Ratio of trunk to leg volume as a new body shape metric for diabetes and mortality.
Body shape is a known risk factor for diabetes and mortality, but the methods estimating body shape, BMI and waist circumference are crude. We determined whether a novel body shape measure, trunk to leg volume ratio, was independently associated with diabetes and mortality. Data from the National Health and Nutritional Examination Survey 1999-2004, a study representative of the US population, were used to generate dual-energy X-ray absorptiometry-derived trunk to leg volume ratio and determine its associations to diabetes, metabolic covariates, and mortality by BMI category, gender, and race/ethnicity group. The prevalence of pre-diabetes and diabetes increased with age, BMI, triglycerides, blood pressure, and decreased HDL level. After adjusting for covariates, the corresponding fourth to first quartile trunk to leg volume ratio odds ratios (OR) were 6.8 (95% confidence interval [CI], 4.9-9.6) for diabetes, 3.9 (95% CI, 3.0-5.2) for high triglycerides, 1.8 (95% CI, 1.6-2.1) for high blood pressure, 3.0 (95% CI, 2.4-3.8) for low HDL, 3.6 (95% CI, 2.8-4.7) for metabolic syndrome, and 1.76 (95% CI, 1.20-2.60) for mortality. Additionally, trunk to leg volume ratio was the strongest independent measure associated with diabetes (P<0.001), even after adjusting for BMI and waist circumference. Even among those with normal BMI, those in the highest quartile of trunk to leg volume ratio had a higher likelihood of death (5.5%) than those in the lowest quartile (0.2%). Overall, trunk to leg volume ratio is driven by competing mechanisms of changing adiposity and lean mass. A high ratio of trunk to leg volume showed a strong association to diabetes and mortality that was independent of total and regional fat distributions. This novel body shape measure provides additional information regarding central adiposity and appendicular wasting to better stratify individuals at risk for diabetes and mortality, even among those with normal BMI.


Characterization of the human lymphocyte beta-adrenergic receptor by photoaffinity labeling. Alterations with desensitization.
Desensitization of the leukocyte beta-receptor system has been associated with a functional uncoupling of the components of the beta-receptor complex. In order to determine whether desensitization and uncoupling of the leukocyte beta-receptor is associated with any structural alterations in the beta-receptor, we studied labeling of lymphocytes using the photoactive beta-adrenergic antagonist p-azido-m-[125I]iodobenzylcarazolol. Labeled peptides were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and detected using autoradiographic techniques. In broken cell preparations, specific labeling was demonstrated in two major peptide bands: mol wt approximately equal to 68,000 and mol wt approximately equal to 55,000. Inhibition of photolabeling was stereospecific and demonstrated an order of potency for agonists consistent with labeling of a beta 2-receptor. Preincubation of cells with the beta-agonist, isoproterenol, resulted in a reduction in beta-adrenergic-mediated adenylate cyclase activity to 60% of control, but no change in total binding sites as determined by [125I]iodocyanopindolol binding. In photolabeling studies, desensitization was associated with a reduction in proportional labeling of the 55,000 mol wt band as compared to the 68,000 mol wt band to 58 +/- 3% of control and a reduction in mobility of the upper band. These studies suggest that structural alterations in the human lymphocyte beta-receptors occur with desensitization, analogous to changes in several other beta-receptor model systems. Also, since the techniques described can identify alterations in human beta-receptor structure, these methods may be exploited to determine whether structural alterations in lymphocyte beta-receptors may occur in human disease states.


Nogo-A inhibition induces recovery from neglect in rats.
Neglect is a complex human cognitive spatial disorder typically induced by damage to prefrontal or posterior parietal association cortices. Behavioral treatments for neglect rarely generalize outside of the therapeutic context or across tasks within the same therapeutic context. Recovery, when it occurs, is spontaneous over the course of weeks to months, but often it is incomplete. A number of studies have indicated that anti-Nogo-A antibodies can be used to enhance plasticity and behavioral recovery following damage to motor cortex, and spinal cord. In the present studies the anti-Nogo-A antibodies IN-1, 7B12, or 11C7 were applied intraventricularly to adult rats demonstrating severe neglect produced by unilateral medial agranular cortex lesions in rats. The three separate anti-Nogo-A antibody groups were treated immediately following the medial agranular cortex lesions. Each of the three antibodies induced dramatic significant behavioral recovery from neglect relative to controls. Severing the corpus callosum to destroy inputs from the contralesional hemisphere resulted in reinstatement of severe neglect, pointing to a possible role of interhemispheric mechanisms in behavioral recovery from neglect.


Liver parameters as part of a non-invasive model for prediction of all-cause mortality after myocardial infarction.
Liver parameters are associated with cardiovascular disease risk and severity of stenosis. It is unclear whether liver parameters could predict the long-term outcome of patients after acute myocardial infarction (AMI). We performed an unbiased analysis of the predictive value of serum parameters for long-term prognosis after AMI. In a retrospective, observational, single-center, cohort study, 569 patients after AMI were enrolled and followed up until 6 years for major adverse cardiovascular events, including cardiac death. Patients were classified into non-survivors (n = 156) and survivors (n = 413). Demographic and laboratory data were analyzed using ensemble feature selection (EFS) and logistic regression. Correlations were performed for serum parameters. Age (73; 64; p < 0.01), alanine aminotransferase (ALT; 93 U/l; 40 U/l; p < 0.01), aspartate aminotransferase (AST; 162 U/l; 66 U/l; p < 0.01), C-reactive protein (CRP; 4.7 U/l; 1.6 U/l; p < 0.01), creatinine (1.6; 1.3; p < 0.01), γ-glutamyltransferase (GGT; 71 U/l; 46 U/l; p < 0.01), urea (29.5; 20.5; p < 0.01), estimated glomerular filtration rate (eGFR; 49.6; 61.4; p < 0.01), troponin (13.3; 7.6; p < 0.01), myoglobin (639; 302; p < 0.01), and cardiovascular risk factors (hypercholesterolemia p < 0.02, family history p < 0.01, and smoking p < 0.01) differed significantly between non-survivors and survivors. Age, AST, CRP, eGFR, myoglobin, sodium, urea, creatinine, and troponin correlated significantly with death (r = -0.29; 0.14; 0.31; -0.27; 0.20; -0.13; 0.33; 0.24; 0.12). A prediction model was built including age, CRP, eGFR, myoglobin, and urea, achieving an AUROC of 77.6% to predict long-term survival after AMI. Non-invasive parameters, including liver and renal markers, can predict long-term outcome of patients after AMI.


Signal transduction and gene expression regulated by calcium release from internal stores in excitable cells.
Calcium regulation of several transcription factors involves different calcium-dependent signaling cascades and engages cytoplasmic as well as nuclear calcium signals. The study of the specific sources of calcium signals involved in regulation of gene expression in skeletal muscle has been addressed only recently. In this tissue, most cytoplasmic and nuclear calcium signals originate from calcium release from internal stores, mediated either by ryanodine receptor (RyR) or IP3 receptor (IP3R) channels. The latter are located both in the sarcoplasmic reticulum (SR) and in the nuclear membrane, and their activation results in long-lasting nuclear calcium increase. The calcium signals mediated by RyR and IP3R are very different in kinetics, amplitude and subcellular localization; an open question is whether these differences are differentially sensed by transcription factors. In neurons, it is well established that calcium entry through L-type calcium channels and NMDA receptors plays a role in the regulation of gene expression. Increasing evidence, however, points to a role for calcium release from intracellular stores in this process. In this article, we discuss how RyR-mediated calcium release contributes to the activation of the calcium-dependent transcription factor CREB and the subsequent LTP generation. We present novel results from our laboratory showing ERK-mediated CREB activation by hydrogen peroxide. This activation takes place in the absence of extracellular calcium and is blocked by inhibitory ryanodine concentrations, suggesting it is caused by redox activation of RyR-mediated calcium release.


The reliability of use of WhatsApp in type 1 and type 2 pediatric supracondylar fractures.
This study aims to evaluate the reliability of the assessment of radiological X-ray images of traumatic injuries in the elbows of children using WhatsApp application, compared to true-size images on a Picture Archiving and Communication System (PACS) screen. Between November 2017 and March 2018, X-ray images of a total of 90 pediatric patients (53 males, 37 females; mean age 6.2 years; range, 2 to 10 years) with an elbow injury were retrospectively evaluated. The images were captured and sent to three orthopedic surgeons via the WhatsApp instant messaging application on an iPhone 7S smartphone. Observers were asked to diagnose and classify for each case over their personal smartphones. The three observers independently assessed the images with a seven-day interval. Following one-week interval, revaluation was conducted using the PACS. Intra- and interobserver reliability were calculated by Cohen Kappa statistics. There was a good agreement between the first and second evaluations by the physicians via WhatsApp (k=0.74). The intraobserver reliability was very good (k=0.8), moderate (k=0.55), and good (k=0.67). There was no significant difference in the intra- and interobserver reliability between the groups. Using WhatsApp for consulting is a reliable method which can be used in the emergency setting for decision-making. Using WhatsApp can improve the efficacy of medical assessment and reduce waiting time in emergency admissions, although this method is not a substitution for evaluation of the images using computer-based PACS.


[Rheumatoid arthritis and atherosclerosis].
Evidence continue to accumulate indicating that patients with rheumatoid arthritis (RA) present an increased risk of cardiovascular disease (and death). The risk factors for coronary artery disease (CAD) in RA are not fully understood. However, a number of possible factors have been described, but more than one may be efficient, such as homocysteine, presence of antiphospholipid antibodies, altered serum levels of selected lipoproteins, and all together may have implications for the atherogenesis observed in these patients. Other factors that may facilitate this process, include corticosteroid use, methotrexate therapy and hormonal factors. However, the relative importance of these specific risk factors for the atherogenesis in this disease is poorly known. Recent findings indicate that cardiac death is increased in RA patients when compared with subjects without arthritis and that generally, the inflammatory process may contribute to atherosclerosis. In addition, other studies indicate that serum concentration of pro-inflammatory cytokines are found elevated at baseline, among patients at risk for future coronary occlusion.


High-efficiency aerosol scatterometer that uses an integrating sphere for the calibration of multiwavelength lidar data.
For the purpose of calibrating multiwavelength lidar data, we developed a scatterometer to measure the aerosol scattering coefficient at the ground level. The system is based on an integrating sphere, cw lasers (532 and 633 nm), and a controlled flow of the ambient air, including aerosol particles. The simulation study and experimental results indicate that the detection efficiency of this instrument is approximately 10%-40% better than that of an integrating nephelometer, because of the wider acceptance angle of the scattered light. The scattering coefficients measured at the two wavelengths, as well as the resulting value of the angstrom exponent, show good correlation with the results simultaneously measured with an integrating nephelometer and an optical particle counter.


Submentalizing: I Am Not Really Reading Your Mind.
The nativist view of mentalizing-the view that humans have an inherent capacity to think about the mental states of others-has been recently reinvigorated by reports that adults and infants automatically represent mental states-that they engage in implicit mentalizing. In this article, I take a close look at the strongest evidence of implicit mentalizing in adults, which suggests that people automatically represent what others see, intend, and believe. I argue that although these experiments have been ingeniously designed and carefully implemented, they do not provide evidence of implicit mentalizing because their results could be due instead to submentalizing-domain-general cognitive mechanisms that simulate the effects of mentalizing in social contexts. These include the processes that mediate involuntary attentional orienting, spatial coding of response locations, object-centered spatial coding of stimulus locations, retroactive interference, and distraction. If my analysis is correct, it suggests that the same domain-general processes can provide a fast and efficient alternative to mentalizing in everyday life, allowing people to navigate a wide range of social situations without thinking about mental states. Thus, submentalizing could be both a substrate and a substitute for mentalizing.


Medial and lateral gap laxity differential in computer-assisted kinematic total knee arthroplasty.
The results of kinematic total knee arthroplasty (KTKA) have been reported in terms of limb and component alignment parameters but not in terms of gap laxities and differentials. In kinematic alignment (KA), balance should reflect the asymmetrical balance of the normal knee, not the classic rectangular flexion and extension gaps sought with gap-balanced mechanical axis total knee arthroplasty (MATKA). This paper aims to address the following questions: 1) what factors determine coronal joint congruence as measured on standing radiographs?; 2) is flexion gap asymmetry produced with KA?; 3) does lateral flexion gap laxity affect outcomes?; 4) is lateral flexion gap laxity associated with lateral extension gap laxity?; and 5) can consistent ligament balance be produced without releases? A total of 192 KTKAs completed by a single surgeon using a computer-assisted technique were followed for a mean of 3.5 years (2 to 5). There were 116 male patients (60%) and 76 female patients (40%) with a mean age of 65 years (48 to 88). Outcome measures included intraoperative gap laxity measurements and component positions, as well as joint angles from postoperative three-foot standing radiographs. Patient-reported outcome measures (PROMs) were analyzed in terms of alignment and balance: EuroQol (EQ)-5D visual analogue scale (VAS), Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS Joint Replacement (JR), and Oxford Knee Score (OKS). Postoperative limb alignment did not affect outcomes. The standing hip-knee-ankle (HKA) angle was the sole positive predictor of the joint line convergence angle (JLCA) (p < 0.001). Increasing lateral flexion gap laxity was consistently associated with better outcomes. Lateral flexion gap laxity did not correlate with HKA angle, the JLCA, or lateral extension gap laxity. Minor releases were required in one third of cases. The standing HKA angle is the primary determinant of the JLCA in KTKA. A rectangular flexion gap is produced in only 11% of cases. Lateral flexion gap laxity is consistently associated with better outcomes and does not affect balance in extension. Minor releases are sometimes required as well, particularly in limbs with larger preoperative deformities. Cite this article: Bone Joint J 2019;101-B:331-339.


pfmdr1 amplification is related to increased Plasmodium falciparum in vitro sensitivity to the bisquinoline piperaquine.
The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC(50) and P = 0.002 for IC(90)) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.


Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance.
Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined a priori based on an extensive curation of the literature published during the last three decades, which led to the enumeration of 380 genes. No correlation was found between clinical samples and established cancer cell lines. As expected, we found up-regulation of genes that would facilitate survival across all cultured cancer cell lines evaluated. More troubling, however, were data showing that all of the cell lines, grown either in vitro or in vivo, bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples they are supposed to model. Although cultured cells can be used to study many aspects of cancer biology and response of cells to drugs, this study emphasizes the necessity for new in vitro cancer models and the use of primary tumor models in which gene expression can be manipulated and small molecules tested in a setting that more closely mimics the in vivo cancer microenvironment so as to avoid radical changes in gene expression profiles brought on by extended periods of cell culture.


Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver.
GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.


Falls Risk in Relation to Activity Exposure in High-Risk Older Adults.
Physical activity is linked to many positive health outcomes, stimulating the development of exercise programs. However, many falls occur while walking and so promoting activity might paradoxically increase fall rates, causing injuries, and worse quality of life. The relationship between activity exposure and fall rates remains unclear. We investigated the relationship between walking activity (exposure to risk) and fall rates before and after an exercise program (V-TIME). One hundred and nine older fallers, 38 fallers with mild cognitive impairment (MCI), and 128 fallers with Parkinson's disease (PD) were randomly assigned to one of two active interventions: treadmill training only or treadmill training combined with a virtual reality component. Participants were tested before and after the interventions. Free-living walking activity was characterized by volume, pattern, and variability of ambulatory bouts using an accelerometer positioned on the lower back for 1 week. To evaluate that relationship between fall risk and activity, a normalized index was determined expressing fall rates relative to activity exposure (FRA index), with higher scores indicating a higher risk of falls per steps taken. At baseline, the FRA index was higher for fallers with PD compared to those with MCI and older fallers. Walking activity did not change after the intervention for the groups but the FRA index decreased significantly for all groups (p ≤ .035). This work showed that V-TIME interventions reduced falls risk without concurrent change in walking activity. We recommend using the FRA index in future fall prevention studies to better understand the nature of intervention programs.


FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines.
One of the pathological hallmarks of Alzheimer's disease is the presence of insoluble extracellular amyloid plaques. These plaques are mainly constituted of amyloid beta peptide (A beta), a proteolytic product of amyloid precursor protein (APP). APP processing also generates the APP intracellular domain (AICD). We have previously demonstrated that AICD interacts with FKBP12, a peptidyl-prolyl cis-trans isomerase (PPIase) ubiquitous in nerve systems. This interaction was interfered by FK506, a clinically used immunosuppressant that has recently been reported to be neuroprotective. To elucidate the roles of FKBP12 in the pathogenesis of Alzheimer's disease, the effect of FKBP12 overexpression on APP processing was evaluated. Our results revealed that APP processing was shifted towards the amyloidogenic pathway, accompanied by a change in the subcellular localization of APP, upon FKBP12 overexpression. This FKBP12-overexpression-induced effect was reverted by FK506. These findings support our hypothesis that FKBP12 may participate in the regulation of APP processing. FKBP12 overexpression may lead to the stabilization of a certain isomer (presumably the cis form) of the Thr668-Pro669 peptide bond in AICD, therefore change its affinity to flotillin-1 or other raft-associated proteins, and eventually change the localization pattern and cause a shift in the proteolytic processing of APP.


Level of viral suppression and the cascade of HIV care in a South African semi-urban setting in 2012.
In 2012, 7 years after the introduction of antiretroviral treatment (ART) in the South African township of Orange Farm, we measured the proportion of HIV-positive people who were virally suppressed, especially among high-risk groups (women 18-29 years and men 25-34 years). A community-based cross-sectional representative survey was conducted among 3293 men and 3473 women. Study procedures included a face-to-face interview and collection of blood samples that were tested for HIV, 11 antiretroviral drugs and HIV-viral load. HIV prevalence was 17.0% [95% confidence interval: 15.7-18.3%] among men and 30.1% [28.5-31.6%] among women. Overall, 59.1% [57.4-60.8%] of men and 79.5% [78.2-80.9%] of women had previously been tested for HIV. When controlling for age, circumcised men were more likely to have been tested compared with uncircumcised men (66.1 vs 53.6%; P < 0.001). Among HIV+, 21.0% [17.7-24.6%] of men and 30.5% [27.7-33.3%] of women tested positive for one or more antiretroviral drugs. Using basic calculations, we estimated that, between 2005 and 2012, ART programs prevented between 46 and 63% of AIDS-related deaths in the community. Among antiretroviral-positive, 91.9% [88.7-94.3%] had viral suppression (viral load <400 copies/ml). The proportion of viral suppression among HIV+ was 27.0% [24.3-29.9%] among women and 17.5% [14.4-20.9%] among men. These proportions were lower among the high-risk groups: 15.6% [12.1-19.7%] among women and 8.4% [5.0-13.1%] among men. In Orange Farm, between 2005 and 2012, ART programs were suboptimal and, among those living with HIV, the proportion with viral suppression was still low, especially among the young age groups. However, our study showed that, in reality, antiretroviral drugs are highly effective in viral suppression at an individual level.


Extracellular vesicles as modulators of the cancer microenvironment.
The tumour microenvironment is a highly complex and dynamic tissue. It comprises not only neoplastic cells, but also other resident cells within the milieu such as stroma and vascular cells in addition to a variable cellular infiltrate from the periphery. A host of soluble factors such as growth factors, chemokines, eicosanoids soluble metabolites and extracellular matrix components have been extensively documented as factors which modulate this environment. However, in recent years there has also been growing interests in the potential roles of extracellular vesicles (EV) in many of the processes governing the nature of cancerous tissue. In this brief review, we have assembled evidence describing several distinct functions for extracellular vesicles in modulating the microenvironment with examples that include immune evasion, angiogenesis and stromal activation. Whilst there remains a great deal to be learnt about the interplay between vesicles and the cancerous environment, it is becoming clear that vesicle-mediated communication has a major influence on key aspects of cancer growth and progression. We conclude that the design of future therapeutics should acknowledge the existence and roles of extracellular vesicles, and seriously consider strategies for circumventing their effects in vivo.


High-resolution ultrasonography in the diagnosis and intraoperative management of peripheral nerve lesions.
The diagnosis of peripheral nerve lesions relies on clinical history, physical examination, electrodiagnostic studies, and radiography. Magnetic resonance neurography offers high-resolution visualization of structural peripheral nerve lesions. The availability of MR neurography may be limited, and the costs can be significant. By comparison, ultrasonography is a portable, dynamic, and economic technology. The authors explored the clinical applicability of high-resolution ultrasonography in the preoperative and intraoperative management of peripheral nerve lesions. The authors completed a retrospective analysis of 13 patients undergoing ultrasonographic evaluation and surgical treatment of nerve lesions at their institution (nerve entrapment [5], trauma [6], and tumor [2]). Ultrasonography was used for diagnostic (12 of 13 cases) and intraoperative management (6 of 13 cases). The authors examine the initial impact of ultrasonography on clinical management. Ultrasonography was an effective imaging modality that augmented electrophysiological and other neuroimaging studies. The modality provided immediate visualization of a sutured peroneal nerve after a basal cell excision, prompting urgent surgical exploration. Ultrasonography was used intraoperatively in 2 cases to identify postoperative neuromas after mastectomy, facilitating focused excision. Ultrasonography correctly diagnosed an inflamed lymph node in a patient in whom MR imaging studies had detected a schwannoma, and the modality correctly diagnosed a tendinopathy in another patient referred for ulnar neuropathy. Ultrasonography was used in 6 patients to guide the surgical approach and to aid in intraoperative localization; it was invaluable in localizing the proximal segment of a radial nerve sectioned by a humerus fracture. In all cases, ultrasonography demonstrated the correct lesion diagnosis and location (100%); in 7 (58%) of 12 cases, ultrasonography provided the correct diagnosis when other imaging and electrophysiological studies were inconclusive or inadequate. High-resolution ultrasonography may provide an economical and accurate imaging modality with utility in diagnosis and management of peripheral nerve lesions. Further research is required to assess the role of ultrasonography in evaluation of peripheral nerve pathology.


Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding.
Heavy menstrual bleeding is one of the most common reasons for referral of premenopausal women to a gynaecologist. Although medical therapy is generally first line, many women eventually will require further treatment. Endometrial ablation by hysteroscopic and more recent "second-generation" devices such as balloon, radiofrequency or microwave ablation offers a day-case surgical alternative to hysterectomy. Complete endometrial destruction is one of the main determinants of treatment success. Surgery is most effective if undertaken when endometrial thickness is less than four millimeters. One option is to perform the surgery in the immediate postmenstrual phase, which is not always practical. The other option is to use hormonal agents that induce endometrial thinning pre-operatively. The most commonly evaluated agents are goserelin (a gonadotrophin-releasing hormone analogue, or GnRHa) and danazol. Other GnRH analogues and progestogens have also been studied, although fewer data are available. It has been suggested that these agents will reduce operating time, improve the intrauterine operating environment and reduce absorption of fluid used for intraoperative uterine cavity distension. They may also improve long-term outcomes, including menstrual loss and dysmenorrhoea. To investigate the effectiveness and safety of pre-operative endometrial thinning agents (GnRH agonists, danazol, estrogen-progestins and progestogens) versus another agent or placebo when given before endometrial destruction in premenopausal women with heavy menstrual bleeding. The following electronic databases were searched to April 2013 for published and unpublished randomised controlled trials that met the inclusion criteria: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO.Other electronic sources of trials included trial registers for ongoing and registered trials; citation indexes; conference abstracts in the Web of Knowledge; the LILACS database for trials from the Portuguese- and Spanish-speaking world; PubMed; and the OpenSIGLE database and Google for grey literature.All searches were performed in consultation with the MDSG Trials Search Co-ordinator. Randomised controlled trials (RCTs) were included if they compared the effects of these agents with one other, or with placebo or no treatment, on relevant intraoperative and postoperative treatment outcomes. Selection of trials was carried out independently by two review authors. Two review authors independently assessed studies for risk of bias and extracted data on surgical outcomes, effectiveness outcomes, proportion of women requiring further surgical therapy during follow-up, endometrial outcome measures, acceptability of use outcomes and quality of life. Data were analysed on an intention-to-treat basis. Dichotomous data were combined for meta-analysis with RevMan software using the Mantel-Haenszel method to estimate pooled risk ratios (RRs). Continuous data were combined for meta-analysis with RevMan software using an inverse variance method to estimate the pooled mean difference (MD) with 95% confidence interval (CI). The overall quality of evidence for the main findings was assessed with the use of GRADE working group methods. Twenty studies with 1969 women were included in this review. These studies compared GnRHa, danazol and progestogens versus placebo or no treatment; GnRHa versus danazol, progestogens, GnRH antagonists or dilatation & curettage; and danazol versus progestogens. Four studies performed more than one comparison.When compared with no treatment, GnRHa used before hysteroscopic resection were associated with a higher rate of postoperative amenorrhoea at 12 months (RR 1.6, 95% CI 1.2 to 2.0, 7 RCTs, 605 women, moderate heterogeneity; I(2) = 40%) and at 24 months (RR 1.62, 95% CI 1.04 to 2.52, 2 RCTs, 357 women, no heterogeneity; I(2) = 0%), a slightly shorter duration of surgery (-3.5 minutes, 95% CI -4.7 to -2.3, 5 RCTs, 156 women, substantial heterogeneity; I(2) = 72%) and greater ease of surgery (RR 0.32, 95% CI 0.22 to 0.46, 2 RCTs, 415 women, low heterogeneity; I(2) = 4%). Postoperative dysmenorrhoea was reduced (RR 0.59, 95% CI 0.40 to 0.87, 2 RCTs, 133 women, no heterogeneity; I(2) = 0%). The use of GnRHa had no effect on intraoperative complication rates (RR 1.47, 95% CI 0.35 to 6.06, 5 RCTs, 592 women, no heterogeneity; I(2) = 0%), and participant satisfaction with this surgery was high irrespective of the use of pre-operative endometrial thinning agents (RR 0.99, 95% CI 0.93 to 1.05, 6 RCTs, 599 women, low heterogeneity; I(2) = 11%). GnRHa produced more consistent endometrial atrophy than was produced by danazol (RR 1.84, 95% CI 1.23 to 2.75, 2 RCTs, 142 women, no heterogeneity; I(2) = 0%). For other intraoperative and postoperative outcomes, any differences were minimal, and no benefits of GnRHa pretreatment were noted in studies in which women underwent second-generation ablation techniques. Both GnRHa and danazol produced side effects in a significant proportion of women, although few studies reported these in detail. Few randomised data were available to allow assessment of the effectiveness of progestogens as endometrial thinning agents. When reported, the long-term effects of endometrial thinning agents on benefits such as postoperative amenorrhoea were reduced with time.The main study weaknesses were that most participants received no follow-up beyond 24 months and that the studies used a small sample size. Heterogeneity for outcomes reported ranged from none to substantial. More than half the trials had no blinding of participants or outcome assessment. Most of the trials were determined to have uncertain selection and reporting bias, as they did not report allocation concealment and evidence of selective reporting was noted. The quality of reporting of adverse events was generally poor, but, when described in the studies, they included menopausal symptoms such as hot flushes, vaginal dryness, hirsutism, decreased libido and voice changes, as well as other side effects such as headache and weight gain. Low-quality evidence suggests that endometrial thinning with GnRHa and danazol before hysteroscopic surgery improves operating conditions and short-term postoperative outcomes. GnRHa produced slightly more consistent endometrial thinning than was produced by danazol, although both achieved satisfactory results. The effect of these agents on longer-term postoperative outcomes was reduced with time. No benefits of GnRHa pretreatment were apparent with second-generation ablation techniques. Also, side effects were more common when these agents were used.


Genomic organization, chromosomal mapping, and promoter analysis of the mouse dentin sialophosphoprotein (Dspp) gene, which codes for both dentin sialoprotein and dentin phosphoprotein.
Our laboratory has reported that two major noncollagenous dentin proteins, dentin sialoprotein and dentin phosphoprotein, are specific cleavage products of a larger precursor protein termed dentin sialophosphoprotein (MacDougall, M., Simmons, D., Luan, X., Nydegger, J., Feng, J. Q., and Gu, T. T. (1997) J. Biol. Chem. 272:835-842). To confirm our single gene hypothesis and initiate in vitro promoter studies, we have characterized the structural organization of the mouse dentin sialophosphoprotein gene. This gene has a transcription unit of approximately 9.4 kilobase pairs and is organized into 5 exons and 4 introns. Exon 1 contains a noncoding 5' sequence, and exon 2 contains the transcriptional start site, signal peptide, and first two amino acids of the NH2 terminus. Exons 3 and 4 contain coding information for 29 and 314 amino acids, respectively. The remainder of the coding information and the untranslated 3' region are contained in exon 5. Chromosomal mapping localized the gene to mouse chromosome 5q21 in close proximity to other dentin/bone matrix genes. Computer analysis of the promoter proximal 1.6-kilobase pair sequence revealed a number of potentially important cis-regulatory sequences; these include the recognition elements of AP-1, AP-2, Msx-1, serum response elements, SP-1, and TCF-1. In vitro studies showed that the DSPP promoter is active in an odontoblast cell line, MO6-G3, with basal activity mapped to -95 bp. Two potential enhancer and suppresser elements were identified in the regions between -1447 and -791 bp and -791 and -95 bp, respectively. The structural organization of the dentin sialophosphoprotein gene confirms our finding that both dentin sialoprotein and dentin phosphoprotein are encoded by a single gene with a continuous open reading frame.


What does S-palmitoylation do to membrane proteins?
S-palmitoylation is post-translational modification, which consists in the addition of a C16 acyl chain to cytosolic cysteines and which is unique amongst lipid modifications in that it is reversible. It can thus, like phosphorylation or ubiquitination, act as a switch. While palmitoylation of soluble proteins allows them to interact with membranes, the consequences of palmitoylation for transmembrane proteins are more enigmatic. We briefly review the current knowledge regarding the enzymes responsible for palmitate addition and removal. We then describe various observed consequences of membrane protein palmitoylation. We propose that the direct effects of palmitoylation on transmembrane proteins, however, might be limited to four non-mutually exclusive mechanistic consequences: alterations in the conformation of transmembrane domains, association with specific membrane domains, controlled interactions with other proteins and controlled interplay with other post-translational modifications.


Sex-Specific Selection and Sex-Biased Gene Expression in Humans and Flies.
Sexual dimorphism results from sex-biased gene expression, which evolves when selection acts differently on males and females. While there is an intimate connection between sex-biased gene expression and sex-specific selection, few empirical studies have studied this relationship directly. Here we compare the two on a genome-wide scale in humans and flies. We find a distinctive "Twin Peaks" pattern in humans that relates the strength of sex-specific selection, quantified by genetic divergence between male and female adults at autosomal loci, to the degree of sex-biased expression. Genes with intermediate degrees of sex-biased expression show evidence of ongoing sex-specific selection, while genes with either little or completely sex-biased expression do not. This pattern apparently results from differential viability selection in males and females acting in the current generation. The Twin Peaks pattern is also found in Drosophila using a different measure of sex-specific selection acting on fertility. We develop a simple model that successfully recapitulates the Twin Peaks. Our results suggest that many genes with intermediate sex-biased expression experience ongoing sex-specific selection in humans and flies.


A simplified echocardiographic technique for detecting continuous-flow left ventricular assist device malfunction due to pump thrombosis.
Malfunction of a continuous-flow left ventricular assist device (CF-LVAD) due to device thrombosis is a potentially life-threatening event that currently presents a diagnostic challenge. We aimed to propose a practical echocardiographic assessment to diagnose LVAD malfunction secondary to pump thrombosis. Among 52 patients implanted with a CF-LVAD from a single center who underwent echocardiographic pump speed-change testing, 12 had suspected pump thrombosis as determined by clinical, laboratory, and/or device parameters. Comprehensive echocardiographic evaluation was performed at baseline pump speed and at each 1,000-rpm interval from the low setting of 8,000 rpm to the high setting of 11,000 rpm in 11 of these patients. Receiver operating characteristic curves and stepwise logistic regression analyses showed that the best diagnostic parameters included changes in the LV end-diastolic diameter (<0.6 cm), aortic valve opening time (<80 msec), and deceleration time of mitral inflow (<70 msec) from lowest to highest pump speed. One parameter was predictive of pump malfunction, with 100% sensitivity and 89% specificity, whereas 2 of 3 parameters increased the sensitivity to 100% and specificity to 95%. The 3 echocardiographic variables of measured changes in LV end-diastolic diameter, aortic valve opening time, and deceleration time of mitral inflow between the lowest (8,000 rpm) and highest pump speed settings (11,000 rpm) during echo-guided pump speed-change testing appear highly accurate in diagnosing device malfunction in the setting of pump thrombosis among patients supported with CF-LVAD. Further investigation is warranted to create and validate a prediction score.


A continuous mental task decreases the physiological response to soccer-specific intermittent exercise.
Epidemiological findings of higher injury incidence during the latter stages of soccer match-play have been attributed to fatigue. To examine the interaction of physical and cognitive responses during soccer-specific intermittent exercise. Ten semi-professional soccer players completed a 90-minute laboratory-based treadmill protocol replicating the activity profile of soccer match-play. Two separate trials were performed in randomised order, with and without the added stressor of a continuous grid-based vigilance task. The exercise task comprised six repetitions of a 15 minute activity profile, separated by a passive 15 minute half-time interval. The vigilance task required continual attention and sporadic target response within a letter grid. Physical response (RPE, heart rate, blood lactate, salivary cortisol) and cognitive performance (response time, response accuracy) were quantified at 15 minute intervals. Completing the exercise task with the vigilance task resulted in decreased physiological (heart rate, blood lactate) response. This may be attributed to externally directed attention, resulting in association with the cognitive task and subsequent dissociation from the physical effort. Response speed generally improved with exercise duration, while there was evidence of impaired accuracy in the early stages of the first half and the latter stages of the second half. The interaction of physical and mental work was not additive in nature. The mental task had a masking effect on the physical response. Performing physical exercise tasks without due regard for appropriate psychological stimuli may therefore overestimate the physiological response.


Low-level light therapy of the eye and brain.
Low-level light therapy (LLLT) using red to near-infrared light energy has gained attention in recent years as a new scientific approach with therapeutic applications in ophthalmology, neurology, and psychiatry. The ongoing therapeutic revolution spearheaded by LLLT is largely propelled by progress in the basic science fields of photobiology and bioenergetics. This paper describes the mechanisms of action of LLLT at the molecular, cellular, and nervous tissue levels. Photoneuromodulation of cytochrome oxidase activity is the most important primary mechanism of action of LLLT. Cytochrome oxidase is the primary photoacceptor of light in the red to near-infrared region of the electromagnetic spectrum. It is also a key mitochondrial enzyme for cellular bioenergetics, especially for nerve cells in the retina and the brain. Evidence shows that LLLT can secondarily enhance neural metabolism by regulating mitochondrial function, intraneuronal signaling systems, and redox states. Current knowledge about LLLT dosimetry relevant for its hormetic effects on nervous tissue, including noninvasive in vivo retinal and transcranial effects, is also presented. Recent research is reviewed that supports LLLT potential benefits in retinal disease, stroke, neurotrauma, neurodegeneration, and memory and mood disorders. Since mitochondrial dysfunction plays a key role in neurodegeneration, LLLT has potential significant applications against retinal and brain damage by counteracting the consequences of mitochondrial failure. Upon transcranial delivery in vivo, LLLT induces brain metabolic and antioxidant beneficial effects, as measured by increases in cytochrome oxidase and superoxide dismutase activities. Increases in cerebral blood flow and cognitive functions induced by LLLT have also been observed in humans. Importantly, LLLT given at energy densities that exert beneficial effects does not induce adverse effects. This highlights the value of LLLT as a novel paradigm to treat visual, neurological, and psychological conditions, and supports that neuronal energy metabolism could constitute a major target for neurotherapeutics of the eye and brain.


p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer.
Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.


Development of genome-wide InDel markers and their integration with SSR, DArT and SNP markers in single barley map.
Development of molecular markers such as SSR (simple sequence repeat), DArT (diversity arrays technology) and SNP (single nucleotide polymorphism) is fundamental for linkage map construction and QTL mapping. However, DArT and SNP genotyping require special tools, and detection of SSR polymorphisms requires time-consuming polyacrylamide electrophoresis. Furthermore, many markers have been mapped in different populations such that their genetic positions are inconsistent. Recently, InDel (insertion and deletion) markers have become popular in genetic map construction and map-based cloning. Aligning genomic DNA sequences in two barley cultivars (Morex and Barke) identified 436,640 InDels. We designed 1140 InDel markers across the barley genome with an average genetic distance of 1 cM, each having a unique location in the barley genome. High-resolution melting (HRM) technology was used to genotype 55 InDel markers; those PCR amplicons with melting temperature differences >0.3 °C were ideal for HRM genotyping. The 1140 InDel markers together with 383 SSRs, 3909 gene-based SNPs and 1544 DArT markers were integrated into single barley genetic map according to their physical map positions. High-density InDel markers with specific genome locations were developed, with 6976 molecular markers (SSRs, DArTs, SNPs and InDels) integrated into single barley genetic map. HRM genotyping of the InDel markers each with single PCR band will facilitate quick map construction and gene fine-mapping.


Glucose-dependent partitioning of arginine to the urea cycle protects β-cells from inflammation.
Chronic inflammation is linked to diverse disease processes, but the intrinsic mechanisms that determine cellular sensitivity to inflammation are incompletely understood. Here, we show the contribution of glucose metabolism to inflammation-induced changes in the survival of pancreatic islet β-cells. Using metabolomic, biochemical and functional analyses, we investigate the protective versus non-protective effects of glucose in the presence of pro-inflammatory cytokines. When protective, glucose metabolism augments anaplerotic input into the TCA cycle via pyruvate carboxylase (PC) activity, leading to increased aspartate levels. This metabolic mechanism supports the argininosuccinate shunt, which fuels ureagenesis from arginine and conversely diminishes arginine utilization for production of nitric oxide (NO), a chief mediator of inflammatory cytotoxicity. Activation of the PC-urea cycle axis is sufficient to suppress NO synthesis and shield cells from death in the context of inflammation and other stress paradigms. Overall, these studies uncover a previously unappreciated link between glucose metabolism and arginine-utilizing pathways via PC-directed ureagenesis as a protective mechanism.


Anhydrous ammonia injuries.
Anhydrous ammonia, a pungent, colorless gas or liquid, is commonly used around the world as a refrigerant and fertilizer in agriculture. It is an alkali causing liquefaction or freeze-dry lesions with skin contact. Initial emergency response involves evacuation, decontamination, first aid and alerting proper authorities. Decontamination must be complete and rescuers must avoid being overcome by fumes. Emergency department care is directed at respiratory, ocular, skin and gastrointestinal treatment. Respiratory and ocular lesions tend to be the most severe and can be used as a triage guide. The need for a multidisciplinary approach to hospital care is stressed. In severe exposures, adult respiratory distress syndrome is a common finding. In children who have ingested aqua ammonia, early endoscopy, aggressive antibiotic therapy and serial dilatations of strictures are recommended. Long-term complications occur predominately to the eyes and respiratory tract.


Driving superfluidity with photoassociation.
We theoretically examine photoassociation of a two-component Fermi degenerate gas. Our focus is on adjusting the atom-atom interaction, and thereby increasing the critical temperature of the BCS transition to the superfluid state. In order to avoid spontaneous decay of the molecules, the photoassociating light must be far-off resonance. Very high light intensities are therefore required for effective control of the BCS transition.


Antibacterial and Biocompatible Titanium-Copper Oxide Coating May Be a Potential Strategy to Reduce Periprosthetic Infection: An In Vitro Study.
Periprosthetic infections are devastating for patients and more efficacious preventive strategies are needed. Surface-modified implants using antibacterial coatings represent an option to cope with this problem; however, manufacturing limitations and cytotoxicity have curbed clinical translation. Among metals with antibacterial properties, copper has shown superior in vitro antibacterial performance while maintaining an acceptable cytotoxicity profile. A thin film containing copper could prevent early biofilm formation to limit periprosthetic infections. This pilot study presents the in vitro antibacterial effect, cytotoxicity, and copper ion elution pattern of a thin film of titanium-copper oxide (TiCuO). (1) Do titanium alloy (Ti6Al4V) discs coated with a thin film of TiCuO reduce Staphylococcus epidermidis biofilm and planktonic cell density compared with uncoated discs? (2) Do Ti6Al4V discs coated with a thin film of TiCuO affect normal human osteoblast viability compared with untreated cells? (3) Is copper ion concentration generated by coated discs lower than previously published copper ion concentrations that cause 50% toxicity in similar human cell lines in vitro (TC50)? Ninety Ti6Al4V discs (12.5 mm diameter; 1.25 mm thick) were used in this study. Seventy-two Ti6Al4V discs were coated with a thin film of either titanium oxide (TiO) or TiCuO containing 20%, 40%, or 80% copper using high-power impulse magnetron sputtering (HiPIMS). Eighteen Ti6Al4V discs remained uncoated for control purposes. We tested antibacterial properties of S epidermidis grown on discs in wells containing growth medium. After 24 hours, planktonic bacteria as well as biofilms removed by sonication were quantitatively cultured. Annexin/Pi staining was used to quantify in vitro normal human osteoblast cell viability at 24 hours and Day 7, respectively. Copper elution was measured at Days 1, 2, 3, 7, 14, and 28 using an inductively coupled plasma mass spectrometer to analyze aliquots of culture medium. Copper ion concentration achieved at 24 hours was compared with previously published TC50 for gingival fibroblast, a phenotypically similar cell line with available data regarding copper ion exposure. Discs coated with TiCuO 80% copper showed greater biofilm and planktonic cell density reduction when compared with other tested compositions (analysis of variance [ANOVA]; p < 0.001). Discs coated with TiCuO 80% copper showed mean biofilm and planktonic cell density of 4.0 log10 (SD = 0.4) and 5.7 log10 (SD = 0.2). Discs coated with TiCuO 80% showed a mean difference in biofilm and planktonic cell density of 2.5 log10 (95% confidence interval [CI], 1.9-3.1 log10; p < 0.001) and 1.2 (95% CI, 0.6-1.8; p < 0.001), respectively, when compared with uncoated discs. Normal human osteoblast viability did not differ among all groups at 24 hours (ANOVA; p = 0.2) and Day 7 (ANOVA; p = 0.7). Discs coated with TiCuO 80% copper showed a mean difference (95% CI) in relative cell viability (%) at 24 hours and Day 7 of 31.1 (95% CI, -19.4 to 81.7; p = 0.4) and -5.0 (95% CI, -7.8 to 17.9; p = 0.9), respectively, when compared with untreated cells. For all TiCuO-coated discs, copper ion elution peaked at 24 hours and slowly decreased in a curvilinear fashion to nearly undetectable levels by Day 28. Discs coated with TiCuO 80% copper showed mean copper ion concentration at 24 hours of 269.4 µmol/L (SD = 25.2 µmol/L) and this concentration was lower than previously published TC50 for similar human cell lines at 24 hours (344 µmol/L, SEM = 44 µmol/L). This pilot study demonstrates a proof of concept that a thin-film implant coating with TiCuO can provide a potent local antibacterial environment while remaining relatively nontoxic to a human osteoblast cell line. Further research in an animal model will be necessary to establish efficacy and safety of this technique and whether it might be useful in the design of implants. A thin film coating with TiCuO demonstrates high antibacterial activity and low cellular cytotoxicity to human osteoblasts in vitro. Taken together, these properties represent a potential strategy for preventing periprosthetic infection if further work in animal models can confirm these results in vivo.


Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic.
Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1alpha) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV- individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1alpha, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1alpha, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.


Culling recolonizing mesopredators increases livestock losses: Evidence from the South African Karoo.
Populations of adaptable mesopredators are expanding globally where passive rewilding and natural recolonization are taking place, increasing the risk of conflict with remaining livestock farmers. We analysed data from two social surveys of farmers in the Karoo, South Africa, where black-backed jackals (Canis mesomelas) and caracals (Caracal caracal) have re-emerged as a threat to sheep farms in the context of falling agricultural employment and the expansion of natural areas. We show that irrespective of measurement approach, lethal control of mesopredators in this fragmented socio-economic landscape was associated with increased livestock losses the following year. Terrain ruggedness was positively, and number of farmworkers negatively, associated with livestock losses. Our study provides further evidence that lethal control of mesopredators in this context is probably counter-productive and supports calls to develop, share and financially support a range of non-lethal methods to protect livestock, especially where natural recolonization of mesopredators is occurring. A graphical abstract can be found in Electronic supplementary material.


Extracranial internal carotid artery calcium volume measurement using computer tomography.
The extent of calcium volume in the carotid arteries of contrast-based computer tomography (CT) is a valuable indicator of stroke risk. This study presents an automated, simple and fast calcium volume computation system. Since the high contrast agent can sometimes obscure the presence of calcium in the CT slices, it is therefore necessary to identify these slices before the corrected volume can be estimated. The system typically consists of segmenting the calcium region from the CT scan into slices based on Hounsfield Unit-based threshold, and subsequently computing the summation of the calcium areas in each slice. However, when the carotid volume has intermittently higher concentration of contrast agent, a dependable approach is adapted to correct the calcium region using the neighboring slices, thereby estimating the correct volume. Furthermore, mitigation is provided following the regulatory constraints by changing the system to semi-automated criteria as a fall back solution. We evaluate the automated and semi-automated techniques using completely manual calcium volumes computed based on the manual tracings by the neuroradiologist. A total of 64 patients with calcified plaque in the internal carotid artery were analyzed. Using the above algorithm, our automated and semi-automated system yields correlation coefficients (CC) of 0.89 and 0.96 against first manual readings and 0.90 and 0.96 against second manual readings, respectively. Using the t-test, there was no significant difference between the automated and semi-automated methods against manual. The intra-observer reliability was excellent with CC 0.98. Compared to automated method, the semi-automated method for calcium volume is acceptable and closer to manual strategy for calcium volume. Further work evaluating and confirming the performance of our semi-automated protocol is now warranted.


A review of medical and allied health learners' satisfaction with their training in women's health.
Graduating learners from Oregon Health and Sciences University programs and from the National College of Naturopathic Medicine were surveyed about their attitudes toward their training in women's health. The survey addressed learner satisfaction with training in women's health, their preferred learning methods, and their clinical comfort in managing 17 clinical problems. The survey addressed knowledge of complementary and alternative medicine. Satisfaction with training in women's health varied by program. Satisfaction increased with increasing proportion of women seen during training. Clinical confidence scores increased with increasing proportion of women seen during training. Physical assault and breast disease were areas of least clinical confidence. All groups preferred learning in clinical rather than didactic settings. Experience with alternative and complementary medicine was very limited except among naturopathic students. Areas of common educational need were identified among a variety of learners. This information will assist educators in designing multidisciplinary programs to meet the needs of this diverse group.


Toxicological effects of patulin mycotoxin on the mammalian system: an overview.
The mycotoxin PAT (4-hydroxy-4H-furo[3,2c]pyran-2[6H]-one) is a secondary metabolic product of molds such as Penicillium, Aspergillus, and Byssochlamys species. PAT is a common contaminant of fruit and vegetable based products, most notably apples. Despite PAT's original discovery as an antibiotic, it has come under heavy scrutiny for its potential to impart negative health effects. Studies investigating these health effects have proved its toxic potential. PAT occurrence in the food commodities poses a serious threat and necessitates novel and cost-effective mitigation methods to remove it from food products. It also creates a demand to improve handling and food processing techniques. With this being the case, several studies have been devoted to understanding the key biological and chemical attributes of PAT. While past research has elucidated a great deal, PAT contamination continues to be a challenge for the food industry. Here, we review its influence within the mammalian system, including its regulation, incidences of experimental evidence of PAT toxicity, its interaction with intracellular components, and the effects of PAT induced systemic toxicity on vital organs. Finally, key areas where future PAT research should focus to best control the PAT contamination problem within the food industry have been addressed.


Proton MRS and neuropsychological correlates in AIDS dementia complex: evidence of subcortical specificity.
Few studies have described the metabolic substrates underlying neuropsychological performance in HIV infection or examined the specificity of these relationships. The authors performed magnetic resonance spectroscopic and neuropsychological evaluations on 61 patients with AIDS dementia complex (stages 1-3) and 39 HIV-positive neurologically asymptomatic individuals. N-acetylaspartate, a marker of mature neurons, choline and myoinositol, both markers of gliosis, and creatine, a reference marker, were measured in the basal ganglia, frontal white matter, and parietal cortex. The neuropsychological evaluation consisted of tests that measured gross and fine motor skills, psychomotor function, information processing speed, and verbal memory. The authors examined performance on individual subtests and an aggregate Z score based on eight subtests (NPZ-8), adjusted for age and education. The NPZ-8 was significantly higher in subjects with greater N-acetylaspartate/creatine in the frontal white matter and was lower in subjects with higher myoinositol/creatine in the basal ganglia. Particularly strong associations were found between measures of gross and fine motor function, which correlated positively with N-acetylaspartate/creatine in the frontal white matter and negatively with myoinositol/creatine in the basal ganglia. Similarly, cognitive processing speed was negatively correlated with myoinositol/creatine in the basal ganglia. In contrast, there were no statistically significant relationships between brain metabolite levels in the parietal cortex and neuropsychological function. This study provides convincing evidence that neuropsychological impairment is associated with reduced markers of mature neurons and increased markers of gliosis in the basal ganglia and frontal white matter. Neural changes as reflected by these metabolite levels may prove useful in identifying individuals at risk for neuropsychological impairment. Prospective studies are needed to elucidate the evolution of these changes in the setting of antiretroviral therapy.


The effects of intraoperative hypothermia and cardiopulmonary bypass on trace metals and their protein binding ratios.
The ability of intraoperative hypothermia to modify the metabolic response to cardiopulmonary bypass (CPB) was assessed by serial alterations in iron, zinc and copper, and in their molar binding ratios to their respective transport proteins, in 20 male patients under-going elective coronary artery surgery and randomised to an operative blood temperature of 28 degrees C or 20 degrees C. Decreases in serum iron and zinc concentrations, typical of the acute phase response, were preceded by early rises. Significant alterations in the metal: protein molar binding ratios preceded significant changes in the serum concentrations of the metals and occurred earliest in the zinc: albumin binding ratio, which was apparent by the time of skin incision. An intraoperative temperature of 20 degrees C modified iron and zinc concentrations and their protein binding ratios during surgery but not in the post-operative period. These early changes in trace metals and their protein binding ratios are a simple and inexpensive method of quantitating the response to surgical injury and may be useful in assessing new interventions in cardiopulmonary bypass. An awareness of the trace element response to surgical injury is essential to avoid misdiagnoses of iron deficiency anaemia or zinc deficiency.


Genomics of lymphoid malignancies reveal major activation pathways in lymphocytes.
Breakdown of tolerance leads to autoimmunity due to emergence of autoreactive T or B cell clones. Autoimmune diseases predispose to lymphoid malignancies and lymphoid malignancies, conversely, can manifest as autoimmune diseases. While it has been clear for a long time that a competitive advantage and uncontrolled growth of lymphocytes contribute to the pathogenesis of both lymphoid malignancies as well as autoimmune diseases, the overlap of the underlying mechanisms has been less well described. Next generation sequencing has led to massive expansion of the available genomic data in many diseases over the last five years. These data allow for comparison of the molecular pathogenesis between autoimmune diseases and lymphoid malignancies. Here, we review the similarities between autoimmune diseases and lymphoid malignancies: 1) Both, autoimmune diseases and lymphoid malignancies are characterized by activation of the same T and B cell signaling pathways, and dysregulation of these pathways can occur through genetic or epigenetic events. 2) In both scenarios, clonal and subclonal evolution of lymphocytes contribute to disease. 3) Development of both diseases not only depends on T or B cell intrinsic factors, such as germline or somatic mutations, but also on environmental factors. These include infections, the presence of other immune cells in the microenvironment, and the cytokine milieu. A better mechanistic understanding of the parallels between lymphomagenesis and autoimmunity may help the development of precision treatment strategies with rationally designed therapeutic agents.


Acquisition of automatic imitation is sensitive to sensorimotor contingency.
The associative sequence learning model proposes that the development of the mirror system depends on the same mechanisms of associative learning that mediate Pavlovian and instrumental conditioning. To test this model, two experiments used the reduction of automatic imitation through incompatible sensorimotor training to assess whether mirror system plasticity is sensitive to contingency (i.e., the extent to which activation of one representation predicts activation of another). In Experiment 1, residual automatic imitation was measured following incompatible training in which the action stimulus was a perfect predictor of the response (contingent) or not at all predictive of the response (noncontingent). A contingency effect was observed: There was less automatic imitation indicative of more learning in the contingent group. Experiment 2 replicated this contingency effect and showed that, as predicted by associative learning theory, it can be abolished by signaling trials in which the response occurs in the absence of an action stimulus. These findings support the view that mirror system development depends on associative learning and indicate that this learning is not purely Hebbian. If this is correct, associative learning theory could be used to explain, predict, and intervene in mirror system development.


Serum cholecystokinin concentrations in dogs with naturally acquired pituitary-dependent hyperadrenocorticism.
OBJECTIVE To determine serum cholecystokinin (CCK) concentrations in dogs with pituitary-dependent hyperadrenocorticism (PDH) and to evaluate associations among CCK concentration, PDH, and gallbladder mucocele (GBM). ANIMALS 14 client-owned dogs with PDH and 14 healthy dogs. PROCEDURES Dogs were separated into 4 groups: healthy dogs without gallbladder sludge (group A; n = 7), healthy dogs with gallbladder sludge (group B; 7), dogs with PDH and gallbladder sludge (group C; 8), and dogs with PDH and GBM (group D; 6). Serum CCK concentrations were then measured before and 1, 2, and 4 hours after consumption of a high-fat meal. Concentrations in dogs with PDH were also measured before and after trilostane treatment. Results were compared among groups and assessment points. RESULTS Preprandial serum CCK concentrations in group C were significantly lower than those in groups A, B, and D, but no significant differences in postprandial CCK concentrations were identified among the groups 1, 2, or 4 hours after the meal. With respect to trilostane treatment of dogs with PDH, no significant differences were identified between pre- and post-trilostane serum CCK concentrations in group C or D. Median CCK concentration after trilostane treatment was higher in group D than in group C, but this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE The outcomes in this study did not support the hypothesis that a low circulating CCK concentration affects the development of GBM in dogs with PDH.


Full-Lung Prophylaxis against SARS-CoV-2 by One-Shot or Booster Intranasal Lentiviral Vaccination in Syrian Golden Hamsters.
Following the breakthrough of numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in recent months and the incomplete efficiency of the currently available vaccines, development of more effective vaccines is desirable. Non-integrative, non-cytopathic and non-inflammatory lentiviral vectors elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models and are particularly suitable for mucosal vaccination, which is acknowledged as the most effective in reducing viral transmission. Here, we demonstrate that a single intranasal administration of a vaccinal lentiviral vector encoding a stabilized form of the original SARS-CoV-2 Spike glycoprotein induces full-lung protection of respiratory tracts and strongly reduces pulmonary inflammation in the susceptible Syrian golden hamster model against the prototype SARS-CoV-2. In addition, we show that a lentiviral vector encoding stabilized Spike of SARS-CoV-2 Beta variant (LV::SBeta-2P) prevents pathology and reduces infectious viral loads in lungs and nasal turbinates following inoculation with the SARS-CoV-2 Omicron variant. Importantly, an intranasal boost with LV::SBeta-2P improves cross-seroneutralization much better in LV::SBeta-2P-primed hamsters than in their counterparts primed with an LV-encoding Spike from the ancestral SARS-CoV-2. These results strongly suggest that an immune imprint with the original Spike sequence has a negative impact on cross-protection against new variants. Our results tackle the issue of vaccine effectiveness in people who have already been vaccinated and have vanished immunity and indicate the efficiency of LV-based intranasal vaccination, either as a single dose or as booster.


Simulations of the BM2 proton channel transmembrane domain from influenza virus B.
BM2 is a small integral membrane protein from influenza B virus which forms proton-permeable channels. Coarse-grained (CG) molecular dynamics simulations have been used to produce a model of the BM2 channel by self-assembly of a tetrameric bundle of BM2 transmembrane helices in a lipid bilayer. The BM2 channel model is conformationally stable on a 5 mus time scale. This CG model was converted to atomistic resolution to refine interhelix and channel-water interactions. Atomistic molecular dynamics simulations indicate that the BM2 channel is closed when no more than two of the four His19 residues are protonated. Protonating a third His19 side chain initiates a conformational change that opens the channel. In summary, our simulations suggest a common mechanism for BM2 and A/M2, whereby changes in helix packing play a functional role in channel gating.


Fragility in dynamic networks: application to neural networks in the epileptic cortex.
Epilepsy is a network phenomenon characterized by atypical activity at the neuronal and population levels during seizures, including tonic spiking, increased heterogeneity in spiking rates, and synchronization. The etiology of epilepsy is unclear, but a common theme among proposed mechanisms is that structural connectivity between neurons is altered. It is hypothesized that epilepsy arises not from random changes in connectivity, but from specific structural changes to the most fragile nodes or neurons in the network. In this letter, the minimum energy perturbation on functional connectivity required to destabilize linear networks is derived. Perturbation results are then applied to a probabilistic nonlinear neural network model that operates at a stable fixed point. That is, if a small stimulus is applied to the network, the activation probabilities of each neuron respond transiently but eventually recover to their baseline values. When the perturbed network is destabilized, the activation probabilities shift to larger or smaller values or oscillate when a small stimulus is applied. Finally, the structural modifications to the neural network that achieve the functional perturbation are derived. Simulations of the unperturbed and perturbed networks qualitatively reflect neuronal activity observed in epilepsy patients, suggesting that the changes in network dynamics due to destabilizing perturbations, including the emergence of an unstable manifold or a stable limit cycle, may be indicative of neuronal or population dynamics during seizure. That is, the epileptic cortex is always on the brink of instability and minute changes in the synaptic weights associated with the most fragile node can suddenly destabilize the network to cause seizures. Finally, the theory developed here and its interpretation of epileptic networks enables the design of a straightforward feedback controller that first detects when the network has destabilized and then applies linear state feedback control to steer the network back to its stable state.


Direct characterization of polyurethanes and additives by atmospheric solid analysis probe with time-of-flight mass spectrometry (ASAP-TOF-MS).
Because of the wide range of formulations, polyurethanes (PURs) are among the most used copolymers. According to their applications, the nature and concentration of the monomers, as well as the additives, are adjusted. As copolymer, this material is difficult to characterize directly by mass spectrometry without sample pretreatment. In this work, atmospheric solid analysis probe mass spectrometry (ASAP-MS) is used to characterize model and commercial PURs with different formulations. Application of a temperature gradient over the ASAP probe allows a soft vaporization of all sample components: additives are detected at lower gas temperature, whereas the polymer is detected at higher gas temperature. Thus, a temporal separation of the molecules as a function of their volatilization and/or degradation temperature is observed. The vaporized products are identified by ASAP thanks to pyrolysis, but also by low energy source fragmentation observed during the analysis. Thus, complete analysis of PURs with only a single time-of-flight (TOF) mass analyzer is realized. The ability of ASAP-MS for differentiation of different chemical structures of PURs (polyester and polyether based PURs) is demonstrated; the main advantage of this technique being that the analysis is performed in one step, directly on the crude polymer.


Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors.
Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β cells for diabetes treatment. A greater understanding of how β cells form during embryonic development will improve current hESC differentiation protocols. All pancreatic endocrine cells, including β cells, are derived from Neurog3-expressing endocrine progenitors. This study characterizes the single-cell transcriptomes of 6,905 mouse embryonic day (E) 15.5 and 6,626 E18.5 pancreatic cells isolated from Neurog3-Cre; Rosa26mT/mG embryos, allowing for enrichment of endocrine progenitors (yellow; tdTomato + EGFP) and endocrine cells (green; EGFP). Using a NEUROG3-2A-eGFP CyT49 hESC reporter line (N5-5), 4,462 hESC-derived GFP+ cells were sequenced. Differential expression analysis revealed enrichment of markers that are consistent with progenitor, endocrine, or previously undescribed cell-state populations. This study characterizes the single-cell transcriptomes of mouse and hESC-derived endocrine progenitors and serves as a resource (https://lynnlab.shinyapps.io/embryonic_pancreas) for improving the formation of functional β-like cells from hESCs.


An assessment of the Azostix strip test.
The approximate concentration of urea in a single, unmeasured drop of blood may be estimated with an Azostix strip in a little over a minute, without the use of laboratory equipment. The test has been assessed by comparing 488 strip readings made by two observers on 331 specimens of blood from patients with plasma urea concentrations determined by the Auto-Analyzer diacetyl monoxime method. Observations were also made on inter- and intra-observer reading differences, on the effect of the period of contact of blood with the reagent zone of the strip and on the effect of different types of illumination. Difficulties with visual colour matching inevitably limit the performance of this type of test. Azostix strips cannot replace laboratory methods, but, provided their limitations are appreciated, and proper technique is observed, they should provide a screening test for azotaemia when laboratory facilities are not readily available. Their place in hospitals would seem to be confined to emergency use as a screening test for severe azotaemia. In general and domiciliary practice they should provide a convenient screening test for azotaemia provided that readings greater than ;20 mg/100 ml' are taken as an indication for further investigation.


Annexin 1, glucocorticoids, and the neuroendocrine-immune interface.
Annexin 1 (ANXA1) was originally identified as a mediator of the anti-inflammatory actions of glucocorticoids (GCs) in the host defense system. Subsequent work confirmed and extended these findings and also showed that the protein fulfills a wider brief and serves as a signaling intermediate in a number of systems. ANXA1 thus contributes to the regulation of processes as diverse as cell migration, cell growth and differentiation, apoptosis, vesicle fusion, lipid metabolism, and cytokine expression. Here we consider the role of ANXA1 in the neuroendocrine system, particularly the hypothalamo-pituitary-adrenocortical (HPA) axis. Evidence is presented that ANXA1 plays a critical role in effecting the negative feedback effects of GCs on the release of corticotrophin (ACTH) and its hypothalamic-releasing hormones and that it is particularly pertinent to the early-onset actions of the steroids that are mediated via a nongenomic mechanism. The paracrine/juxtacrine mode of ANXA1 action is discussed in detail, with particular reference to the significance of the secondary processing of ANXA1, the processes that control the intracellular and transmembrane trafficking of the protein of the molecule and the mechanism of ANXA1 action on its target cells. In addition, the role of ANXA1 in the perinatal programming of the HPA axis is discussed.


Intratumoral Heterogeneity: From Diversity Comes Resistance.
Tumors consist of a heterogeneous mixture of functionally distinct cancer cells. These functional differences can be caused by varying levels of receptor activity, differentiation, and distinct metabolic and epigenetic states. Intratumoral heterogeneity can lead to interdependence among different subpopulations of cells for sustained tumor growth. In addition, subpopulations can vary widely in their responses to therapeutic agents. As such, it is believed that intratumoral heterogeneity may underlie incomplete treatment responses, acquired and innate resistance, and disease relapse observed in the clinic in response to conventional chemotherapy and targeted agents.


The increasing genetic diversity of HIV-1 in the UK, 2002-2010.
HIV-1 is typically categorized by genetically distinct viral subtypes. Viral subtypes are usually compartmentalized by ethnicity and transmission group and, thus, convey important epidemiological information, as well as possibly influencing the rate of disease progression. We aim to describe the prevalence and time trends of subtypes observed among key populations living with HIV-1 in the UK. Analyses of reverse transcriptase and protease sequences generated from HIV-1-positive antiretroviral-naive patients as part of routine resistance testing between 2002 and 2010 in all public health and NHS laboratories in the UK. Subtype was assigned centrally using the SCUEAL algorithm. Subtyping results were combined with data from the UK Collaborative HIV Cohort Study and the UK HIV and AIDS Reporting System. Analyses adjusted for the number of national HIV-1 diagnoses made each year within demographic subgroups. Viral subtypes were described overall, over time and by demographic subgroup. Subtype B diagnoses (39.9%) have remained stable since 2005, whereas subtype C diagnoses (34.3%) were found to decline in prevalence from 2004. Across most demographic subgroups, the prevalence of non-B non-C subtypes has increased over time, in particular novel recombinant forms (9.9%), subtype G (2.7%), and CRF01 AE (2.0%). HIV-1 subtypes are increasingly represented across all demographic subgroups and this could be evidence of sexual mixing. Between 2002 and 2010, the prevalence of novel recombinant forms has increased in all demographic subgroups. This increasing genetic diversity and the effect of subtype on disease progression may impact future HIV-1 treatment and prevention.


Forensic Footwear Reliability: Part I-Participant Demographics and Examiner Agreement.
In order to assess the extent of agreement between forensic footwear examiners in the United States, a reliability study was performed by West Virginia University between February 2017 and August 2018. Over the span of 19 months, 70 examiners each performed 12 comparisons and reported a total of 840 conclusions. For each comparison, participants were queried on a number of factors in order to determine the degree to which different types of features were identified, evaluated, and weighted, before arriving at a final decision regarding the strength of the association or disassociation between questioned and test impressions. Preliminary results from this study are divided into a series of three summaries. This manuscript (Part I) describes participant demographics as well as community agreement in both feature identification/annotation, and final reporting. Results indicate considerable variation in feature identification/annotation (as low as 66.5% agreement), but higher consistency in the reporting of overall conclusions. For mated pairs, this agreement was 79.7% ± 14.1% (median of 85.7% and a 90% confidence interval between 75.9% and 83.2%). For nonmated pairs, the equivalent overall agreement was 89.8% ± 6.69% (median of 91.4% and a 90% confidence interval between 87.4% and 92.1%). These estimates of agreement are further compared with previous published findings, and collectively, the work extends the body of knowledge concerning reliability in forensic footwear comparisons and conclusions.


Emergency department use and hospitalizations among homeless adults with substance dependence and mental disorders.
Homelessness, substance use, and mental disorders each have been associated with higher rates of emergency department (ED) use and hospitalization. We sought to understand the correlation between ED use, hospital admission, and substance dependence among homeless individuals with concurrent mental illness who participated in a 'Housing First' (HF) intervention trial. The Vancouver At Home study consisted of two randomized controlled trials addressing homeless individuals with mental disorders who have "high" or "moderate" levels of need. Substance dependence was determined at baseline prior to randomization, using the Mini International Neuropsychiatric Interview diagnostic tool, version 6.0. To assess health service use, we reviewed the number of ED visits and the number of hospital admissions based on administrative data for six urban hospitals. Negative binomial regression modeling was used to test the independent association between substance dependence and health service use (ED use and hospitalization), adjusting for HF intervention, age, gender, ethnicity, education, duration of lifetime homelessness, mental disorders, chronic health conditions, and other variables that were selected a priori to be potentially associated with use of ED services and hospital admission. Of the 497 homeless adults with mental disorders who were recruited, we included 381 participants in our analyses who had at least 1 year of follow-up and had a personal health number that could be linked to administrative health data. Of this group, 59% (n = 223) met criteria for substance dependence. We found no independent association between substance dependence and ED visits or hospital admissions [rate ratio (RR) = 0.85; 95% CI 0.62-1.17 and RR = 1.21; 95% CI 0.83-1.77, respectively]. The most responsible diagnoses (defined as the diagnosis that accounts for the length of stay) for hospital admissions were schizo-affective disorder, schizophrenia-related disorder, or bipolar affective disorder; collectively reported in 48% (n = 263) of admissions. Fifteen percent (n = 84) of hospital admissions listed substance dependence as the most responsible diagnosis. Substance dependence was not independently associated with ED use or hospital admission among homeless adults with mental disorders participating in an HF trial. Hospital admissions among this cohort were primarily associated with severe mental disorders. ISRCTN57595077 and ISRCTN66721740.


CNS leptin action modulates immune response and survival in sepsis.
Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency in ob/ob mice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.


Sequence analyses of just four genes to detect extensively drug-resistant Mycobacterium tuberculosis strains in multidrug-resistant tuberculosis patients undergoing treatment.
The rapid detection of Mycobacterium tuberculosis isolates resistant to second-line drugs is crucial for the institution of appropriate treatment regimens as early as possible. Although molecular methods have successfully been used for the rapid detection of resistance to first-line drugs, there are limited data on mutations that confer resistance to second-line drugs. To address this question, we analyzed Mycobacterium tuberculosis strains resistant to ofloxacin (n = 26) and to capreomycin and/or amikacin (n = 48) from Uzbekistan for variations in target genes (gyrA, gyrB, rrs, and tlyA). Strains susceptible to ofloxacin (n = 49) and capreomycin and/or amikacin (n = 39) were included as controls. Mutations in gyrA or gyrB were found in 96% (25/26 strains) of the ofloxacin-resistant strains, while none of the susceptible strains displayed mutations in those two genes. The most common mutation occurred in gyrA at codon 94 (17/26 strains [65.4%]), followed by mutations at codons 90 and 91. Two strains showed a mutation in gyrB, at codons 485 and 543, respectively; both mutations have not been reported previously. The most frequent mutation in strains resistant to both amikacin and capreomycin was A1401G in rrs (34/40 strains [85.0%]). Three strains had mutations in tlyA, of which two (at codons 18 and 118) were associated with resistance to capreomycin alone. Overall, none of the 10 resistant strains (5 amikacin-resistant and capreomycin-susceptible strains) and none of the 39 susceptible control strains had mutations in the genes investigated. Our results clearly demonstrate the potential of sequence analyses of short regions of relatively few target genes for the rapid detection of resistance to second-line drugs among strains isolated from patients undergoing treatment for multidrug-resistant tuberculosis. The mechanisms that confer amikacin resistance in this setting remain unclear.


[Loperamide abuse in anxiety disorder].
Anxiety disorders often accompany somatic correlates of anxiety such as abdominal trouble and diarrhoea. Nevertheless, misuse of antidiarrhoeals has been described only once. We report on a 34-year-old woman who abused loperamide for over 10 years, taking up to 16 mg per day. Loperamide is an opioid that stimulates opioid receptors in the gastrointestinal tract, thereby inhibiting intestinal secretion and propulsive peristalsis, probably without affecting the central nervous system. As our patient's digestive trouble was a consequence of her states of anxiety, diazepam application helped against her diarrhoea as well. This second strategy of self-medication gained particular importance for her, when even high doses of loperamide stopped having an effect. So she developed a benzodiazepine dependence. As soon as she began treatment as an inpatient, her feelings of anxiety became less and the diarrhoea disappeared.


Orbital motion of optically trapped particles in Laguerre-Gaussian beams.
A theoretical examination of off-axial trapping in non-paraxial Laguerre-Gaussian beams is presented for both the Rayleigh and Mie regimes. It is well known that the force acting on a particle may be divided into a term proportional to the intensity gradient and another representing the scattering force. The latter term may be further sub-divided into a dissipative radiation force and a term dependent on the electric field gradient. For Rayleigh particles in Laguerre-Gaussian beams, it is shown that the field gradient term contributes exactly half of the scattering force. This may be compared with a plane wave, in which it makes zero contribution. The off-axis trapping positions for spheres with radii varying from 0.1 to 0.5 mum and a range of refractive indices are calculated numerically in the Mie regime, using a conjugate gradient approach. Azimuthal forces and orbital torques are presented for particles in their trapping positions, for beams with different orbital angular momentum and polarization states. The components of a "spin" torque, acting through the center of the particle, are also computed for absorbing particles in the Mie regime.


Beyond deforestation: restoring forests and ecosystem services on degraded lands.
Despite continued forest conversion and degradation, forest cover is increasing in countries across the globe. New forests are regenerating on former agricultural land, and forest plantations are being established for commercial and restoration purposes. Plantations and restored forests can improve ecosystem services and enhance biodiversity conservation, but will not match the composition and structure of the original forest cover. Approaches to restoring forest ecosystems depend strongly on levels of forest and soil degradation, residual vegetation, and desired restoration outcomes. Opportunities abound to combine ambitious forest restoration and regeneration goals with sustainable rural livelihoods and community participation. New forests will require adaptive management as dynamic, resilient systems that can withstand stresses of climate change, habitat fragmentation, and other anthropogenic effects.


Testing the four-factor model of personality vulnerability to alcohol misuse: a three-wave, one-year longitudinal study.
The 4-factor model of personality vulnerability identifies 4 personality risk factors for alcohol misuse: hopelessness, anxiety sensitivity, impulsivity, and sensation seeking. These personality traits are associated with distinct mechanisms and motivations for alcohol misuse. Individuals high in hopelessness drink to regulate dysphoric affect, while those high in anxiety sensitivity drink to reduce anxiety and to conform to peer expectations. Individuals high in sensation seeking are highly sensitive to the rewarding properties of alcohol, and misuse alcohol to maximize enjoyment. Impulsivity is a broad risk factor contributing to all drinking motives. We hypothesized that personality vulnerabilities would indirectly predict alcohol quantity and problems through specific drinking motives theorized by the 4-factor model. The present study tested hypotheses using a 3-wave, 1-year longitudinal study of undergraduate drinkers (N = 302). Data were analyzed using multilevel path analysis. Hopelessness and impulsivity were positively related to drinking motives in the expected fashion. Anxiety sensitivity was related to coping-anxiety and conformity motives only in the between-subjects model (partially supporting hypotheses), while sensation seeking was generally unrelated to all drinking motives and alcohol outcomes (failing to support hypotheses). Enhancement motives predicted alcohol quantity and problems at both levels, coping-depression motives predicted alcohol problems at the between-subjects level only, and coping-anxiety, conformity, and social motives failed to predict alcohol outcomes beyond other motives. Overall, this study partially supports the 4-factor model, with the strongest support emerging for impulsivity and hopelessness. This study suggests that personality traits such as impulsivity and hopelessness may be important targets in prevention and treatment with undergraduate drinkers.