uptake by cells requires specific binding of the major serum iron-transport protein, transferrin, to cell surface transferrin receptors, followed by endocytosis of the receptor-ligand complexes and release of iron from endosomal vesicles to the cytoplasm. The structural and functional aspects of this pathway are reviewed. Intracellular iron either serves as a substrate for the biosynthesis of haem and iron-containing proteins or is stored in ferritin deposits. Recent studies are presented which establish that iron plays an important role in the maintenance of its own homeostasis by regulating coordinately the expression of both the transferrin receptor and ferritin. The elucidation of these regulatory mechanisms may become important to the understanding of certain disorders in iron-metabolism.


Dynamic antigen-specific T-cell responses after point-source exposure to Mycobacterium tuberculosis.
The kinetics of Mycobacterium tuberculosis-specific Th1-type T-cell responses after M. tuberculosis infection are likely to be important in determining clinical outcome. To investigate the kinetics of T-cell responses, in the context of a point-source school tuberculosis outbreak, in three groups of contacts who differed by preventive treatment status and tuberculin skin test (TST) results: 38 treated TST-positive students, 11 untreated TST-positive staff, and 14 untreated students with negative or borderline TST results. We used the ex vivo IFN-gamma enzyme-linked immunospot assay (ELISpot) to track T cells specific for two region of difference 1 (RD1) antigens, early secretory antigenic target 6 and culture filtrate protein 10, for 18 mo after cessation of tuberculosis exposure. The treated TST-positive students had an average 68% decline in frequencies of RD1-specific IFN-gamma-secreting T cells per year (p < 0.0001) and 6 of 38 students had no detectable RD1-specific T cells by 18 mo. No change in frequencies of these cells was observed in the untreated TST-positive staff (p = 0.38) and none were ELISpot-negative at 18 mo. Of the 14 untreated students, 7 were persistently ELISpot-positive (all of whom had borderline TST results), and 7 became ELISpot-negative (all but one had negative TST results) during follow-up. The decrease in M. tuberculosis-specific T cells and their disappearance in a proportion of treated students likely reflect declining antigenic and bacterial load in vivo induced by antibiotic treatment. The observed disappearance of M. tuberculosis-specific T cells in the untreated TST-negative contacts suggests that an acute resolving infection may occur in some contacts.


Coupling of energy metabolism and synaptic transmission at the transcriptional level: role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes.
Neuronal activity and energy metabolism are tightly coupled processes. Regions high in neuronal activity, especially of the glutamatergic type, have high levels of cytochrome c oxidase (COX). Perturbations in neuronal activity affect the expressions of COX and glutamatergic NMDA receptor subunit 1 (NR1). The present study sought to test our hypothesis that the coupling extends to the transcriptional level, whereby NR1 and possibly other NR subunits and COX are coregulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), which regulates all COX subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutations, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Grin 1 (NR1), Grin 2b (NR2b) and COX subunit genes, but not of Grin2a and Grin3a genes. These transcripts were upregulated by KCl and downregulated by tetrodotoxin (TTX) in cultured primary neurons. However, silencing of NRF-1 with small interference RNA blocked the upregulation of Grin1, Grin2b, and COX induced by KCl, and overexpression of NRF-1 rescued these transcripts that were suppressed by TTX. NRF-1 binding sites on Grin1 and Grin2b genes are also highly conserved among mice, rats, and humans. Thus, NRF-1 is an essential transcription factor critical in the coregulation of NR1, NR2b, and COX, and coupling exists at the transcriptional level to ensure coordinated expressions of proteins important for synaptic transmission and energy metabolism.


Quantitative and qualitative assessment of morphology in sagittal synostosis: mid-sagittal vector analysis.
Consensus remains lacking regarding the optimal surgical treatment modality for sagittal synostosis. There is, however, wide agreement that objective analytical methods are required to demonstrate the characteristic morphology of the condition and to substantiate the benefits of specified surgical techniques. Simple calculated anthropomorphic indices, such as the cranial index, are commonly used but fail to provide satisfactory representation of morphology, which is far more complex than can be represented by its simple length-width ratio. Techniques to provide more comprehensive, yet practical, assessment of morphology are needed for analytic purposes. Herein, we introduce vector analysis as an objective, computed tomography (CT)-based morphometric technique for assessment of cranial morphology; this work represents the first application of the technique mid-sagittal vector analysis (MSVA). MSVA is a single plane application that was devised to address dysmorphology in sagittal synostosis. It was our hypothesis that MSVA would quantitatively and qualitatively depict preoperative morphology and postoperative correction in specific regions. Sixteen patients undergoing cranial reshaping surgery for sagittal synostosis were included in the study. All patients underwent routine preoperative and 1 year postoperative CT scans, from which the MSVA was derived. MSVA is a radial vector analysis in which distances to the cranial surface are measured from a single reference point origin in the sagittal plane. Preoperative morphology, characterized by respective vectors, was analyzed in three regions: the frontal, vertex, and occipital regions. Comparison with postoperative paired data was conducted for each patient. The analysis of postoperative change demonstrated (1) decrease in prominence in the frontal and occipital regions, (2) increase in height and forward translation of the vertex, and (3) ability to distinguish and qualify frontal versus occipital bossing and correction thereof. We conclude that the longitudinal differences associated with scaphocephaly are well characterized and differentiated by MSVA. Quantitative and qualitative assessment identifies three relevant regions affected by the condition and its treatment: the frontal, vertex, and occipital regions. The transverse dimension is not addressed in this single plane analysis; a more comprehensive application will require additional planes of analysis and the development of a normative database.


The chloroplast genome of Nicotiana sylvestris and Nicotiana tomentosiformis: complete sequencing confirms that the Nicotiana sylvestris progenitor is the maternal genome donor of Nicotiana tabacum.
The tobacco cultivar Nicotiana tabacum is a natural amphidiploid that is thought to be derived from ancestors of Nicotiana sylvestris and Nicotiana tomentosiformis. To compare these chloroplast genomes, DNA was prepared from isolated chloroplasts from green leaves of N. sylvestris and N. tomentosiformis, and subjected to whole-genome shotgun sequencing. The N. sylvestris chloroplast genome comprises of 155,941 bp and shows identical gene organization with that of N. tabacum, except one ORF. Detailed comparison revealed only seven different sites between N. tabacum and N. sylvestris; three in introns, two in spacer regions and two in coding regions. The chloroplast DNA of N. tomentosiformis is 155,745 bp long and possesses also identical gene organization with that of N. tabacum, except four ORFs and one pseudogene. However, 1,194 sites differ between these two species. Compared with N. tabacum, the nucleotide substitution in the inverted repeat was much lower than that in the single-copy region. The present work confirms that the chloroplast genome from N. tabacum was derived from an ancestor of N. sylvestris, and suggests that the rate of nucleotide substitution of the chloroplast genomes from N. tabacum and N. sylvestris is very low.


Prediagnostic serum concentrations of organochlorine compounds and risk of testicular germ cell tumors.
Recent findings suggest that exposure to organochlorine (OC) compounds, chlordanes and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in particular, may increase the risk of developing testicular germ cell tumors (TGCTs). To further investigate this question, we conducted a nested case-control study of TGCTs within the Norwegian Janus Serum Bank cohort. The study was conducted among individuals with serum collected between 1972 and 1978. TGCT cases diagnosed through 1999 (n = 49; 27-62 years of age at diagnosis) were identified through linkage to the Norwegian Cancer Registry. Controls (n =51) were matched to cases on region, blood draw year, and age at blood draw. Measurements of 11 OC insecticide compounds and 34 polychlorinated biphenyl (PCB) congeners were performed using gas chromatography/high-resolution mass spectrometry. Case-control comparisons of lipid-adjusted analyte concentrations were performed using the Wilcoxon signed-rank test. Odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles of analyte concentration were calculated using conditional logistic regression. TGCT cases had elevated concentrations of p,p'-DDE (tertile 3 vs. tertile 1 OR (OR(T3)) 2.2; 95% CI, 0.7-6.5; p(Wilcoxon) = 0.07), oxychlordane (OR(T3) 3.2; 95% CI, 0.6-16.8; p(Wilcoxon) = 0.05), trans-nonachlor (OR(T3) 2.6; 95% CI, 0.7-8.9; p(Wilcoxon) = 0.07), and total chlordanes (OR(T3) 2.0; 95% CI, 0.6-7.2; p(Wilcoxon) = 0.048) compared with controls, although no ORs were statistically significant. Seminoma cases had significantly lower concentrations of PCB congeners 44, 49, and 52 and significantly higher concentrations of PCBs 99, 138, 153, 167, 183, and 195. Our study provides additional but qualified evidence supporting an association between exposures to p,p'-DDE and chlordane compounds, and possibly some PCB congeners, and TGCT risk.


Role of Porphyromonas gingivalis FeoB2 in metal uptake and oxidative stress protection.
Porphyromonas gingivalis, a gram-negative anaerobic bacterium, is a recognized periodontopathogen. It exhibits a high degree of aerotolerance and is able to survive in host cells, indicating that efficient oxidative stress protection mechanisms must be present in this organism. Manganese homeostasis plays a major role in oxidative stress protection in a variety of organisms; however, the transport and role of this metal in P. gingivalis is not well understood. Analysis of the genome of P. gingivalis W83 revealed the presence of two genes encoding homologs of a ferrous iron transport protein, FeoB1 and FeoB2. FeoB2 has been implicated in manganese accumulation in P. gingivalis. We sought to determine the role of the FeoB2 protein in metal transport as well as its contribution to resistance to oxygen radicals. Quantitative reverse transcriptase PCR analyses demonstrated that expression of feoB2 is induced in the presence of oxygen. The role of FeoB2 was investigated using an isogenic mutant strain deficient in the putative transporter. We characterized the FeoB2-mediated metal transport using (55)Fe(2+) and (54)Mn(2+). The FeoB2-deficient mutant had dramatically reduced rates of manganese uptake (0.028 pmol/min/10(7) bacteria) compared with the parental strain (0.33 pmol/min/10(7) bacteria) (after 20 min of uptake using 50 nM of (54)Mn(2+)). The iron uptake rates, however, were higher in the mutant strain (0.75 pmol/min/10(7) bacteria) than in the wild type (0.39 pmol/min/10(7) bacteria). Interestingly, reduced survival rates were also noted for the mutant strain after exposure to H(2)O(2) and to atmospheric oxygen compared to the parental strain cultured under the same conditions. In addition, in vitro infection of host cells with the wild type, the FeoB2-deficient mutant, and the same-site revertant revealed that the mutant had a significantly decreased capability for intracellular survival in the host cells compared to the wild-type strain. Our results demonstrate that feoB2 encodes a major manganese transporter required for protection of the bacterium from oxidative stress generated by atmospheric oxygen and H(2)O(2). Furthermore, we show that FeoB2 and acquisition of manganese are required for intracellular survival of P. gingivalis in host cells.


Genetic diversity and historical demography of Atlantic bigeye tuna (Thunnus obesus).
Bigeye (Thunnus obesus) is a large, pelagic, and migratory species of tuna that inhabits tropical and temperate marine waters worldwide. Previous studies based on mitochondrial RFLP data have shown that bigeye tunas from the Atlantic Ocean are the most interesting from a genetic point of view. Two highly divergent mitochondrial haplotype clades (I and II) coexist in the Atlantic Ocean. One is almost exclusive of the Atlantic Ocean whereas the other is also found in the Indo-Pacific Ocean. Bigeye tuna from the Atlantic Ocean is currently managed as a single stock, although this assumption remains untested at the genetic level. Therefore, genetic diversity was determined at the mitochondrial control region to test the null hypothesis of no population structure in bigeye tuna from the Atlantic Ocean. A total of 331 specimens were sampled from four locations in the Atlantic Ocean (Canada, Azores, Canary Islands, and Gulf of Guinea), and one in the Indian and Pacific Oceans, respectively. The reconstructed neighbor-joining phylogeny confirmed the presence of Clades I and II throughout the Atlantic Ocean. No apparent latitudinal gradient of the proportions of both clades in the different collection sites was observed. Hierarchical AMOVA tests and pairwise phi(ST) comparisons involving Atlantic Ocean Clades I and II were consistent with a single stock of bigeye tuna in the Atlantic Ocean. Population genetic analyses considering phylogroups independently supported gene flow within Clade II throughout the Atlantic Ocean, and within Clade I between Atlantic and Indo-Pacific Oceans. The latter result suggests present uni-directional gene flow from the Indo-Pacific into the Atlantic Ocean. Moreover, mismatch analyses dated divergence of Clades I and II during the Pleistocene, as previously proposed. In addition, migration rates were estimated using coalescent methods, and showed a net migration from Atlantic Ocean feeding grounds towards the Gulf of Guinea, the best-known spawning ground of Atlantic bigeye tuna.


Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction.
Metabolic Syndrome (MetS) represents a constellation of markers that indicates a predisposition to diabetes, cardiovascular disease and other pathologic states. The definition and treatment are a matter of current debate and there is not general agreement on a precise definition or, to some extent, whether the designation provides more information than the individual components. We consider here five indicators that are central to most definitions and we provide evidence from the literature that these are precisely the symptoms that respond to reduction in dietary carbohydrate (CHO). Carbohydrate restriction is one of several strategies for reducing body mass but even in the absence of weight loss or in comparison with low fat alternatives, CHO restriction is effective at ameliorating high fasting glucose and insulin, high plasma triglycerides (TAG), low HDL and high blood pressure. In addition, low fat, high CHO diets have long been known to raise TAG, lower HDL and, in the absence of weight loss, may worsen glycemic control. Thus, whereas there are numerous strategies for weight loss, a patient with high BMI and high TAG is likely to benefit most from a regimen that reduces CHO intake. Reviewing the literature, benefits of CHO restriction are seen in normal or overweight individuals, in normal patients who meet the criteria for MetS or in patients with frank diabetes. Moreover, in low fat studies that ameliorate LDL and total cholesterol, controls may do better on the symptoms of MetS. On this basis, we feel that MetS is a meaningful, useful phenomenon and may, in fact, be operationally defined as the set of markers that responds to CHO restriction. Insofar as this is an accurate characterization it is likely the result of the effect of dietary CHO on insulin metabolism. Glucose is the major insulin secretagogue and insulin resistance has been tied to the hyperinsulinemic state or the effect of such a state on lipid metabolism. The conclusion is probably not surprising but has not been explicitly stated before. The known effects of CHO-induced hypertriglyceridemia, the HDL-lowering effect of low fat, high CHO interventions and the obvious improvement in glucose and insulin from CHO restriction should have made this evident. In addition, recent studies suggest that a subset of MetS, the ratio of TAG/HDL, is a good marker for insulin resistance and risk of CVD, and this indicator is reliably reduced by CHO restriction and exacerbated by high CHO intake. Inability to make this connection in the past has probably been due to the fact that individual responses have been studied in isolation as well as to the emphasis of traditional therapeutic approaches on low fat rather than low CHO. We emphasize that MetS is not a disease but a collection of markers. Individual physicians must decide whether high LDL, or other risk factors are more important than the features of MetS in any individual case but if MetS is to be considered it should be recognized that reducing CHO will bring improvement. Response of symptoms to CHO restriction might thus provide a new experimental criterion for MetS in the face of on-going controversy about a useful definition. As a guide to future research, the idea that control of insulin metabolism by CHO intake is, to a first approximation, the underlying mechanism in MetS is a testable hypothesis.


Immediate Blood Draw for CD4+ Cell Count Is Associated with Linkage to Care in Durban, South Africa: Findings from Pathways to Engagement in HIV Care.
Timely linkage to care by newly-diagnosed HIV+ individuals remains a significant challenge to achieving UNAIDS 90-90-90 goals. Current World Health Organization (WHO) guidelines recommend initiating anti-retroviral treatment (ART) regardless of CD4+ count, with priority given to those with CD4+ <350 cells/μl. We evaluated the impact of not having a day-of-diagnosis CD4+ count blood draw, as recommended by South African guidelines, on time to linkage, using data from a prospective cohort study. Individuals (N = 2773) were interviewed prior to HIV counseling and testing at three public sector primary care clinics in the greater Durban area; 785 were newly-diagnosed and eligible for the cohort study; 459 (58.5%) joined and were followed for eight months with three structured assessments. Linkage to care, defined as returning to clinic for CD4+ count results, and day-of-diagnosis blood draw were self-reported. Overall, 72.5% did not have a day-of-diagnosis CD4+ count blood draw, and 19.2% of these never returned. Compared with a day-of-diagnosis blood draw, the adjusted hazard ratio of linkage (AHRlinkage) associated with not having day-of-diagnosis blood draw was 0.66 (95%CI: 0.51, 0.85). By 4 months, 54.8% of those without day-of-diagnosis blood draw vs. 75.2% with one were linked to care (chi-squared p = 0.004). Of those who deferred blood draw, 48.3% cited clinic-related and 51.7% cited personal reasons. AHRlinkage was 0.60 (95%CI: 0.44, 0.82) for clinic-related and 0.53 (95%CI: 0.38, 0.75) for personal reasons relative to having day-of-diagnosis blood draw. Newly-diagnosed HIV+ individuals who did not undergo CD4+ count blood draw on the day they were diagnosed-regardless of the reason for deferring-had delayed linkage to care relative to those with same-day blood draw. To enhance prompt linkage to care even when test and treat protocols are implemented, all diagnostic testing required before ART initiation should be performed on the same day as HIV testing/diagnosis. This may require modifying clinic procedures to enable overnight blood storage if same-day draws cannot be performed, and providing additional counseling to encourage newly-diagnosed individuals to complete day-of-diagnosis testing. Tracking HIV+ individuals via clinic registries should commence immediately from diagnosis to reduce these early losses to care.


Histopathology of diaphragm disease of the small intestine: a study of 10 cases from a single institution.
Diaphragm disease (DD) is an uncommon gastrointestinal abnormality typical of nonsteroidal anti-inflammatory drug (NSAID)-induced injury. DD of the small intestine is well defined in its gross appearance (multiple circumferential stenosing lesions); however, its histologic features have been studied in few cases. To better define and update the histologic features of DD, we describe 10 cases in which patients underwent resection of portions of small intestine for DD. Selected gross features and 12 microscopic features were assessed. The typical gross appearance of DD was associated with focal chronic injury of the mucosa with mild to moderate inflammatory infiltrate. A wide array of additional abnormalities was found: eosinophilic enteritis (3 cases), inflammatory fibroid polyp (1 case), enteritis cystica profunda (1 case), villous atrophy (1 case), and neuromuscular and vascular hamartoma-like changes (9 cases). DD and, therefore, NSAID-related injury, should be considered in the differential diagnosis of several conditions affecting the small intestine.


Altered helper T lymphocyte function associated with chronic hepatitis B virus infection and its role in response to therapeutic vaccination in humans.
Theradigm-hepatitis B virus (HBV) is an experimental lipopeptide vaccine designed to stimulate induction of HBV-specific CTL responses in HLA-A2 individuals. Previous studies had demonstrated high immunogenicity in healthy volunteers, but comparatively weak CTL responses in chronically infected HBV patients. Herein, we examined helper T lymphocyte (HTL) responses in chronically infected patients. Despite normal proliferation and IL-2 secretion, IL-12 and IFN-gamma secretion in vitro in response to the vaccine was reduced compared with healthy volunteers. A similar pattern of cytokine secretion was observed following mitogen stimulation, suggesting a general altered balance of Th1/Th2 responses. Further analysis indicated that HTL recall responses to whole tetanus toxoid protein were reduced in chronically infected subjects, and reduced responsiveness correlated with the outcome of Theradigm-HBV immunization. Finally, experiments in HBV transgenic mice indicated that the nonnatural Pan DR HTL epitope, PADRE, is capable of inducing high levels of IFN-gamma secretion and that its inclusion in a lipopeptide incorporating an immunodominant Ld-restricted CTL epitope resulted in breaking tolerance at the CTL level. Overall, our results demonstrate an alteration in the quality of HTL responses induced in chronically infected HBV patients and suggest that use of a potent HTL epitope may be important to overcome CTL tolerance against specific HBV Ags.


Glucose tolerance during antihypertensive therapy in patients with diabetes mellitus.
Many antihypertensive drugs have adverse effects on glycemic control when they are used in diabetic patients. This was noted for thiazide diuretics in 1960, and the mechanism of the effects remains uncertain. Indirect evidence suggests that changes in the serum potassium are at least contributory, although the principal mechanism of thiazide-induced hyperglycemia is probably a reduction in the insulin response to glucose. Beta blockers also adversely affect blood sugar control but only by a small margin. The main cause for concern with beta blockers, however, is their effect during hypoglycemia in which nonselective agents delay blood sugar recovery. In diabetic patients, the institution of antihypertensive therapy should be followed by a reassessment to note any changes in sugar, potassium, and lipids, or side effects.


Association between parity and lumbar spine degenerative disorders in young women.
Introduction: Estrogen helps to maintain the health of collagen-containing tissues including the intervertebral disc. Estrogen deficiency after menopause negatively affects the quality of vertebral end plates and induces development of degenerative disc disease (DDD). However, there is no study examining the relationship between parity and spinal degeneration in young women. The aim of this study was to define the relationship between parity and development of vertebral endplate signal changes and DDD in young premenopausal women.Materials and methods: This case-control case study included 224 patients aged 20-40 years with a history of low back pain for at least 3 months. Pfirrmann's grade, Modic changes (MCs), and Schmorl's nodes (SNs) were graded based on magnetic resonance images. Patients' parity, demographics, body mass index, physical activity level, and disability scores were assessed using a questionnaire.Results: The prevalence of abnormal total Pfirrmann's score (>10) and MCs was higher in primiparous patients than multiparous and grand-multiparous; however, it was not statistically significant. The presence of SN was statistically significantly associated with low parity. According to multivariate logistic regression analysis, it was found that the number of births increases by 1 unit, the abnormality in Pfirrmann's score decreases by 1.36 times.Conclusions: This cross-sectional study shows that parity is associated with DDD and vertebral end plate changes. SNs were significantly associated with parity. Modic changes and DDD were less common in grand multipara and multipara young women than in primipara women. These results indicate that low parity may possibly be associated with the development of spinal degeneration.


Will the Effects of Sea-Level Rise Create Ecological Traps for Pacific Island Seabirds?
More than 18 million seabirds nest on 58 Pacific islands protected within vast U.S. Marine National Monuments (1.9 million km2). However, most of these seabird colonies are on low-elevation islands and sea-level rise (SLR) and accompanying high-water perturbations are predicted to escalate with climate change. To understand how SLR may impact protected islands and insular biodiversity, we modeled inundation and wave-driven flooding of a globally important seabird rookery in the subtropical Pacific. We acquired new high-resolution Digital Elevation Models (DEMs) and used the Delft3D wave model and ArcGIS to model wave heights and inundation for a range of SLR scenarios (+0.5, +1.0, +1.5, and +2.0 m) at Midway Atoll. Next, we classified vegetation to delineate habitat exposure to inundation and identified how breeding phenology, colony synchrony, and life history traits affect species-specific sensitivity. We identified 3 of 13 species as highly vulnerable to SLR in the Hawaiian Islands and quantified their atoll-wide distribution (Laysan albatross, Phoebastria immutabilis; black-footed albatross, P. nigripes; and Bonin petrel, Pterodroma hypoleuca). Our models of wave-driven flooding forecast nest losses up to 10% greater than passive inundation models at +1.0 m SLR. At projections of + 2.0 m SLR, approximately 60% of albatross and 44% of Bonin petrel nests were overwashed displacing more than 616,400 breeding albatrosses and petrels. Habitat loss due to passive SLR may decrease the carrying capacity of some islands to support seabird colonies, while sudden high-water events directly reduce survival and reproduction. This is the first study to simulate wave-driven flooding and the combined impacts of SLR, groundwater rise, and storm waves on seabird colonies. Our results highlight the need for early climate change planning and restoration of higher elevation seabird refugia to prevent low-lying protected islands from becoming ecological traps in the face of rising sea levels.


Language-selective and domain-general regions lie side by side within Broca's area.
In 1861, Paul Broca stood up before the Anthropological Society of Paris and announced that the left frontal lobe was the seat of speech. Ever since, Broca's eponymous brain region has served as a primary battleground for one of the central debates in the science of the mind and brain: Is human cognition produced by highly specialized brain regions, each conducting a specific mental process, or instead by more general-purpose brain mechanisms, each broadly engaged in a wide range of cognitive tasks? For Broca's area, the debate focuses on specialization for language versus domain-general functions such as hierarchical structure building (e.g., [1, 2]), aspects of action processing (e.g., [3]), working memory (e.g., [4]), or cognitive control (e.g., [5-7]). Here, using single-subject fMRI, we find that both ideas are right: Broca's area contains two sets of subregions lying side by side, one quite specifically engaged in language processing, surrounded by another that is broadly engaged across a wide variety of tasks and content domains.


Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21.
Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.


Differential responses in superior mesenteric artery blood flow may explain the variant pressor responses to clonidine in two groups with sympathetic denervation.
1. Measurement of superior mesenteric artery blood flow along with systemic and regional haemodynamic changes in blood pressure, heart rate, cardiac index, forearm blood flow, digital skin blood flow and index finger temperature were made before and after administration of clonidine (2 micrograms/kg body weight intravenously) in 10 patients with multiple-system atrophy, 10 patients with pure autonomic failure and 15 age-matched healthy control subjects. 2. After clonidine, blood pressure fell in patients with multiple-system atrophy and control subjects but not in patients with pure autonomic failure. 3. Resting superior mesenteric artery blood flow was similar in patients with multiple-system atrophy and control subjects, but was higher in patients with pure autonomic failure. The fall in blood pressure after clonidine was accompanied by active dilatation of the superior mesenteric artery in patients with multiple-system atrophy and control subjects. This did not occur in patients with pure autonomic failure. 4. After clonidine, there was a fall in cardiac index in patients with multiple-system atrophy. 5. After clonidine, changes in other haemodynamic parameters were not significant in any group, except for a fall in forearm blood flow and a rise in index finger temperature in control subjects. 6. We conclude that after clonidine there are differential superior mesenteric artery blood flow responses in the two groups with autonomic failure (multiple-system atrophy and pure autonomic failure). These may relate to differences in the site of the sympathetic lesion, which is considered to be mainly central in multiple-system atrophy but peripheral in pure autonomic failure.(ABSTRACT TRUNCATED AT 250 WORDS)


World Health Organization (WHO) antibiotic regimen against other regimens for the treatment of leprosy: a systematic review and meta-analysis.
To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88-1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78-1.31)) in PB leprosy. Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed.


Evolution of the modern baboon (Papio hamadryas): A reassessment of the African Plio-Pleistocene record.
Baboons (Papio hamadryas) are among the most successful extant primates, with a minimum of six distinctive forms throughout Sub-Saharan Africa. However, their presence in the fossil record is unclear. Three early fossil taxa are generally recognized, all from South Africa: Papio izodi, Papio robinsoni and Papio angusticeps. Because of their derived appearance, P. angusticeps and P. robinsoni have sometimes been considered subspecies of P. hamadryas and have been used as biochronological markers for the Plio-Pleistocene hominin sites where they are found. We reexamined fossil Papio forms from across Africa with an emphasis on their distinguishing features and distribution. We find that P. robinsoni and P. angusticeps are distinct from each other in several cranial features, but overlap extensively in dental size. Contrary to previous assessments, no diagnostic cranio-mandibular material suggests these two forms co-occur, and dental variation at each site is comparable to that within P. h. ursinus, suggesting that only one form is present in each case. P izodi, however, may co-occur with P. robinsoni, or another Papio form, at Sterkfontein Member 4. P izodi appears more primitive than P. robinsoni and P. angusticeps. P. robinsoni is slightly distinct from P. hamadryas subspecies in its combination of features while P. angusticeps might be included within one of the modern P. hamadryas varieties (i.e., P. h. angusticeps). No definitive Papio fossils are currently documented in eastern Africa until the Middle Pleistocene, pointing to southern Africa as the geographic place of origin for the genus. These results have implications for Plio-Pleistocene biochronology and baboon evolution.


Genetic pathway in acquisition and loss of vancomycin resistance in a methicillin resistant Staphylococcus aureus (MRSA) strain of clonal type USA300.
An isolate of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 with reduced susceptibility to vancomycin (SG-R) (i.e, vancomycin-intermediate S. aureus, VISA) and its susceptible "parental" strain (SG-S) were recovered from a patient at the end and at the beginning of an unsuccessful vancomycin therapy. The VISA phenotype was unstable in vitro generating a susceptible revertant strain (SG-rev). The availability of these 3 isogenic strains allowed us to explore genetic correlates of antibiotic resistance as it emerged in vivo. Compared to the susceptible isolate, both the VISA and revertant strains carried the same point mutations in yycH, vraG, yvqF and lspA genes and a substantial deletion within an intergenic region. The revertant strain carried a single additional frameshift mutation in vraS which is part of two component regulatory system VraSR. VISA isolate SG-R showed complex alterations in phenotype: decreased susceptibility to other antibiotics, slow autolysis, abnormal cell division and increased thickness of cell wall. There was also altered expression of 239 genes including down-regulation of major virulence determinants. All phenotypic properties and gene expression profile returned to parental levels in the revertant strain. Introduction of wild type yvqF on a multicopy plasmid into the VISA strain caused loss of resistance along with loss of all the associated phenotypic changes. Introduction of the wild type vraSR into the revertant strain caused recovery of VISA type resistance. The yvqF/vraSR operon seems to function as an on/off switch: mutation in yvqF in strain SG-R turns on the vraSR system, which leads to increase in vancomycin resistance and down-regulation of virulence determinants. Mutation in vraS in the revertant strain turns off this regulatory system accompanied by loss of resistance and normal expression of virulence genes. Down-regulation of virulence genes may provide VISA strains with a "stealth" strategy to evade detection by the host immune system.


Adenovirus-mediated overexpression of liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in gluconeogenic rat hepatoma cells. Paradoxical effect on Fru-2,6-P2 levels.
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase has been postulated to be a metabolic signaling enzyme, which acts as a switch between glycolysis and gluconeogenesis in mammalian liver by regulating the level of fructose 2,6-bisphosphate. The effect of overexpressing the bifunctional enzyme was studied in FAO cells transduced with recombinant adenoviral constructs of either the wild-type enzyme or a double mutant that has no bisphosphatase activity or protein kinase phosphorylation site. With both constructs, the mRNA and protein were overexpressed by 150- and 40-fold, respectively. Addition of cAMP to cells overexpressing the wild-type enzyme increased the S0.5 for fructose 6-phosphate of the kinase by 1.5-fold but had no effect on the overexpressed double mutant. When the wild-type enzyme was overexpressed, there was a decrease in fructose 2,6-bisphosphate levels, even though 6-phosphofructo-2-kinase maximal activity increased more than 22-fold and was in excess of fructose-2,6-bisphosphatase maximal activity. The kinase:bisphosphatase maximal activity ratio was decreased, indicating that the overexpressed enzyme was phosphorylated by cAMP-dependent protein kinase. Overexpression of the double mutant resulted in a 28-fold increase in kinase maximal activity and a 3-4-fold increase in fructose 2,6-bisphosphate levels. Overexpression of this form inhibited the rate of glucose production from dihydroxyacetone by 90% and stimulated the rate of lactate plus pyruvate production by 200%. In contrast, overexpression of the wild-type enzyme enhanced glucose production and inhibited lactate plus pyruvate production. These results provide direct support for fructose 2,6-bisphosphate as a regulator of gluconeogenic/glycolytic pathway flux and suggest that regulation of bifunctional enzyme activities by covalent modification is more important than the amount of the protein.


Divergent Classification Methods of Post-Concussion Syndrome after Mild Traumatic Brain Injury: Prevalence Rates, Risk Factors, and Functional Outcome.
Mild traumatic brain injury (mTBI) is a common diagnosis and approximately one third of mTBI patients experience a variety of cognitive, emotional, psychosocial, and behavioral post-concussion symptoms. When a cluster of these symptoms persists for more than 3 months they are often classified as post-concussion syndrome (PCS). The objective of this study was to determine prevalence rates, risk factors, and functional outcome associated with PCS 6 months after mTBI, applying divergent classification methods. Follow-up questionnaires at 6 months after mTBI included the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and the Glasgow Outcome Scale Extended (GOSE). The RPQ was analyzed according to different classification methods: the mapped International Classification of Diseases, 10th revision (ICD-10)/Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the RPQ total score, the RPQ3 and the three-factor model using two different cutoff points (mild or worse and moderate or worse). Our results from a sample of 731 mTBI patients showed that prevalence rates of PCS ranged from 11.4% to 38.7% using divergent classification methods. According to all eight methods, 6.3% (n = 46) of mTBI patients experienced PCS. Applying the divergent classification methods resulted in a different set of predictors being statistically significantly associated with PCS, and a different percentage of overlap with functional impairment, measured with the GOSE. In conclusion, depending on the classification method and rating score used, prevalence rates of PCS deviated considerably. For future research, consensus regarding the diagnostic criteria for PCS and the analysis of the RPQ should be reached, to enhance comparability of studies regarding PCS after mTBI.


New evidence on the state of stress of the san andreas fault system.
Contemporary in situ tectonic stress indicators along the San Andreas fault system in central California show northeast-directed horizontal compression that is nearly perpendicular to the strike of the fault. Such compression explains recent uplift of the Coast Ranges and the numerous active reverse faults and folds that trend nearly parallel to the San Andreas and that are otherwise unexplainable in terms of strike-slip deformation. Fault-normal crustal compression in central California is proposed to result from the extremely low shear strength of the San Andreas and the slightly convergent relative motion between the Pacific and North American plates. Preliminary in situ stress data from the Cajon Pass scientific drill hole (located 3.6 kilometers northeast of the San Andreas in southern California near San Bernardino, California) are also consistent with a weak fault, as they show no right-lateral shear stress at approximately 2-kilometer depth on planes parallel to the San Andreas fault.


Arsenic bioavailability to rice is elevated in Bangladeshi paddy soils.
Some paddy soils in the Bengal delta are contaminated with arsenic (As) due to irrigation of As-laden groundwater, which may lead to yield losses and elevated As transfer to the food chain. Whether these soils have a higher As bioavailability than other soils containing either geogenic As or contaminated by mining activities was investigated in a pot experiment. Fourteen soils varying in the source and the degree (4-138 mg As kg 1⁻¹) of As contamination were collected, 10 from Bangladeshi paddy fields (contaminated by irrigation water) and two each from China and the UK (geogenic or mining impacted), for comparison. Bangladeshi soils had higher percentages of the total As extractable by ammonium phosphate (specifically sorbed As) than other soils and also released more As into the porewater upon flooding. Porewater As concentrations increased with increasing soil As concentrations more steeply in Bangladeshi soils, with arsenite being the dominant As species. Rice growth and grain yield decreased markedly in Bangladeshi soils containing > 13 mg As kg 1⁻¹, but not in the other soils. Phosphate-extractable or porewater As was a better indicator of As bioavailability than total soil As. Rice straw As concentrations increased with increasing soil As concentrations; however, As phytotoxicity appeared to result in lower grain As concentrations. The relative proportions of inorganic As and dimethylarsinic acid (DMA) in grain varied among soils, and the percentage DMA was larger in greenhouse-grown plants than grain samples collected from the paddy fields of the same soil and the same rice cultivar, indicating a strong environmental influence on As species found in rice grain. This study shows that Bangladeshi paddy soils contaminated by irrigation had a higher As bioavailability than other soils, resulting in As phytotoxicity in rice and substantial yield losses.


A review of the evidence for overlap among unexplained clinical conditions.
Unexplained clinical conditions share features, including symptoms (fatigue, pain), disability out of proportion to physical examination findings, inconsistent demonstration of laboratory abnormalities, and an association with "stress" and psychosocial factors. This literature review examines the nature and extent of the overlap among these unexplained clinical conditions and the limitations of previous research. English-language articles were identified by a search of the MEDLINE database from 1966 to January 2001 by using individual syndromes and their hallmark symptoms as search terms. Studies that assessed patients with at least one unexplained clinical condition and that included information on symptoms, overlap with other unexplained clinical conditions, or physiologic markers. Conditions examined were the chronic fatigue syndrome, fibromyalgia, the irritable bowel syndrome, multiple chemical sensitivity, temporomandibular disorder, tension headache, interstitial cystitis, and the postconcussion syndrome. Information on authorship, patient and control groups, eligibility criteria, case definitions, study methods, and major findings. Many similarities were apparent in case definition and symptoms, and the proportion of patients with one unexplained clinical condition meeting criteria for a second unexplained condition was striking. Tender points on physical examination and decreased pain threshold and tolerance were the most frequent and consistent objective findings. A major shortcoming of all proposed explanatory models is their inability to account for the occurrence of unexplained clinical conditions in many affected patients. Overlap between unexplained clinical conditions is substantial. Most studies are limited by methodologic problems, such as case definition and the selection and recruitment of case-patients and controls.


A profile of the demographics and training characteristics of professional modern dancers.
Modern dancers are a unique group of artists, performing a diverse repertoire in dance companies of various sizes. In this study, 184 professional modern dancers in the United States (males N=49, females N=135), including members of large and small companies as well as freelance dancers, were surveyed regarding their demographics and training characteristics. The mean age of the dancers was 30.1 +/- 7.3 years, and they had danced professionally for 8.9 +/- 7.2 years. The average Body Mass Index (BMI) was 23.6 +/- 2.4 for males and 20.5 +/- 1.7 for females. Females had started taking dance class earlier (age 6.5 +/- 4.2 years) as compared to males (age 15.6 +/- 6.2 years). Females were more likely to have begun their training in ballet, while males more often began with modern classes (55% and 51% respectively, p < 0.0001). The professional modern dancers surveyed spent 8.3 +/- 6.0 hours in class and 17.2 +/- 12.6 hours in rehearsal each week. Eighty percent took modern technique class and 67% reported that they took ballet technique class. The dancers who specified what modern technique they studied (N=84) reported between two and four different techniques. The dancers also participated in a multitude of additional exercise regimens for a total of 8.2 +/- 6.6 hours per week, with the most common types being Pilates, yoga, and upper body weightlifting. The dancers wore many different types of footwear, depending on the style of dance being performed. For modern dance alone, dancers wore 12 different types of footwear. Reflecting the diversity of the dancers and companies surveyed, females reported performing for 23.3 +/- 14.0 weeks (range: 2-52 weeks) per year; males reported performing 20.4 +/- 13.9 weeks (range: 1-40) per year. Only 18% of the dancers did not have any health insurance, with 54% having some type of insurance provided by their employer. However, 23% of the dancers purchased their own insurance, and 22% had insurance provided by their families. Only 16% of dancers reported that they had Workers' Compensation coverage, despite the fact that they were all professionals, including many employed by major modern dance companies across the United States. It is concluded that understanding the training profile of the professional modern dancer should assist healthcare providers in supplying appropriate medical care for these performers.


PU.1 binding to ets motifs within the equine infectious anemia virus long terminal repeat (LTR) enhancer: regulation of LTR activity and virus replication in macrophages.
Binding of the transcription factor PU.1 to its DNA binding motif regulates the expression of a number of B-cell- and myeloid-specific genes. The long terminal repeat (LTR) of macrophage-tropic strains of equine infectious anemia virus (EIAV) contains three PU.1 binding sites, namely an invariant promoter-proximal site as well as two upstream sites. We have previously shown that these sites are important for EIAV LTR activity in primary macrophages (W. Maury, J. Virol. 68:6270-6279, 1994). Since the sequences present in these three binding motifs are not identical, we sought to determine the role of these three sites in EIAV LTR activity. While DNase I footprinting studies indicated that all three sites within the enhancer were bound by recombinant PU.1, reporter gene assays demonstrated that the middle motif was most important for basal levels of LTR activity in macrophages and that the 5' motif had little impact. The impact of the 3' site became evident in Tat transactivation studies, in which the loss of the site reduced Tat-transactivated expression 40-fold. In contrast, elimination of the 5' site had no effect on Tat-mediated activity. Binding studies were performed to determine whether differences in PU.1 binding affinity for the three sites correlated with the relative impact of each site on LTR transcription. While small differences were observed in the binding affinities of the three sites, with the promoter-proximal site having the strongest binding affinity, these differences could not account for the dramatic differences observed in the transcriptional effects. Instead, the promoter-proximal position of the 3' motif appeared to be critical for its transcriptional impact and suggested that the PU.1 sites may serve different roles depending upon the location of the sites within the enhancer. Infectivity studies demonstrated that an LTR containing an enhancer composed of the three PU.1 sites was not sufficient to drive viral replication in macrophages. These findings indicate that while the promoter-proximal PU.1 site is the most critical site for EIAV LTR activity in the presence of Tat, other elements within the enhancer are needed for EIAV replication in macrophages.


Roles of nonstructural polyproteins and cleavage products in regulating Sindbis virus RNA replication and transcription.
Using vaccinia virus to express Sindbis virus (SIN) nonstructural proteins (nsPs) and template RNAs, we showed previously that synthesis of all three viral RNAs occurred only during expression of either the entire nonstructural coding region or the polyprotein precursors P123 and P34. In this report, the vaccinia virus system was used to express cleavage-defective polyproteins and nsP4 proteins containing various N-terminal extensions to directly examine the roles of the P123 and P34 polyproteins in RNA replication. Replication and subgenomic mRNA transcription occurred during coexpression of P34 and P123 polyproteins in which cleavage was blocked at either or both of the 1/2 and 2/3 sites. For all cleavage-defective P123 polyproteins, however, the ratio of subgenomic to genomic RNA was decreased, suggesting that both the 1/2 and 2/3 cleavages are required for efficient subgenomic RNA transcription. These studies indicate that the uncleaved P123 polyprotein can function as a component of the viral replicase capable of synthesizing both plus- and minus-strand RNAs. In contrast, cleavage-defective P34 was unable to function in RNA replication, even in complementation experiments in which minus-strand RNAs were provided by nsP4. A P34 polyprotein whose cleavage site was not altered could only function in RNA replication in the presence of an active nsP2 protease. Although nsP4, the putative RNA polymerase, was capable of synthesizing only minus-strand RNAs during coexpression with P123, the addition of only 22 upstream residues to nsP4 allowed both replication and transcription of subgenomic RNA to occur. These data show that the conserved domains of both nsP3 and the nsP4 polymerase do not need to be present in a P34 polyprotein to form a functional plus-strand replicase-transcriptase and suggest that the presence of an active nsP2 protease and a cleavable 3/4 site correlates with synthesis of all virus-specific RNA species.


Gene expression profile changes in cotton root and hypocotyl tissues in response to infection with Fusarium oxysporum f. sp. vasinfectum.
Microarray analysis of large-scale temporal and tissue-specific plant gene expression changes occurring during a susceptible plant-pathogen interaction revealed different gene expression profile changes in cotton root and hypocotyl tissues. In hypocotyl tissues infected with Fusarium oxysporum f. sp. vasinfectum, increased expression of defense-related genes was observed, whereas few changes in the expression levels of defense-related genes were found in infected root tissues. In infected roots, more plant genes were repressed than were induced, especially at the earlier stages of infection. Although many known cotton defense responses were identified, including induction of pathogenesis-related genes and gossypol biosynthesis genes, potential new defense responses also were identified, such as the biosynthesis of lignans. Many of the stress-related gene responses were common to both tissues. The repression of drought-responsive proteins such as aquaporins in both roots and hypocotyls represents a previously unreported response of a host to pathogen attack that may be specific to vascular wilt diseases. Gene expression results implicated the phytohormones ethylene and auxin in the disease process. Biochemical analysis of hormone level changes supported this observation.


Native extracellular matrix/fibroin hydrogels for adipose tissue engineering with enhanced vascularization.
Adipose tissue engineering is a promising field for regeneration of soft tissue defects. However, vascularization is needed since nutrients and oxygen cannot reach cells in thick implants by diffusion. Obtaining a biocompatible scaffold with good mechanical properties is another problem. In this study, we aimed to develop thick and vascularized adipose tissue constructs supporting cell viability and adipose tissue regeneration. Hydrogels were prepared by mixing rat decellularized adipose tissue (DAT) and silk fibroin (Fib) at different v/v ratios (3:1, 1:1 and 1:3) and vortexing. Gelation times decreased with increasing fibroin ratio Among hydrogel groups 1:3-DAT:Fib ratio group showed similar mechanical properties with adipose tissue. Both pre-adipocytes and pre-endothelial cells, pre-differentiated from adipose derived stem cells (ASCs), were encapsulated in hydrogels at a 1: 3 ratio. In vitro analyses showed that hydrogels with 1:3 (v/v) DAT:Fib ratio supported better cell viability. Pre-adipocytes had lipid vesicles, and pre-endothelial cells formed tubular structures inside hydrogels only after 3 days in vitro. When endothelial and adipogenic pre-differentiated ASCs (for 7 days before encapsulation) were encapsulated together into 1:3-DAT:Fib hydrogels both cell types continued to differentiate into the committed cell lineage. Vascularization process in the hydrogels implanted with adipogenic and endothelial pre-differentiated ASCs took place between the first and second week after implantation which was faster than observed in the empty hydrogels. ASCs pre-differentiated towards adipogenic lineage inside hydrogels had begun to accumulate lipid vesicles after 1 week of subcutaneous implantation Based on these results, we suggest that 1:3-DAT:Fib hydrogels with enhanced vascularization hold promise for adipose tissue engineering.


Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia.
Stimulating angiogenesis by gene transfer approaches offers the hope of treating tissue ischemia which is untreatable by currently practiced techniques of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic molecules, making them ideal candidates for novel gene transfer protocols designed to promote new blood vessel growth. In this study, an ex vivo gene therapy approach utilizing cell encapsulation was employed to deliver VEGF and FGF-2 in a continuous and localized manner. C(2)C(12) myoblasts were genetically engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantation in vivo. Therapeutic efficacy was evaluated in a model of acute skin flap ischemia. Capsules were positioned under the distal, ischemic region of the flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing either form of VEGF had no effect on flap survival, but induced a modest increase in distal vascular supply. Delivery of FGF-2 significantly improved flap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization was significantly increased by FGF-2 (P < 0.01), with numerous vessels, many of which had a large lumen diameter, growing in the proximity of the implanted capsules. These results demonstrate that FGF-2, delivered from encapsulated cells, is more efficacious than either VEGF(121) or VEGF(165) in treating acute skin ischemia and improving skin flap survival. Furthermore, these data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia.


Age-associated telomere shortening in mouse oocytes.
Oocytes may undergo two types of aging. The first is induced by exposure to an aged ovarian microenvironment before being ovulated, known as 'reproductive or maternal aging', and the second by either a prolonged stay in the oviduct before fertilization or in vitro aging prior to insemination, known as 'postovulatory aging'. However, the molecular mechanisms underlying these aging processes remain to be elucidated. As telomere shortening in cultured somatic cells triggers replicative senescence, telomere shortening in oocytes during reproductive and postovulatory aging may predict developmental competence. This study aimed to ascertain the mechanisms underlying altered telomere biology in mouse oocytes during reproductive and postovulatory aging. We studied Tert expression patterns, telomerase activity, cytosolic reactive oxygen species (ROS) production, and telomere length in fresh oocytes from young versus reproductively-aged female mice retrieved from oviducts at 14 h post-human chorionic gonadotropin (hCG), in vivo or in vitro postovulatory-aged mouse oocytes at 23 h post-hCG. Oocytes were collected from super-ovulated C57BL/6 J mice of 6-8 weeks or 42-48 weeks of age. mRNA and protein expressions of the Tert gene were quantified using real-time quantitative reverse transcriptase polymerase chain reaction (Q-PCR) and immunochemistry. Telomerase activity was measured by a telomeric repeat amplification protocol assay, while telomere length was measured by Q-PCR and quantitative fluorescence in situ hybridization analyses. The abundance of Tert expression in oocytes significantly decreased during reproductive and postovulatory aging. Immunofluorescent staining clearly demonstrated an altered pattern and intensity of TERT protein expression in oocytes during reproductive aging. Furthermore, relative telomerase activity (RTA) in oocytes from reproductively-aged females was significantly lower than that in oocytes from young females. In contrast, RTA in postovulatory-aged oocytes was similar to that in fresh oocytes. Oocytes from reproductively-aged females and postovulatory-aged oocytes showed higher ROS levels than oocytes from young females. Relative telomere length (RTL) was remarkably shorter in oocytes from reproductively-aged females compared to oocytes from young females. However, postovulatory aging had no significant effect on RTL of oocytes. Long-term adverse effects of low telomerase activity and increased ROS exposure are likely associated with telomere shortening in oocytes from reproductively-aged female mice.


Simpson's paradox visualized: the example of the rosiglitazone meta-analysis.
Simpson's paradox is sometimes referred to in the areas of epidemiology and clinical research. It can also be found in meta-analysis of randomized clinical trials. However, though readers are able to recalculate examples from hypothetical as well as real data, they may have problems to easily figure where it emerges from. First, two kinds of plots are proposed to illustrate the phenomenon graphically, a scatter plot and a line graph. Subsequently, these can be overlaid, resulting in a overlay plot. The plots are applied to the recent large meta-analysis of adverse effects of rosiglitazone on myocardial infarction and to an example from the literature. A large set of meta-analyses is screened for further examples. As noted earlier by others, occurrence of Simpson's paradox in the meta-analytic setting, if present, is associated with imbalance of treatment arm size. This is well illustrated by the proposed plots. The rosiglitazone meta-analysis shows an effect reversion if all trials are pooled. In a sample of 157 meta-analyses, nine showed an effect reversion after pooling, though non-significant in all cases. The plots give insight on how the imbalance of trial arm size works as a confounder, thus producing Simpson's paradox. Readers can see why meta-analytic methods must be used and what is wrong with simple pooling.


Haemostatic drugs for traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of death and disability. Intracranial bleeding is a common complication of TBI, and intracranial bleeding can develop or worsen after hospital admission. Haemostatic drugs may reduce the occurrence or size of intracranial bleeds and consequently lower the morbidity and mortality associated with TBI. To assess the effects of haemostatic drugs on mortality, disability and thrombotic complications in patients with traumatic brain injury. We searched the electronic databases: Cochrane Injuries Group Specialised Register (3 February 2009), CENTRAL (The Cochrane Library 2009, Issue 1), MEDLINE (1950 to Week 3 2009), PubMed (searched 3 February 2009 (last 180 days)), EMBASE (1980 to Week 4 2009), CINAHL (1982 to January 2009), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to January 2009), ISI Web of Science: Conference Proceedings Citation Index - Science (CPCI-S) (1990 to January 2009). We included published and unpublished randomised controlled trials comparing haemostatic drugs (antifibrinolytics: aprotinin, tranexamic acid (TXA), aminocaproic acid or recombined activated factor VIIa (rFVIIa)) with placebo, no treatment, or other treatment in patients with acute traumatic brain injury. Two review authors independently examined all electronic records, and extracted the data. We judged that there was clinical heterogeneity between trials so we did not attempt to pool the results of the included trials. The results are reported separately. We included two trials. One was a post-hoc analysis of 30 TBI patients from a randomised controlled trial of rFVIIa in blunt trauma patients. The risk ratio for mortality at 30 days was 0.64 (95% CI 0.25 to 1.63) for rFVIIa compared to placebo. This result should be considered with caution as the subgroup analysis was not pre-specified for the trial. The other trial evaluated the effect of rFVIIa in 97 TBI patients with evidence of intracerebral bleeding in a computed tomography (CT) scan. The corresponding risk ratio for mortality at the last follow up was 1.08 (95% CI 0.44 to 2.68). The quality of the reporting of both trials was poor so it was difficult to assess the risk of bias. There is no reliable evidence from randomised controlled trials to support the effectiveness of haemostatic drugs in reducing mortality or disability in patients with TBI. New randomised controlled trials assessing the effects of haemostatic drugs in TBI patients should be conducted. These trials should be large enough to detect clinically plausible treatment effects.


LIM-homeobox gene Lhx5 is required for normal development of Cajal-Retzius cells.
Cajal-Retzius (C-R) cells play important roles in the lamination of the mammalian cortex via reelin secretion. The genetic mechanisms underlying the development of these neurons have just begun to be unraveled. Here, we show that two closely related LIM-homeobox genes Lhx1 and Lhx5 are expressed in reelin+ cells in various regions in the mouse telencephalon at or adjacent to sites where the C-R cells are generated, including the cortical hem, the mantle region of the septal/retrobulbar area, and the ventral pallium. Whereas Lhx5 is expressed in all of these reelin-expressing domains, Lhx1 is preferentially expressed in the septal area and in a continuous domain spanning from lateral olfactory region to caudomedial territories. Genetic ablation of Lhx5 results in decreased reelin+ and p73+ cells in the neocortical anlage, in the cortical hem, and in the septal, olfactory, and caudomedial telencephalic regions. The overall reduction in number of C-R cells in Lhx5 mutants is accompanied by formation of ectopic reelin+ cell clusters at the caudal telencephalon. Based on differential expression of molecular markers and by fluorescent cell tracing in cultured embryos, we located the origin of reelin+ ectopic cell clusters at the caudomedial telencephalic region. We also confirmed the existence of a normal migration stream of reelin+ cells from the caudomedial area to telencephalic olfactory territories in wild-type embryos. These results reveal a complex role for Lhx5 in regulating the development and normal distribution of C-R cells in the developing forebrain.


Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study.
To determine whether menopausal hormone therapy (HT) affects regional brain volumes, including hippocampal and frontal regions. Brain MRI scans were obtained in a subset of 1,403 women aged 71-89 years who participated in the Women's Health Initiative Memory Study (WHIMS). WHIMS was an ancillary study to the Women's Health Initiative, which consisted of two randomized, placebo-controlled trials: 0.625 mg conjugated equine estrogens (CEE) with or without 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet. Scans were performed, on average, 3.0 years post-trial for the CEE + MPA trial and 1.4 years post-trial for the CEE-Alone trial; average on-trial follow-up intervals were 4.0 years for CEE + MPA and 5.6 years for CEE-Alone. Total brain, ventricular, hippocampal, and frontal lobe volumes, adjusted for age, clinic site, estimated intracranial volume, and dementia risk factors, were the main outcome variables. Compared with placebo, covariate-adjusted mean frontal lobe volume was 2.37 cm(3) lower among women assigned to HT (p = 0.004), mean hippocampal volume was slightly (0.10 cm(3)) lower (p = 0.05), and differences in total brain volume approached significance (p = 0.07). Results were similar for CEE + MPA and CEE-Alone. HT-associated reductions in hippocampal volumes were greatest in women with the lowest baseline Modified Mini-Mental State Examination scores (scores <90). Conjugated equine estrogens with or without MPA are associated with greater brain atrophy among women aged 65 years and older; however, the adverse effects are most evident in women experiencing cognitive deficits before initiating hormone therapy.


Self-monitoring of blood glucose: language and financial barriers in a managed care population with diabetes.
Self-monitoring of blood glucose (SMBG) is a cornerstone of diabetes care, but little is known about barriers to this self-care practice. This cross-sectional study examines SMBG practice patterns and barriers in 44,181 adults with pharmacologically treated diabetes from the Kaiser Permanente Northern California Region who responded to a health survey (83% response rate). The primary outcome is self-reported frequency of SMBG. Although most patients reported some level of SMBG monitoring, 60% of those with type 1 diabetes and 67% of those with type 2 diabetes reported practicing SMBG less frequently than recommended by the American Diabetes Association (three to four times daily for type 1 diabetes, and once daily for type 2 diabetes treated pharmacologically). Significant independent predictors of nonadherent practice of SMBG included longer time since diagnosis, less intensive therapy, male sex, age, belonging to an ethnic minority, having a lower education and neighborhood income, difficulty communicating in English, higher out-of-pocket costs for glucometer strips (especially for subjects with lower incomes), smoking, and excessive alcohol consumption. Considerable gaps persist between actual and recommended SMBG practices in this large managed care organization. A somewhat reduced SMBG frequency in subjects with linguistic barriers, some ethnic minorities, and subjects with lower education levels suggests the potential for targeted, culturally sensitive, multilingual health education. The somewhat lower frequency of SMBG among subjects paying higher out-of-pocket expenditures for strips suggests that removal of financial barriers by providing more comprehensive coverage for these costs may enhance adherence to recommendations for SMBG.


Psoriasin (S100A7) expression is altered during skin tumorigenesis.
Psoriasin (S100A7) expression has previously been associated with psoriasiform hyperplasia as well as with tumor progression in breast cancer. Its expression profile for different stages of skin lesions is unknown. The aim of this study was to determine the relationship between psoriasin (S100A7) and tumor progression in skin. Psoriasin was assessed by immunohistochemistry and levels of expression determined by semi-quantitative scoring in skin biopsies from 50 patients. The cohort included normal skin, actinic keratosis, squamous carcinoma in-situ, invasive squamous cell carcinoma, and basal cell carcinoma. In normal skin, psoriasin was rarely detected in epidermis but was expressed in underlying adnexae. In abnormal epidermis psoriasin was frequently expressed in abnormal keratinocytes in actinic keratosis, in-situ and invasive squamous cell carcinoma, but was rarely observed in the basal epidermal layer or in superficial or invasive basal cell carcinoma. The highest levels of expression were seen within squamous carcinoma in-situ. Significantly reduced levels of expression were observed in both unmatched (p = 0.0001) and matched (p < 0.004) invasive squamous cell carcinoma. Psoriasin expression within abnormal squamous lesions correlated with mitotic count (r = 0.54, p = 0.0036), however no significant relation was found with the intensity of dermal inflammatory cell infiltrates assessed within each pathology. These results suggest that altered psoriasin expression occurs in abnormal epidermis and that downregulation may be related to the onset of invasion in squamous cell carcinoma in skin.


Intraspecific individual variation of temperature tolerance associated with oxygen demand in the European sea bass (Dicentrarchus labrax).
The European sea bass (Dicentrarchus labrax) is an economically important fish native to the Mediterranean and Northern Atlantic. Its complex life cycle involves many migrations through temperature gradients that affect the energetic demands of swimming. Previous studies have shown large intraspecific variation in swimming performance and temperature tolerance, which could include deleterious and advantageous traits under the evolutionary pressure of climate change. However, little is known of the underlying determinants of this individual variation. We investigated individual variation in temperature tolerance in 30 sea bass by exposing them to a warm temperature challenge test. The eight most temperature-tolerant and eight most temperature-sensitive fish were then studied further to determine maximal swimming speed (U CAT), aerobic scope and post-exercise oxygen consumption. Finally, ventricular contractility in each group was determined using isometric muscle preparations. The temperature-tolerant fish showed lower resting oxygen consumption rates, possessed larger hearts and initially recovered from exhaustive exercise faster than the temperature-sensitive fish. Thus, whole-animal temperature tolerance was associated with important performance traits. However, the temperature-tolerant fish also demonstrated poorer maximal swimming capacity (i.e. lower U CAT) than their temperature-sensitive counterparts, which may indicate a trade-off between temperature tolerance and swimming performance. Interestingly, the larger relative ventricular mass of the temperature-tolerant fish did not equate to greater ventricular contractility, suggesting that larger stroke volumes, rather than greater contractile strength, may be associated with thermal tolerance in this species.


Financial Risk Protection for Neurosurgical Care in Indonesia and the Philippines: A Primer on Health Financing for the Global Neurosurgeon.
Which conditions treated by neurosurgeons cause the worst economic hardship in low middle-income in countries? How can public health financing be responsive to the inequities in the delivery of neurosurgical care? This review article frames the objectives of equity, quality, and efficiency in health financing to the goals of global neurosurgery. In order to glean provider perspectives on the affordability of neurosurgical care in low-resource settings, we did a survey of neurosurgeons from Indonesia and the Philippines and identified that the care of socioeconomically disadvantaged patients with malignant intracranial tumors were found to incur the highest out-of-pocket expenses. Additionally, the surveyed neurosurgeons also observed that treatment of traumatic brain injury may have to require greater financial subsidies. It is therefore imperative to frame health financing alongside the goals of equity, efficiency, and quality of neurosurgical care for the impoverished. Using principles and perspectives from managerial economics and public health, we conceptualize an implementation framework that addresses both the supply and demand sides of healthcare provision as applied to neurosurgery. For the supply side, strategic purchasing enables a systematic and contractual management of payment arrangements that provide performance-based economic incentives for providers. For the demand side, conditional cash transfers similarly leverages on financial incentives on the part of patients to reward certain health-seeking behaviors that significantly influence clinical outcomes. These health financing strategies are formulated in order to ultimately build neurosurgical capacity in LMICs, improve access to care for patients, and ensure financial risk protection.


The impact of facecards on patients' knowledge, satisfaction, trust, and agreement with hospital physicians: a pilot study.
Simple interventions such as facecards can improve patients' knowledge of names and roles of hospital physicians, but the effect on other aspects of the patient-physician relationship is not clear. To pilot an intervention to improve familiarity with physicians and assess its potential to improve patients' satisfaction, trust, and agreement with physicians. Cluster randomized controlled trial assessing the impact of physician facecards. Physician facecards included pictures of physicians and descriptions of their roles. We performed structured interviews of randomly selected patients to assess outcomes. One of 2 similar hospitalist units and 1 of 2 teaching-service units in a large teaching hospital were randomly selected to implement the intervention. Satisfaction with physician communication and overall hospital care was assessed using the Hospital Consumer Assessment of Healthcare Providers and Systems. Trust and agreement were each assessed through instruments used in prior research. Overall, 138 patients completed interviews, with no differences in age, sex, or race between those receiving facecards and those not. More patients who received facecards correctly identified ≥1 hospital physician (89.1% vs 51.1%; P < 0.01) and their role (67.4% vs 16.3%; P < 0.01) than patients who had not received facecards. Patients had high baseline levels of satisfaction, trust, and agreement with hospital physicians, and we found no significant differences with the use of facecards. Physician facecards improved patients' knowledge of the names and roles of hospital physicians. Larger studies are needed to assess the impact on satisfaction, trust, and agreement with physicians.


Community management of schizophrenia. A two-year follow-up of a behavioural intervention with families.
The relapse and readmission rates of schizophrenic patients who participated in a controlled trial of a nine-month behavioural family intervention trial based on the EE status of their relatives are presented at two years. The patients who received the behavioural family intervention had lower rates of relapse and readmission than patients from high-EE homes who had received a short educational programme or routine treatment. The relapse rate of the behavioural family intervention group (33%) was the same as that of the low-EE group (33%), and significantly lower than that of the non-intervention high-EE group (59%).


Social factors associated with centenarian rate (CR) in 32 OECD countries.
Over the last fifty years, the number of centenarians has dramatically increased. The centenarian rate (CR) is representative of the general longevity prevalent in a nation; it indicates the number of individuals aged 100 years or above at a given date divided by the size of the corresponding cohort of a given age. Two important attributes of the CR (50-54) are that it reflects both unchanged age-specific fertility and the absence of migration in populations. It can generally be used in longevity-based evaluations of the broader concept of successful ageing. As such, this retrospective analysis of the social factors that contribute to the CR (50-54) may help to identify the factors associated with successful ageing.This study estimates the CR (50-54) and elucidates the influence of social factors on successful ageing and the CR (50-54), examining 32 member countries of the Organization for Economic Co-operation and Development (OECD). The social indicators for this study were obtained from the United Nations database. The data for the analysis of centenarians in the 32 OECD countries were obtained from the world population prospects conducted by the United Nations. Associations between social factors and CR (50-54) were assessed using Pearson correlation coefficients and regression models. Significant positive correlations were found between the CR (50-54) and the social factors of expenditure on health as a percentage of gross domestic product (HEGDP: r = 0.411, p < 0.021), general government expenditure on health as a percentage of total government expenditure (GGEH: r = 0.474, p < 0.006), the proportion of fixed-telephone subscriptions in the population (FTS: r = 0.489, p < 0.005), and the human development index (HDI: r = 0.486, p < 0.005). Finally, these CR (50-54) predictors were used to form a model of successful ageing, with higher HEGDP and GGEH as health expenditure, higher FTS as standard of living, and higher HDI as social well-being (R2 = 0.573, P < 0.025). The findings suggest that an increased CR (50-54) is affected by multiple social factors involved in successful ageing. Therefore, if they wish to improve their country's CR (50-54), governments must strengthen their existing support services for the elderly through making improvements to standards of living, social well-being and through increased financing of the health sector.