Epidemiology and moral philosophy.
To an increasing extent ethical controversies affect and sometimes obstruct public health work and epidemiological research. In order to improve communication between the concerned parties a model for identification and analysis of ethical conflicts in individual-based research has been worked out in co-operation between epidemiologists and moral philosophers. The model has two dimensions. One dimension specifies relevant ethical principles (as beneficence, non-maleficence, autonomy and justice). The other dimension specifies the groups of persons involved in the conflict under consideration (for example: the study-population, individuals who may benefit from the results, the researchers and their personnel, the community at large). The model has been applied to the problem of legitimacy of case-register research and to problems in psychiatric health services research as well as epidemiological research.


Inhibition of T-antigen-binding cells by idiotypic antisera.
Shared idiotypy between B- and T-cell receptors specific for the antigen L-tyrosine-p-azophenyltrimethylammonium [tyr(TMA)] was studied in an antigen-binding assay using idiotypic antisera. These idiotypic reagents were prepared by inoculation of rabbits with purified anti-tyr(TMA) antibody raised in strain 13 guinea pigs. The antisera blocked 78-83% of the antigen-binding T cells (T-ABC) and 50-55% of the antigen-binding B cells (B-ABC) from tyr(TMA)-immune strain 13 and outbred lymph node cells (LNC). An excess of normal guinea pig Ig in the ABC assay did not affect the ability of the idiotypic antisera to block T- and B-ABC. Nylon wool-passed tyr(TMA)-immune LNC were trypsin treated resulting in a 75% loss of T-ABC. The trypsin-treated population was then cultured for 16 h which resulted in a return of T-ABC to 92% of pretrypsin values. 77% of these regenerated T-ABC could be blocked with idiotypic antisera. Specificity of the idiotypic antisera was tested in L-tyrosine-p-azobenzenearsonate-immune guinea pig LNC. Neither T- nor B-ABC were blocked in this heterologous system. Further blocking experiments were performed to characterize the nature of the T-ABC receptor. A variety of anti-Ig reagents, some of which block B-ABC, do not inhibit T-ABC suggesting that variable regions on T cells are not linked to Ig Constant regions.


Ag+-induced photoluminescence enhancement in lanthanide post-functionalized MOFs and Ag+ sensing.
The robust gallium carboxylate Ga(OH)(btec)·0.5H2O (MIL-61) is selected as a parent MOF to prepare Ln-MIL-61 by PSM. This work investigates the luminescence of Ln-doped MIL-61 (Ln = Eu3+, Tb3+, Sm3+, Dy3+) in the visible light region. Upon 314 nm excitation, the emission spectra of Eu-MIL-61, Tb-MIL-61 and Eu/Tb-MIL-61 all exhibit their respective strong sharp emission bands. However, Sm-MIL-61 and Dy-MIL-61 show very similar emission to MIL-61 and almost no luminescence of Sm3+ and Dy3+. In this work, the weak fluorescence of Sm3+ or Dy3+ doped MIL-61 is effectively sensitized by Ag+. Besides, single-phase white-light emitters based on the resulting 4d-4f heterometallic co-doped MOFs can be realized. Furthermore, Sm-MIL-61 shows more highly sensitive and selective sensing towards Ag+, and is a promising optical sensor for Ag+ detection in a few daily water samples.


Immune reconstitution disease associated with parasitic infections following initiation of antiretroviral therapy.
The aim of this article is to review the literature concerning immune reconstitution disease associated with parasitic infections during antiretroviral therapy. Immune reconstitution disease is most commonly associated with mycobacterial, chronic viral and invasive fungal infections. The spectrum of infections recognized to be associated with this phenomenon is expanding, however, and now includes a number of parasite infections (protozoal and helminthic). A total of 24 suspected cases have been reported in association with the following diseases: leishmaniasis in its various forms (visceral, cutaneous, mucosal and post-kala-azar dermal leishmaniasis), toxoplasmosis, cryptosporidiosis, schistosomiasis and strongyloidiasis. All cases associated with helminthic infections (schistosomiasis and strongyloidiasis) occurred in immigrants from tropical countries living in high-income countries; four of the patients with leishmaniasis were either immigrants or migrants who had moved out of endemic areas. As access to antiretroviral therapy expands in resource-limited settings, the clinical spectrum, frequency and impact of immune reconstitution disease associated with parasitic infections must be defined. Reports of immune reconstitution disease associated with parasitic infections are increasing, with many occurring in immigrants or migrants from areas where these diseases are endemic. The importance of such cases in antiretroviral therapy programmes in resource-limited settings, however, is not yet known.


Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial.
Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomised controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates. 117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or varenicline plus nicotine patch (15 mg/16 hour). Varenicline use commenced one week prior to the target quit date (TQD), patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over 4 weeks post-TQD. Medication use and smoking status were established at 1, 4 and 12 weeks. Participants lost to follow-up were included as continuing smokers. 92% of participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse effects. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 week and 4 weeks post-TQD (69% vs 59%, p=0.28 and 60% vs 59%, p=0.91, in the nicotine patch and placebo patch arm, respectively), or self reported abstinence rates at 12 weeks (36% vs. 29%, p=0.39, NS). The efficacy of varenicline was not enhanced by the addition of nicotine patches, although further trials would be useful to exclude the possibility of type II error. Clinicaltrials.gov NCT01184664.


Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans.
BACKGROUNDThe live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODSWe performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTSAll BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSIONThe breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATIONClinicalTrials.gov NCT02453048, NCT00870350.FUNDINGILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.


CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19.
Establishing signal transduction thresholds that regulate B lymphocyte responses to foreign Ags and tolerance to self Ags is critical for humoral immune responses. The effects of altered signaling thresholds in B lymphocytes were examined in CD19-deficient mice and transgenic mice that expressed human CD19 at varying densities. Human CD19 restored normal B cell function and development to CD19-deficient mice when expressed at levels comparable to those of circulating human B cells. While CD19 expression levels were found to be developmentally regulated and tightly controlled in normal mice, two- or threefold changes in cell surface CD19 expression in transgenic mice dramatically affected B cell development, mitogen responses, serum Ig levels, humoral immune responses, and germinal center formation. B cells from mice that overexpressed CD19 also had decreased levels of surface IgM and a cell surface phenotype consistent with increased signaling in these cells. These results suggest that CD19 may serve similar functions in humans and mice and that CD19 defines signaling thresholds in vivo for the Ag receptor as well as other cell surface receptors that regulate B lymphocyte selection, activation, and differentiation.


Histiocytoid eccrine sweat gland carcinoma of the eyelid: report of a case.
This report describes the 12th documented case of histiocytoid, diffuse or signet-ring cell eccrine sweat gland carcinoma of the eyelid, a rare neoplasm that characteristically affects older men and mimics distant metastasis. Clinically, the patient was thought to have a colonic metastasis. Histologically, the neoplasm comprised sheets and cords of polygonal, eosinophilic cells, with dispersed larger, rounded single cells resembling histiocytes, and cells with cytoplasmic lumina or a signet-ring appearance. Occasional duct formation was also seen. The features were reminiscent of both the histiocytoid and lobular variants of breast carcinoma. Ultrastructurally, the presence of nonintestinal type microvilli with a length : width ratio in excess of 16 were consistent with an eccrine origin, but also raised the possibility of metastatic mesothelioma. However, a metastatic lesion was excluded by clinical and imaging investigations. There has been no recurrence 3 years after primary excision.


ERp57 is essential for efficient folding of glycoproteins sharing common structural domains.
ERp57 is a member of the protein disulphide isomerase family of oxidoreductases, which are involved in native disulphide bond formation in the endoplasmic reticulum of mammalian cells. This enzyme has been shown to be associated with both calnexin and calreticulin and, therefore, has been proposed to be a glycoprotein-specific oxidoreductase. Here, we identify endogenous substrates for ERp57 by trapping mixed disulphide intermediates between enzyme and substrate. Our results demonstrate that the substrates for this enzyme are mostly heavily glycosylated, disulphide bonded proteins. In addition, we show that the substrate proteins share common structural domains, indicating that substrate specificity may involve specific structural features as well as the presence of an oligosaccharide side chain. We also show that the folding of two of the endogenous substrates for ERp57 is impaired in ERp57 knockout cells and that prevention of an interaction with calnexin or calreticulin perturbs the folding of some, but not all, substrates with multiple disulphide bonds. These results suggest a specific role for ERp57 in the isomerisation of non-native disulphide bonds in specific glycoprotein substrates.


Gorillas with white sclera: A naturally occurring variation in a morphological trait linked to social cognitive functions.
Human eye morphology is considered unique among the primates in that humans possess larger width/height ratios (WHR), expose a greater amount of visible sclera (SSI; width of exposed eyeball/width of visible iris), and critically, have a white sclera due to a lack of pigmentation. White sclera in humans amplifies gaze direction, whereas the all-dark eyes of apes are hypothesized to conceal gaze from others. This study examines WHR and SSI in humans (N = 13) and gorillas (N = 85) engaged in direct and averted gazes and introduces a qualitative assessment of sclera color to evaluate variations in sclera pigmentation. The results confirm previous findings that humans possess a larger WHR than gorillas but indicate that humans and gorillas display similar amounts of visible sclera. Additionally, 72% (N = 124) of gorilla eyes in this sample deviated from the assumed all-dark eye condition. This questions whether gaze camouflage is the primary function of darkened sclera in non-human primates or whether other functional roles can be ascribed to the sclera, light or dark. We argue that white sclera evolved to amplify direct gazes in humans, which would have played a significant role in the development of ostensive communication, which is communication that both shows something and shows the intention to show something. We conclude that the horizontal elongation of the human eye, rather than sclera color, more reliably distinguishes human from great ape eyes, represented here by gorillas.


A nonlinear derivative scheme applied to edge detection.
This paper presents a nonlinear derivative approach to addressing the problem of discrete edge detection. This edge detection scheme is based on the nonlinear combination of two polarized derivatives. Its main property is a favorable signal-to-noise ratio (SNR) at a very low computation cost and without any regularization. A 2D extension of the method is presented and the benefits of the 2D localization are discussed. The performance of the localization and SNR are compared to that obtained using classical edge detection schemes. Tests of the regularized versions and a theoretical estimation of the SNR improvement complete this work.


Leveraging Coupled Interaction for Multimodal Alzheimer's Disease Diagnosis.
As the population becomes older worldwide, accurate computer-aided diagnosis for Alzheimer's disease (AD) in the early stage has been regarded as a crucial step for neurodegeneration care in recent years. Since it extracts the low-level features from the neuroimaging data, previous methods regarded this computer-aided diagnosis as a classification problem that ignored latent featurewise relation. However, it is known that multiple brain regions in the human brain are anatomically and functionally interlinked according to the current neuroscience perspective. Thus, it is reasonable to assume that the extracted features from different brain regions are related to each other to some extent. Also, the complementary information between different neuroimaging modalities could benefit multimodal fusion. To this end, we consider leveraging the coupled interactions in the feature level and modality level for diagnosis in this paper. First, we propose capturing the feature-level coupled interaction using a coupled feature representation. Then, to model the modality-level coupled interaction, we present two novel methods: 1) the coupled boosting (CB) that models the correlation of pairwise coupled-diversity on both inconsistently and incorrectly classified samples between different modalities and 2) the coupled metric ensemble (CME) that learns an informative feature projection from different modalities by integrating the intrarelation and interrelation of training samples. We systematically evaluated our methods with the AD neuroimaging initiative data set. By comparison with the baseline learning-based methods and the state-of-the-art methods that are specially developed for AD/MCI (mild cognitive impairment) diagnosis, our methods achieved the best performance with accuracy of 95.0% and 80.7% (CB), 94.9% and 79.9% (CME) for AD/NC (normal control), and MCI/NC identification, respectively.


Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules.
Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.


Development and validation of a questionnaire to measure asthma control.
International guidelines on asthma management indicate that the primary goal of treatment should be optimum asthma control. The aim of this study was to develop and validate the Asthma Control Questionnaire (ACQ). The authors generated a list of all symptoms used to assess control and sent it to 100 asthma clinicians who were members of guidelines committees (18 countries). They scored each symptom for its importance in evaluating asthma control. From the 91 responses, the five highest scoring symptoms were selected for the ACQ. In addition, there is one question on beta2-agonist use and another on airway calibre (total questions=7). The ACQ was tested in a 9-week observational study of 50 adults with symptomatic asthma. The ACQ and other measures of asthma health status were assessed at baseline, 1, 5 and 9 weeks. In patients whose asthma was stable between clinic visits, reliability of the ACQ was high (intraclass correlation coefficient (ICC)=0.90). The questionnaire was very responsive to change in asthma control (p<0.0001). Cross-sectional and longitudinal validity were supported by correlations between the ACQ and other measures of asthma health status being close to a priori predictions. In conclusion, the Asthma Control Questionnaire has strong evaluative and discriminative properties and can be used with confidence to measure asthma control.


Physiological tonicity improves human chondrogenic marker expression through nuclear factor of activated T-cells 5 in vitro.
Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype. Human articular chondrocytes were isolated and subsequently expanded at control tonicity (280 mOsm) or at moderately elevated, physiological tonicity (380 mOsm). The effects of physiological tonicity on chondrocyte proliferation and chondrogenic marker expression were evaluated. The role of Tonicity-responsive Enhancer Binding Protein in response to physiological tonicity was investigated using nuclear factor of activated T-cells 5 (NFAT5) RNA interference. Moderately elevated, physiological tonicity (380 mOsm) did not affect chondrocyte proliferation, while higher tonicities inhibited proliferation and diminished cell viability. Physiological tonicity improved expression of chondrogenic markers and NFAT5 and its target genes, while suppressing dedifferentiation marker collagen type I and improving type II/type I expression ratios >100-fold. Effects of physiological tonicity were similar in osteoarthritic and normal (nonosteoarthritic) chondrocytes, indicating a disease-independent mechanism. NFAT5 RNA interference abolished tonicity-mediated effects and revealed that NFAT5 positively regulates collagen type II expression, while suppressing type I. Physiological tonicity provides a simple, yet effective, means to improve phenotypical characteristics during cytokine-free isolation and in vitro expansion of human articular chondrocytes. Our findings will lead to the development of improved cell-based repair strategies for chondral lesions and provides important insights into mechanisms underlying osteoarthritic progression.


Enteroendocrine Dynamics - New Tools Reveal Hormonal Plasticity in the Gut.
The recent intersection of enteroendocrine cell biology with single-cell technologies and novel in vitro model systems has generated a tremendous amount of new data. Here we highlight these recent developments and explore how these findings contribute to the understanding of endocrine lineages in the gut. In particular, the concept of hormonal plasticity, the ability of endocrine cells to produce different hormones over the course of their lifetime, challenges the classic notion of cell types. Enteroendocrine cells travel in the course of their life through different signaling environments that directly influence their hormonal repertoire. In this context, we examine how enteroendocrine cell fate is determined and modulated by signaling molecules such as bone morphogenetic proteins (BMPs) or location along the gastrointestinal tract. We analyze advantages and disadvantages of novel in vitro tools, adult stem cell or iPS-derived intestinal organoids, that have been crucial for recent findings on enteroendocrine development and plasticity. Finally, we illuminate the future perspectives of the field and discuss how understanding enteroendocrine plasticity can lead to new therapeutic approaches.


Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis.
: The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness (p = 0.03) and a different microbial profile compared to those with lower adherence (p = 0.03). Prevotella-9 and Agathobacter were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile (p = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness (p = 0.001), and there was a dose-response association between coffee drinking and relative abundance of Veillonella (p = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.


EPA guidance on eMental health interventions in the treatment of posttraumatic stress disorder (PTSD).
The aim of this EPA guidance was to develop recommendations on eMental health interventions in the treatment of posttraumatic stress disorder (PTSD). A systematic literature search was performed and 40 articles were retrieved and assessed with regard to study characteristics, applied technologies, therapeutic approaches, diagnostic ascertainment, efficacy, sustainability of clinical effects, practicability and acceptance, attrition rates, safety, clinician-supported vs. non-supported interventions and active vs. waiting-list controls. The reviewed studies showed a great heterogeneity concerning study type, study samples, interventions and outcome measures. Based on these findings, five graded recommendations dealing with symptom reduction, acceptability, type of administration, clinician support, self-efficacy and coping were developed.


Reduced uncertainty as a diagnostic benefit: an initial assessment of somatostatic receptor scintigraphy's value in detecting distant metastases of carcinoid liver tumours.
This paper employs classical concepts of diminishing marginal utility to demonstrate that risk-aversion can increase the perceived value of diagnostic procedures and thus raise optimum diagnostic expenditures. The theory is applied to a model in the spirit of Phelps and Mushlin's initial technology assessments. The specific evaluation is the cost-effectiveness of somatostatin receptor scintigraphy used to detect distant metastases of carcinoid liver tumours in a patient otherwise eligible for surgical resection of the liver. Data for the model are taken from published sources and financial databases, when available, and otherwise from a senior clinician's experience (LKK). The quantitative results indicate that receptor scintigraphy may have two beneficial impacts to risk-neutral individuals. First, it may reduce the combined costs of therapy and treatment because the diagnostic procedure costs less than the expected savings generated by avoiding inappropriate surgeries. Second, it may improve the patient's expected health-status-adjusted life years (HSALY) because the information allows physicians to better match treatment to the cancer's stage. Finally the paper demonstrates that risk aversion, as embodied in classical diminishing marginal utility applied to health status, can increase the value of the diagnostic tests and can lead the patient to choose a less beneficial treatment. An illustrative risk-averse utility function changed the optimum treatment from surgery to chemotherapy and increased scintigraphy's benefit by 500%.


Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.
Layering of neurons in the cerebral cortex and cerebellum requires Reelin, an extracellular matrix protein, and mammalian Disabled (mDab1), a cytosolic protein that activates tyrosine kinases. Here, we report the requirement for two other proteins, cell surface receptors termed very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both receptors can bind mDab1 on their cytoplasmic tails and are expressed in cortical and cerebellar layers adjacent to layers that express Reelin. mDab1 expression is upregulated in knockout mice that lack both VLDLR and ApoER2. Inversion of cortical layers and absence of cerebellar foliation in these animals precisely mimic the phenotype of mice lacking Reelin or mDab1. These findings suggest that VLDLR and ApoER2 participate in transmitting the extracellular Reelin signal to intracellular signaling processes initiated by mDab1.


A controlled trial of the impact of the family practice nurse on volume, quality, and cost of rural health services.
Rural Newfoundland communities with and without expanded role nurses were compared on a before and after basis. The rural communities are located in a geographically isolated area served by a 40-bed hospital staffed by salaried physicians. Primary care visits within the community increased by 186 per cent after establishment of the family practice nurse community clinic and attendance at the hospital decreased by 35 per cent. Acute care days in hospital decreased 5 per cent in the experimental group and increased by 39 per cent in the control group. A major portion of the community based visits provided to the experimental group were classed as preventive. The total annual health service cost per 1,000 persons in the experimental group increased slightly more than in the control group (26 versus 21 per cent). Adequate management of certain indicator conditions and drugs was maintained by the family practice nurse when compared to the adequacy rating for the physician during the same time period.


The effect of minocycline on the masticatory movements following the inferior alveolar nerve transection in freely moving rats.
To determine the effects of inferior alveolar nerve transection (IAN-X) on masticatory movements in freely moving rats and to test if microglial cells in the trigeminal principal sensory nucleus (prV) or motor nucleus (motV) may be involved in modulation of mastication, the effects of microglial cell inhibitor minocycline (MC) on masticatory jaw movements, microglia (Iba1) immunohistochemistry and the masticatory jaw movements and related masticatory muscle EMG activities were studied in IAN-X rats. The number of Iba1-immunoreactive (IR) cells both in prV and motV was significantly larger in IAN-X rats compared with sham rats on day 3 after IAN-X. The intraperitoneal (i.p.) administration of MC caused a significant reduction of the number of Iba1-IR cells both in prV and motV that was evident on day 14 after IAN-X. Furthermore, a significant reduction of the number of Iba1-IR cells could be observed in motV but not in prV after microinjection (m.i.) of MC into the motV of IAN-X rats. The rats also exhibited a significant decrease in the head-withdrawal threshold on the side ipsilateral to the IAN-X compared to the threshold before IAN-X and it lasted to day 14. In addition, IAN-X markedly affected the ability to rat to carry out mastication. The number of complete masticatory sequences was significantly decreased. Furthermore, the total masticatory sequence time and food preparatory (PP) period duration was significantly elongated in compared to sham rats. Although IAN-X significantly affected the total number of chewing cycles within the RC period of a masticatory sequence, it had no effect on the duration of the chewing cycles. On the other hand, systemic administration of MC (both i.p. and m.i.) in IAN-X rats significantly improved decreased head-withdrawal threshold and the impaired masticatory jaw movements. The present findings reveal that the strong modulation of masticatory jaw movements occurs following microglial cell activation after IAN-X, and the modulation recovers after inhibition of the microglial cell activation by MC, suggesting that microglial cell activation in the motV as well as in the prV has a pivotal role in modulating mastication following trigeminal nerve injury associated with orofacial neuropathic pain.


[Olfactory bulb neurogenesis and its neurological impact].
Contrary to the long-held dogma according to which the adult mammalian brain does not produce neurons anymore, neuronal turnover has been reported in two discrete areas of the adult brain: the hippocampus and the olfactory bulb. Adult-generated neurons are produced from neural stem cells located in the hippocampal subgranular zone and the subventricular zone of the lateral ventricles. Recently, number of genetic and epigenetic factors that modulate proliferation of stem cells, migration, differentiation and survival of newborn neurons have been characterized. We know that neurogenesis increases in the diseased brain, after stroke or after traumatic brain injury. Importantly, progenitors from the subventricular zone, but not from the subgranular zone, are incorporated at the sites of injury, where they replace some of the degenerated neurons. Thus, the central nervous system has the capacity to regenerate itself after injury and, today, researchers develop strategies aimed at promoting neurogenesis in diseased areas. This basic research is attracting a lot of attention because of the hope that it will lead to regeneration and reconstruction therapy for the damaged brain. In this review, we discuss major findings concerning the organization of the neurogenic niche located in the subventricular zone and examine both intrinsic and extrinsic factors that regulate adult neurogenesis. Then, we present evidences for the intrinsic capability of the adult brain for cell replacement, and shed light on recent works demonstrating that one can greatly enhance appropriate brain cell replacement by using molecular cues known to endogenously control proliferation, migration, differentiation and/or survival of subventricular zone progenitors. Finally, we review some of the advantages and limits of strategies aimed at using endogenous progenitors and their relevance to human clinics.


Control of GABARAP-mediated autophagy by the Golgi complex, centrosome and centriolar satellites.
Within minutes of induction of autophagy by amino-acid starvation in mammalian cells, multiple autophagosomes form throughout the cell cytoplasm. During their formation, the autophagosomes sequester cytoplasmic material and deliver it to lysosomes for degradation. How these organelles can be so rapidly formed and how their formation is acutely regulated are major questions in the autophagy field. Protein and lipid trafficking from diverse cell compartments contribute membrane to, or regulate the formation of the autophagosome. In addition, recruitment of Atg8 (in yeast), and the ATG8-family members (in mammalian cells) to autophagosomes is required for efficient autophagy. Recently, it was discovered that the centrosome and centriolar satellites regulate autophagosome formation by delivery of an ATG8-family member, GABARAP, to the forming autophagosome membrane, the phagophore. We propose that GABARAP regulates phagophore expansion by activating the ULK complex, the amino-acid controlled initiator complex. This finding reveals a previously unknown link between the centrosome, centriolar satellites and autophagy.


Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis.
To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry. Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis. Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.


Water Quality Monitoring for Lake Constance with a Physically Based Algorithm for MERIS Data.
A physically based algorithm is used for automatic processing of MERIS level 1B full resolution data. The algorithm is originally used with input variables for optimization with different sensors (i.e. channel recalibration and weighting), aquatic regions (i.e. specific inherent optical properties) or atmospheric conditions (i.e. aerosol models). For operational use, however, a lake-specific parameterization is required, representing an approximation of the spatio-temporal variation in atmospheric and hydrooptic conditions, and accounting for sensor properties. The algorithm performs atmospheric correction with a LUT for at-sensor radiance, and a downhill simplex inversion of chl-a, sm and y from subsurface irradiance reflectance. These outputs are enhanced by a selective filter, which makes use of the retrieval residuals. Regular chl-a sampling measurements by the Lake's protection authority coinciding with MERIS acquisitions were used for parameterization, training and validation.


A comparison of the accuracy of clinical decisions based on full-text articles and on journal abstracts alone: a study among residents in a tertiary care hospital.
Many clinicians depend solely on journal abstracts to guide clinical decisions. This study aims to determine if there are differences in the accuracy of responses to simulated cases between resident physicians provided with an abstract only and those with full-text articles. It also attempts to describe their information-seeking behaviour. Seventy-seven resident physicians from four specialty departments of a tertiary care hospital completed a paper-based questionnaire with clinical simulation cases, then randomly assigned to two intervention groups-access to abstracts-only and access to both abstracts and full-text. While having access to medical literature, they completed an online version of the same questionnaire. The average improvement across departments was not significantly different between the abstracts-only group and the full-text group (p=0.44), but when accounting for an interaction between intervention and department, the effect was significant (p=0.049) with improvement greater with full-text in the surgery department. Overall, the accuracy of responses was greater after the provision of either abstracts-only or full-text (p<0.0001). Although some residents indicated that 'accumulated knowledge' was sufficient to respond to the patient management questions, in most instances (83% of cases) they still sought medical literature. Our findings support studies that doctors will use evidence when convenient and current evidence improved clinical decisions. The accuracy of decisions improved after the provision of evidence. Clinical decisions guided by full-text articles were more accurate than those guided by abstracts alone, but the results seem to be driven by a significant difference in one department.


Chemical and cytotoxic analyses of brown Brazilian propolis (Apis mellifera) and its in vitro activity against itraconazole-resistant Sporothrix brasiliensis.
This study aimed to evaluate the chemical composition and cytotoxic activity of brown Brazilian propolis and its in vitro activity against itraconazole-resistant Sporothrix brasiliensis from animal sporotrichosis. Propolis was acquired commercially and prepared as a hydroalcoholic extract. Chemical analysis was evaluated by liquid chromatography coupled to mass spectrometry of ultra-efficiency. The cell viability was evaluated by MTT test in MDBK cells of 50 to 0.09 μg/mL. For antifungal tests, twenty isolates of Sporothrix brasiliensis from dogs (n = 11) and cats (n = 9) with sporotrichosis were tested to itraconazole (16-0.0313 μg/mL) and to propolis (3.125-0.09 mg/mL) by broth microdilution technique (CLSI M38-A2), adapted to natural products. The results were expressed in minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC). Itraconazole showed activity between MIC values of 0.25 to greater than 16 μg/mL, and 88.9% (08/09) and 72.7% (08/11) of S. brasiliensis from cats and dogs, respectively, were considered itraconazole-resistant. All Sporothrix brasiliensis were sensitive to brown propolis between MIC values of 0.19-1.56 mg/mL, including the itraconazole-resistant isolates, whereas the MFC values of propolis were from 0.78 to greater than 3.125 mg/mL. Propolis maintained a medium to high cell viability between concentration of 0.78 to 0.09 μg/mL, and p-coumaric acid was the major compound. Brown Brazilian propolis is a promising antifungal candidate against sporotrichosis and more studies need to be undertaken to evaluate its safe use to understand its efficacy.


Molecular weight characterization of single globular proteins using optical nanotweezers.
We trap a set of molecular weight standard globular proteins using a double nanohole optical trap. The root mean squared variation of the trapping laser transmission intensity gives a linear dependence with the molecular weight, showing the potential for analysis of globular proteins. The characteristic time of the autocorrelation of the trapping laser intensity variations scales with a -2/3 power dependence with the volume of the particle. A hydrodynamic laser tweezer model is used to explain these dependencies. Since this is a single particle technique that operates in solution and can be used to isolate an individual particle, we believe that it provides an interesting alternative to existing analysis methods and shows promise to expand the capabilities of protein related studies to the single particle level.


[The Role of Colombian Psychiatrists in the Midst of the COVID 19 Pandemic].
The COVID-19 pandemic is having an impact on multiple levels, one being the way of providing mental health care services. A study was proposed in order to identify the standpoints regarding the role we must assume as psychiatrists in the setting of this pandemic in Colombia. A study was developed employing a Delphi-type methodology. Three types of psychiatrist were included for the application of the instrument: directors of academic psychiatry programmes, directors of mental health institutions and private practitioners. Responses were collected over the course of a month (between April and May) by 24 participants corresponding to 14 private practitioners (58.3%), 6 heads of academic programmes (25.1%) and 4 directors of mental health services (16.6%). The results, grouped around the psychiatric work, describe the impact generated by the pandemic and the possible role of the specialist. Consistency was identified around the need to provide a differential approach according to the vulnerabilities of each group of people exposed to the pandemic; as well as the remote provision of health care through technology, often using videoconferencing.


Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of color.
Postinflammatory hyperpigmentation is a common sequelae of inflammatory dermatoses that tends to affect darker skinned patients with greater frequency and severity. Epidemiological studies show that dyschromias, including postinflammatory hyperpigmentation, are among the most common reasons darker racial/ethnic groups seek the care of a dermatologist. The treatment of postinflammatory hyperpigmentation should be started early to help hasten its resolution and begins with management of the initial inflammatory condition. First-line therapy typically consists of topical depigmenting agents in addition to photoprotection including a sunscreen. Topical tyrosinase inhibitors, such as hydroquinone, azelaic acid, kojic acid, arbutin, and certain licorice extracts, can effectively lighten areas of hypermelanosis. Other depigmenting agents include retinoids, mequinol, ascorbic acid, niacinamide, N-acetyl glucosamine, and soy with a number of emerging therapies on the horizon. Topical therapy is typically effective for epidermal postinflammatory hyperpigmentation; however, certain procedures, such as chemical peeling and laser therapy, may help treat recalcitrant hyperpigmentation. It is also important to use caution with all of the above treatments to prevent irritation and worsening of postinflammatory hyperpigmentation.


Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.
GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.


First-in-class candidate therapeutics that target mitochondria and effectively prevent cancer cell metastasis: mitoriboscins and TPP compounds.
Cancer stem cells (CSCs) have been proposed to be responsible for tumor recurrence, distant metastasis and drug-resistance, in the vast majority of cancer patients. Therefore, there is an urgent need to identify new drugs that can target and eradicate CSCs. To identify new molecular targets that are unique to CSCs, we previously compared MCF7 2D-monolayers with 3D-mammospheres, which are enriched in CSCs. We observed that 25 mitochondrial-related proteins were >100-fold over-expressed in 3D-mammospheres. Here, we used these 25 proteins to derive short gene signatures to predict distant metastasis (in N=1,395 patients) and tumor recurrence (in N=3,082 patients), by employing a large collection of transcriptional profiling data from ER(+) breast cancer patients. This analysis resulted in a 4-gene signature for predicting distant metastasis, with a hazard ratio of 1.91-fold (P=2.2e-08). This provides clinical evidence to support a role for CSC mitochondria in metastatic dissemination. Next, we employed a panel of mitochondrial inhibitors, previously shown to target mitochondria and selectively inhibit 3D-mammosphere formation in MCF7 cells and cell migration in MDA-MB-231 cells. Remarkably, these five mitochondrial inhibitors had only minor effects or no effect on MDA-MB-231 tumor formation, but preferentially and selectively inhibited tumor cell metastasis, without causing significant toxicity. Mechanistically, all five mitochondrial inhibitors have been previously shown to induce ATP-depletion in cancer cells. Since 3 of these 5 inhibitors were designed to target the large mitochondrial ribosome, we next interrogated whether genes encoding the large mitochondrial ribosomal proteins (MRPL) also show prognostic value in the prediction of distant metastasis in both ER(+) and ER(-) breast cancer patients. Interestingly, gene signatures composed of 6 to 9 MRPL mRNA-transcripts were indeed sufficient to predict distant metastasis, tumor recurrence and Tamoxifen resistance. These gene signatures could be useful as companion diagnostics to assess which patients may benefit most from anti-mito-ribosome therapy. Overall, our studies provide the necessary proof-of-concept, and in vivo functional evidence, that mitochondrial inhibitors can successfully and selectively target the biological process of cancer cell metastasis. Ultimately, we envision that mitochondrial inhibitors could be employed to develop new treatment protocols, for clinically providing metastasis prophylaxis, to help prevent poor clinical outcomes in cancer patients.


Self-perceived strengths among people who are homeless.
This study examined self-perceived strengths among 116 people who were homeless. Those who had experienced a longer period of current homelessness tended to report fewer personal strengths (r = -0.23). Nonetheless, in spite of their marginalized position in society, the vast majority of participants (114 out of 116) perceived personal strengths. A prior diagnosis with mental illness was not associated with the number of strengths reported, but self-perception of strengths was associated with altruistic orientation. The Values in Action (VIA) taxonomy of character strengths captured many of the responses generated by this population. The most frequently mentioned character categories included social intelligence, kindness, persistence, authenticity and humour. The most frequently mentioned other strengths included personal skills (e.g. music, sports), job skills, intelligence and education. The results have relevance for efforts to build self-perceptions that facilitate escape from homelessness.


The genetics of dopa decarboxylase in Drosophila melanogaster. II. Isolation and characterization of dopa-decarboxylase-deficient mutants and their relationship to the alpha-methyl-dopa-hypersensitive mutants.
Of 84 lethals isolated over the dopa decarboxylase (DDC) deficiency Df(2L)50, 8 have been identified as DDC-deficient alleles on the basis of their effect on DDC activity when heterozygous over the Cgamma-O balancer chromosome with activities ranging from 28% to 53% of controls. Some of the Ddc-deficient alleles exhibit intracistronic complementation. Most of the complementing pairs of alleles are much reduced in viability, e.g. less than 5% of expected, and express a common syndrome of mutant phenes which can reasonably be inferred to derive from inadequately sclerotinized cuticle. Individuals heterozygous for the noncomplementing allele, Ddcn7, over the 12-band DDC deficiency, Df (2L)130, die at the end of embryogenesis as unhatched larvae with unpigmented mouth parts. The Ddc alleles and the l(2) amd alpha-methyl dopa (alphaMD) hypersensitive alleles are both located within the 11 band region 37B10-C7. The l(2) and locus is immediately to the right of hk(2-53.6). Ddc has been mapped within 0.004 Map Units to the right of l(2) and with a maximum estimated recombination frequency of 0.01%. None of the Ddc/CgammaOstrains are sensitive to the dietary administration of alpha-methyl dopa (alphaMD), and complementation occurs between the Ddc deficient alleles and the l(2) amd alleles both on the basis of viability and DDC activity. No effect on DDC by the amd alleles has been found to date. Even in the complementing heterozygote, amdH1/amdH89, the level of activity, thermostability, and in vitro alphaMD inhibition of DDC remains unaffected. Although no biochemical phene has yet been established for the alphaMD hypersensitive amd alleles, it seems likely that the two groups of mutants are functionally related.


Prevalence, incidence and geographical distribution of Toxoplasma gondii antibodies in pregnant women in Denmark.
The purpose of this study was to determine the prevalence and incidence of toxoplasmosis in pregnant women in Denmark, and to estimate the incidence of congenital toxoplasmosis. Consecutive serum samples from 5,402 women were analysed for specific IgG and IgM Toxoplasma gondii antibodies by EIA. The prevalence of IgG antibodies was 27.4%. The seroconversion rate was estimated to be 1.16% per year (SE = 0.0017) in all age groups, consistent with an incidence of acute toxoplasmosis in pregnant women of 0.65%. Specific IgM antibodies were present in sera from 29 women. Based on an assumed maternofetal transmission rate of 50%, the incidence of congenital toxoplasmosis was estimated to be 0.33%. Based on these data it is predicted that about 410 pregnant women are infected with T. gondii every year in Denmark, and that about 200 children every year are infected in utero by T. gondii. There was no difference in the prevalence of antibodies in women from rural or urban areas, or from different parts of Denmark.


Facilitated ion transport in all-solid-state flexible supercapacitors.
The realization of highly flexible and all-solid-state energy-storage devices strongly depends on both the electrical properties and mechanical integrity of the constitutive materials and the controlled assembly of electrode and solid electrolyte. Herein we report the preparation of all-solid-state flexible supercapacitors (SCs) through the easy assembly of functionalized reduced graphene oxide (f-RGO) thin films (as electrode) and solvent-cast Nafion electrolyte membranes (as electrolyte and separator). In particular, the f-RGO-based SCs (f-RGO-SCs) showed a 2-fold higher specific capacitance (118.5 F/g at 1 A/g) and rate capability (90% retention at 30 A/g) compared to those of all-solid-state graphene SCs (62.3 F/g at 1A/g and 48% retention at 30 A/g). As proven by the 4-fold faster relaxation of the f-RGO-SCs than that of the RGO-SCs and more capacitive behavior of the former at the low-frequency region, these results were attributed to the facilitated ionic transport at the electrical double layer by means of the interfacial engineering of RGO by Nafion. Moreover, the superiority of all-solid-state flexible f-RGO-SCs was demonstrated by the good performance durability under the 1000 cycles of charging and discharging due to the mechanical integrity as a consequence of the interconnected networking structures. Therefore, this research provides new insight into the rational design and fabrication of all-solid-state flexible energy-storage devices as well as the fundamental understanding of ion and charge transport at the interface.


Fresnel lens-encoded binary phase-only filters for optical pattern recognition.
We describe a technique for reducing false signals from optical correlators using binary phase-only filters (BPOF's). Since the impulse-response function of the BPOF contains both the target object and the inverted version of it, the output consists of the correlation of the input object with both of these objects. In our research a Fresnel phase plate lens is encoded onto the BPOF. As a result the correlation with the desired target is on a converging beam, and the correlation with the undesired inverted image of the target is on a diverging beam. Experimental results show that these filters reject inverted input objects.


The impact of food allergy on the daily activities of children and their families.
Food allergy affects a significant number of children, and its management requires considerable time and vigilance. To determine the impact of food allergy on the daily activities of food allergic children and their families. Caregivers of food allergic children from a university-based allergy practice completed a questionnaire that evaluated their perception of the impact of their child's food allergy on family activities. Of the 87 families who completed the study, more than 60% of caregivers reported that food allergy significantly affected meal preparation and 49% or more indicated that food allergy affected family social activities. Forty-one percent of parents reported a significant impact on their stress levels and 34% reported that food allergy had an impact on school attendance, with 10% choosing to home school their children because of food allergy. The number of food allergies had a significant impact on activity scores, but the existence of comorbid conditions such as asthma and atopic dermatitis did not significantly affect the results. Food allergy has a significant effect on activities of families of food allergic children. Further study is needed to determine more detailed effects of food allergy on parent-child interactions and development.


The permeation mechanism of organic cations through a CNG mimic channel.
Several channels, ranging from TRP receptors to Gap junctions, allow the exchange of small organic solute across cell membrane. However, very little is known about the molecular mechanism of their permeation. Cyclic Nucleotide Gated (CNG) channels, despite their homology with K+ channels and in contrast with them, allow the passage of larger methylated and ethylated ammonium ions like dimethylammonium (DMA) and ethylammonium (EA). We combined electrophysiology and molecular dynamics simulations to examine how DMA interacts with the pore and permeates through it. Due to the presence of hydrophobic groups, DMA enters easily in the channel and, unlike the alkali cations, does not need to cross any barrier. We also show that while the crystal structure is consistent with the presence of a single DMA ion at full occupancy, the channel is able to conduct a sizable current of DMA ions only when two ions are present inside the channel. Moreover, the second DMA ion dramatically changes the free energy landscape, destabilizing the crystallographic binding site and lowering by almost 25 kJ/mol the binding affinity between DMA and the channel. Based on the results of the simulation the experimental electron density maps can be re-interpreted with the presence of a second ion at lower occupancy. In this mechanism the flexibility of the channel plays a key role, extending the classical multi-ion permeation paradigm in which conductance is enhanced by the plain interaction between the ions.


Molecular and clinical delineation of the 17q22 microdeletion phenotype.
Deletions involving 17q21-q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1-q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8-2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ~8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.


Subtherapeutic Posaconazole Exposure and Treatment Outcome in Patients With Invasive Fungal Disease.
Posaconazole exposure seems to be subtherapeutic in some patients with invasive fungal disease. Due to the pharmacokinetic variability of posaconazole, therapeutic drug monitoring may help to optimize the efficacy of this antifungal drug. A retrospective study of patients treated with posaconazole from January 2008 to April 2014 and for whom posaconazole serum concentrations were available was conducted. Risk factors for underexposure of posaconazole were detected, and the relationship between posaconazole exposure and treatment outcome according to the European Organization for Research and Treatment of Cancer (EORTC) criteria was assessed. Seventy patients met the inclusion criteria, 45 patients received posaconazole as treatment, and 25 patients received posaconazole as a prophylactic. Posaconazole serum trough concentrations were <1.25 mg/L in 44.4% of patients receiving treatment and <0.7 mg/L in 40.0% of patients receiving prophylactic posaconazole. Multiple linear regression analysis showed a significant, independent, and negative association of the posaconazole serum trough concentration with a lack of enteral nutrition (P < 0.001), vomiting (P = 0.035), the use of a proton pump inhibitor or H2-receptor antagonist (P < 0.001), a liquid diet (P = 0.002), concomitant chemotherapy (P = 0.004), and a posaconazole dose frequency of 2 times daily (P = 0.015). A higher posaconazole concentration was associated with a better treatment outcome [odds ratio = 22.22 (95% confidence interval, 3.40-145.33); P = 0.001]. Posaconazole exposure is insufficient in more than 40% of patients at risk of or with invasive fungal disease, and posaconazole exposure is positively correlated with a successful treatment outcome. Therapeutic drug monitoring of posaconazole can detect underexposure and can be helpful in treatment optimization.


Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts.
Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis.


Challenge testing the lactoperoxidase system against a range of bacteria using different activation agents.
Lactoperoxidase (LP) exerts antimicrobial effects in combination with H(2)O(2) and either thiocyanate (SCN(-)) or a halide (e.g., I(-)). Garlic extract in the presence of ethanol has also been used to activate the LP system. This study aimed to determine the effects of 3 LP activation systems (LP+SCN(-)+H(2)O(2); LP+I(-)+H(2)O(2); LP + garlic extract + ethanol) on the growth and activity of 3 test organisms (Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus cereus). Sterilized milk was used as the reaction medium, and the growth pattern of the organisms and a range of keeping quality (KQ) indicators (pH, titratable acidity, ethanol stability, clot on boiling) were monitored during storage at the respective optimum growth temperature for each organism. The LP+I(-)+ H(2)O(2) system reduced bacterial counts below the detection limit shortly after treatment for all 3 organisms, and no bacteria could be detected for the duration of the experiment (35 to 55 h). The KQ data confirmed that the milk remained unspoiled at the end of the experiments. The LP + garlic extract + ethanol system, on the other hand, had no effect on the growth or KQ with P. aeruginosa, but showed a small retardation of growth of the other 2 organisms, accompanied by small increases (5 to 10 h) in KQ. The effects of the LP+SCN(-)+H(2)O(2) system were intermediate between those of the other 2 systems and differed between organisms. With P. aeruginosa, the system exerted total inhibition within 10 h of incubation, but the bacteria regained viability after a further 5 h, following a logarithmic growth curve. This was reflected in the KQ indicators, which implied an extension of 15 h. With the other 2 bacterial species, LP+SCN(-)+H(2)O(2) exerted an obvious inhibitory effect, giving a lag phase in the growth curve of 5 to 10 h and KQ extension of 10 to 15 h. When used in combination, I(-) and SCN(-) displayed negative synergy.


Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model.
The liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.). In order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO₂). Here we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO₂ and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity). Overall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology.


The Obesity Paradox in Cancer: a Review.
There is a common perception that excess adiposity, commonly approximated by body mass index (BMI), is associated with reduced cancer survival. A number of studies have emerged challenging this by demonstrating that overweight and early obese states are associated with improved survival. This finding is termed the "obesity paradox" and is well recognized in the cardio-metabolic literature but less so in oncology. Here, we summarize the epidemiological findings related to the obesity paradox in cancer. Our review highlights that many observations of the obesity paradox in cancer reflect methodological mechanisms including the crudeness of BMI as an obesity measure, confounding, detection bias, reverse causality, and a specific form of the selection bias, known as collider bias. It is imperative for the oncologist to interpret the observation of the obesity paradox against the above methodological framework and avoid the misinterpretation that being obese might be "good" or "protective" for cancer patients.


Minority student and teaching assistant interactions in STEM.
Graduate student teaching assistants from underrepresented groups may provide salient role models and enhanced instruction to minority students in STEM fields. We explore minority student-TA interactions in an important course in the sciences and STEM - introductory chemistry labs - at a large public university. The uncommon assignment method of students to TA instructors in these chemistry labs overcomes selection problems, and the small and active learning classroom setting with required attendance provides frequent interactions with the TA. We find evidence that underrepresented minority students are less likely to drop courses and are more likely to pass courses when assigned to minority TAs, but we do not find evidence of effects for grades and medium-term outcomes. The effects for the first-order outcomes are large with a decrease in the drop rate by 5.5 percentage points on a base of 6 percent, and an increase in the pass rate of 4.8 percentage points on a base of 93.6 percent. The findings are similar when we focus on Latinx student - Latinx TA interactions. The findings are robust to first-time vs. multiple enrollments in labs, specifications with different levels of fixed effects, limited choice of TA race, limited information of TAs, and low registration priority students. The findings have implications for debates over increasing diversity among PhD students in STEM fields because of spillovers to minority undergraduates.


Effects of chromium picolinate on glycemic control and kidney of the obese Zucker rat.
Chromium picolinate (Cr(pic)3) is advocated as adjuvant therapy for impaired glycemic control, despite concerns for DNA damage. Potential toxicity of Cr(pic)3 should be greater for the kidney that accumulates chromium. Therefore, we tested the hypothesis that Cr(pic)3 treatment of obese Zucker rats (OZR) exacerbates renal abnormalities associated with dysglycemia. Male OZR were treated with diets lacking or containing 5 and 10 mg/kg of chromium, as Cr(pic)3, for 20 weeks; lean Zucker rats (LZR) served as controls. Glycemic and renal effects of Cr(pic)3 were determined in the context of indices of oxidative stress and inflammation. The OZR displayed increased fasting plasma glucose and insulin in association with enlarged pancreatic islets exhibiting collagen and periodic acid Schiff-positive deposits compared to LZR; Cr(pic)3 treatment did not affect these parameters. The OZR, irrespective of Cr(pic)3, excreted more albumin than LZR. Also, other indices of renal function or histopathology were not affected by Cr(pic)3 treatment. Urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), an index of oxidative DNA damage, was greater in the OZR than LZR; dietary Cr(pic)3 treatment attenuated 8-OHdG excretion. However, immunostaining of kidney for 8-OHdG revealed similar staining pattern and intensity, despite significant renal accumulation of chromium in Cr(pic)3-treated groups. Finally, increased renal nitrotyrosine and cyclooxygenase-2 levels and urinary excretion of monocyte chemoattractant protein-1 of OZR were partially reversed by Cr(pic)3 treatment. Dietary Cr(pic)3 treatment of OZR does not beneficially influence glycemic status or increase the risk for oxidative DNA damage; rather, the treatment attenuates indices of oxidative stress and inflammation.


Antimicrobial susceptibilities and plasmid contents of Neisseria gonorrhoeae isolates from commercial sex workers in Dhaka, Bangladesh: emergence of high-level resistance to ciprofloxacin.
Commercial sex workers (CSWs) serve as the most important reservoir of sexually transmitted diseases (STD), including gonorrhea. Periodic monitoring of the antimicrobial susceptibility profile of Neisseria gonorrhoeae in a high-risk population provides essential clues regarding the rapidly changing pattern of antimicrobial susceptibilities. A study concerning the prevalence of gonococcal infection among CSWs was conducted in Bangladesh. The isolates were examined with regards to their antimicrobial susceptibility to, and the MICs of, penicillin, tetracycline, ciprofloxacin, cefuroxime, ceftriaxone, and spectinomycin by disk diffusion and agar dilution methods. The total plasmid profile of the isolates was also analyzed. Of the 224 CSWs, 94 (42%) were culture positive for N. gonorrhoeae. There was a good correlation between the results of the disk diffusion and agar dilution methods. Some 66% of the isolates were resistant to penicillin, and 34% were moderately susceptible to penicillin. Among the resistant isolates, 23.4% were penicillinase-producing N. gonorrhoeae (PPNG). 60.6% of the isolates were resistant and 38.3% were moderately susceptible to tetracycline, 17.5% were tetracycline-resistant N. gonorrhoeae, 11.7% were resistant and 26.6% had reduced susceptibility to ciprofloxacin, 2.1% were resistant and 11.7% had reduced susceptibility to cefuroxime, and 1% were resistant to ceftriaxone. All PPNG isolates contained a 3.2-MDa African type of plasmid, and a 24.2-MDa conjugative plasmid was present in 34.1% of the isolates. Since quinolones such as ciprofloxacin are recommended as the first line of therapy for gonorrhea, the emergence of significant resistance to ciprofloxacin will limit the usefulness of this drug for treatment of gonorrhea in Bangladesh.


Adding acceptance and commitment therapy to exposure and response prevention for obsessive-compulsive disorder: A randomized controlled trial.
The objective of this study was to test whether treatment acceptability, exposure engagement, and completion rates could be increased by integrating acceptance and commitment therapy (ACT) with traditional exposure and response prevention (ERP). 58 adults (68% female) diagnosed with obsessive-compulsive disorder (OCD; M age = 27, 80% white) engaged in a multisite randomized controlled trial of 16 individual twice-weekly sessions of either ERP or ACT + ERP. Assessors unaware of treatment condition administered assessments of OCD, depression, psychological flexibility, and obsessional beliefs at pretreatment, posttreatment, and six-month follow-up. Treatment acceptability, credibility/expectancy, and exposure engagement were also assessed. Exposure engagement was high in both conditions and there were no significant differences in exposure engagement, treatment acceptability, or dropout rates between ACT + ERP and ERP. OCD symptoms, depression, psychological inflexibility, and obsessional beliefs decreased significantly at posttreatment and were maintained at follow-up in both conditions. No between-group differences in outcome were observed using intent to treat and predicted data from multilevel modeling. ACT + ERP and ERP were both highly effective treatments for OCD, and no differences were found in outcomes, processes of change, acceptability, or exposure engagement.


Revisiting Bertin Matrices: New Interactions for Crafting Tabular Visualizations.
We present Bertifier, a web app for rapidly creating tabular visualizations from spreadsheets. Bertifier draws from Jacques Bertin's matrix analysis method, whose goal was to "simplify without destroying" by encoding cell values visually and grouping similar rows and columns. Although there were several attempts to bring this method to computers, no implementation exists today that is both exhaustive and accessible to a large audience. Bertifier remains faithful to Bertin's method while leveraging the power of today's interactive computers. Tables are formatted and manipulated through crossets, a new interaction technique for rapidly applying operations on rows and columns. We also introduce visual reordering, a semi-interactive reordering approach that lets users apply and tune automatic reordering algorithms in a WYSIWYG manner. Sessions with eight users from different backgrounds suggest that Bertifier has the potential to bring Bertin's method to a wider audience of both technical and non-technical users, and empower them with data analysis and communication tools that were so far only accessible to a handful of specialists.


A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness.
Vitamin D insufficiency/deficiency is commonly observed in black youth. The aim was to determine 25-hydroxyvitamin D [25(OH)D] in response to 2000 IU vitamin D supplementation over time; to evaluate the relation between 25(OH)D concentrations and total body fat mass by dual-energy x-ray absorptiometry; and to determine whether vitamin D supplementation improves arterial stiffness measured by pulse wave velocity (PWV). We conducted a randomized, blinded, controlled clinical trial. Forty-nine normotensive black boys and girls, aged 16.3 ± 1.4 yr, were randomly assigned to either the control group (400 IU/d; n = 24) or the experimental group (2000 IU/d; n = 25). Plasma 25(OH)D values at baseline and at 4, 8, and 16 wk were 34.0 ± 10.6, 44.9 ± 9.4, 51.2 ± 11.1, and 59.8 ± 18.2 nmol/liter, respectively, for the control group; and 33.1 ± 8.7, 55.0 ± 11.8, 70.9 ± 22.0, and 85.7 ± 30.1 nmol/liter, respectively, for the experimental group. The experimental group vs. the control group reached significantly higher 25(OH)D concentrations at 8 and 16 wk, respectively. Partial correlation analyses indicated that total body fat mass at baseline was significantly and inversely associated with 25(OH)D concentrations in response to the 2000-IU supplement across time. Furthermore, carotid-femoral PWV increased from baseline (5.38 ± 0.53 m/sec) to posttest (5.71 ± 0.75 m/sec) in the control group (P = 0.016), whereas in the experimental group carotid-femoral PWV decreased from baseline (5.41 ± 0.73 m/sec) to posttest (5.33 ± 0.79 m/sec) (P = 0.031). Daily 2000 IU vitamin D supplementation may be effective in optimizing vitamin D status and counteracting the progression of aortic stiffness in black youth. Plasma 25(OH)D concentrations in response to the 2000 IU/d supplementation are negatively modulated by adiposity.


Histopathological characterisation of retinal lesions associated to Diplostomum species (Platyhelminthes: Trematoda) infection in polymorphic Arctic charr Salvelinus alpinus.
The eye represents an immune privileged organ where parasites can escape host reactions. This study provides the first systematic evidence of the pathology associated with Diplostomum sp. infection in the eye retina of fish (i.e. Arctic charr). Histological sections showed that the trematodes caused mechanical disengagement between the retinal pigmentary epithelium and the neurosensory retina, with damaged cones and rods in the outer segment and epithelium reduced to a single layer of pigmentary cells. The metacercariae were "floating" in possibly fluid-filled vesicles together with several round cells, mostly located in the anterio-dorsal and anterio-ventral areas of the eye near the iris. The round cells may indicate internal retinal damage repair mechanisms, without connections to the general immune system. Metacercariae intestines contained pigmented cellular debris indicating that they feed on retinal epithelium. These retinal lesions may have similar vision effects as focal retinal detachment in vertebrates. Diplostomum metacercaria alters fish visual acuity but may in a lesser degree lead to a severe or total visual impairment because of repairing mechanisms. The pathology in the retina seems thereby to be dependent on fish size, age and dose.


A low proportion of rare bacterial taxa responds to abiotic changes compared with dominant taxa.
In many studies, rare bacterial taxa have been found to increase in response to environmental changes. These changes have been proposed to contribute to the insurance of ecosystem functions. However, it has not been systematically tested if rare taxa are more likely to increase in abundance than dominant taxa. Here, we study whether rare soil bacterial taxa are more likely to respond to environmental disturbances and if rare taxa are more opportunistic than dominant taxa. To test this, we applied nine different disturbance treatments to a grassland soil and observed changes in bacterial community composition over 7 days. While 12% of the dominant taxa changed in abundance, only 1% of the rare taxa showed any effect. Rare taxa increased in response to a single disturbance treatment only, while dominant taxa responded to up to five treatments. We conclude that rare taxa are not more likely to contribute to community dynamics after disturbances than dominant taxa. Nevertheless, as rare taxa outnumber abundant taxa with here 230 taxa that changed significantly, the chance is high that some of these rare taxa might act as ecologically important keystone taxa. Therefore, rare and abundant taxa might both contribute to ecosystem insurance.


Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death.
We investigated the clinical and biological significance of p130cas, an important cell signaling molecule, in ovarian carcinoma. Expression of p130cas in ovarian tumors, as assessed by immunohistochemistry, was associated with tumor characteristics and patient survival. The effects of p130cas gene silencing with small interfering RNAs incorporated into neutral nanoliposomes (siRNA-DOPC), alone and in combination with docetaxel, on in vivo tumor growth and on tumor cell proliferation (proliferating cell nuclear antigen) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were examined in mice bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) or taxane-resistant (HeyA8-MDR) ovarian tumors (n = 10 per group). To determine the specific mechanisms by which p130cas gene silencing abrogates tumor growth, we measured cell viability (MTT assay), apoptosis (fluorescence-activated cell sorting), autophagy (immunoblotting, fluorescence, and transmission electron microscopy), and cell signaling (immunoblotting) in vitro. All statistical tests were two-sided. Of 91 ovarian cancer specimens, 70 (76%) had high p130cas expression; and 21 (24%) had low p130cas expression. High p130cas expression was associated with advanced tumor stage (P < .001) and higher residual disease (>1 cm) following primary cytoreduction surgery (P = .007) and inversely associated with overall survival and progression-free survival (median overall survival: high p130cas expression vs low expression, 2.14 vs 9.1 years, difference = 6.96 years, 95% confidence interval = 1.69 to 9.48 years, P < .001; median progression-free survival: high p130cas expression vs low expression, 1.04 vs 2.13 years, difference = 1.09 years, 95% confidence interval = 0.47 to 2.60 years, P = .01). In mice bearing orthotopically implanted HeyA8 or SKOV3ip1 ovarian tumors, treatment with p130cas siRNA-DOPC in combination with docetaxel chemotherapy resulted in the greatest reduction in tumor growth compared with control siRNA therapy (92%-95% reduction in tumor growth; P < .001 for all). Compared with control siRNA therapy, p130cas siRNA-DOPC reduced SKOV3ip1 cell proliferation (31% reduction, P < .001) and increased apoptosis (143% increase, P < .001) in vivo. Increased tumor cell apoptosis may have persisted despite pan-caspase inhibition by the induction of autophagy and related signaling pathways. Increased p130cas expression is associated with poor clinical outcome in human ovarian carcinoma, and p130cas gene silencing decreases tumor growth through stimulation of apoptotic and autophagic cell death.


Retrieval analysis of PEEK rods for posterior fusion and motion preservation.
The purpose of this study was to analyze explanted PEEK rod spinal systems in the context of their clinical indications. We evaluated damage to the implant and histological changes in explanted periprosthetic tissues. 12 patients implanted with 23 PEEK rods were revised between 2008 and 2012. PEEK rods were of the same design (CD Horizon Legacy, Medtronic, Memphis TN, USA). Retrieved components were assessed for surface damage mechanisms, including plastic deformation, scratching, burnishing, and fracture. Patient history and indications for PEEK rod implantation were obtained from analysis of the medical records. 11/12 PEEK rod systems were employed for fusion at one level, and motion preservation at the adjacent level. Surgical complications in the PEEK cohort included a small dural tear in one case that was immediately repaired. There were no cases of PEEK rod fracture or pedicle screw fracture. Retrieved PEEK rods exhibited scratching, as well as impressions from the set screws and pedicle screw saddles. PEEK debris was observed in two patient tissues, which were located adjacent to PEEK rods with evidence of scratching and burnishing. This study documents the surface changes and tissue reactions for retrieved PEEK rod stabilization systems. Permanent indentations by the set screws and pedicle screws were the most prevalent observations on the surface of explanted PEEK rods.


Contribution of actin cytoskeletal alterations to ATP depletion and calcium-induced proximal tubule cell injury.
The actin cytoskeleton of rabbit proximal tubules was assessed by deoxyribonuclease (DNase) binding, sedimentability of detergent-insoluble actin, laser-scanning confocal microscopy, and ultrastructure during exposure to hypoxia, antimycin, or antimycin plus ionomycin. One-third of total actin was DNase reactive in control cells prior to deliberate depolymerization, and a similar proportion was unsedimentable from detergent lysates during 2.5 h at 100,000 g. Tubules injured by hypoxia or antimycin alone, without glycine, showed Ca(2+)-dependent pathology of the cytoskeleton, consisting of increases in DNase-reactive actin, redistribution of pelletable actin, and loss of microvilli concurrent with lethal membrane damage. In contrast, tubules similarly depleted of ATP and incubated with glycine showed no significant changes of DNase-reactive actin or actin sedimentability for up to 60 min, but, nevertheless, developed substantial loss of basal membrane-associated actin within 15 min and disruption of actin cores and clubbing of microvilli at durations > 30 min. These structural changes that occurred in the presence of glycine were not prevented by limiting Ca2+ availability or pH 6.9. Very rapid and extensive cytoskeletal disruption followed antimycin-plus-ionomycin treatment. In this setting, glycine and pH 6.9 decreased lethal membrane damage but did not ameliorate pathology in the cytoskeleton or microvilli; limiting Ca2+ availability partially protected the cytoskeleton but did not prevent lethal membrane damage. The data suggest that both ATP depletion-dependent but Ca(2+)-independent, as well as Ca(2+)-mediated, processes can disrupt the actin cytoskeleton during acute proximal tubule cell injury; that both types of change occur, despite protection afforded by glycine and reduced pH against lethal membrane damage; and that Ca(2+)-independent processes primarily account for prelethal actin cytoskeletal alterations during simple ATP depletion of proximal tubule cells.


Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.
Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent.


Intrauterine environmental and genetic influences on the association between birthweight and cardiovascular risk factors: studies in twins as a means of testing the fetal origins hypothesis.
Evidence has accumulated that low birthweight is associated with several risk factors for cardiovascular disease. However, it is not known whether or not these associations are due to a programmed response to intrauterine malnutrition or genetic factors influencing both birthweight and cardiovascular risk factors. Twin studies offer a unique opportunity to distinguish between intrauterine and genetic origins of the association between birthweight and cardiovascular risk. In our twin cohort, low birthweight was associated with insulin resistance, lower HDL and shorter height within both dizygotic and monozygotic twin pairs, suggesting that these associations are, at least in part, independent of genetic factors. In contrast, low birthweight was associated with blood pressure, total and LDL cholesterol, fibrinogen and sympathetic activation within dizygotic twin pairs, but not within monozygotic twin pairs. These differences between dizygotic and monozygotic twins suggest that these associations are, at least in part, due to genetic factors. Therefore, both intrauterine environmental and genetic factors appear to play a role in the association between birthweight and cardiovascular risk factors. In the future, strategies may be developed targeted at improving or preventing impaired intrauterine growth. However, the effects of interventions that comprise changes in environment within the normal range may be limited due to the possible important role of genetic factors.


Lessons from the Far End: Caterpillar FRASS-Induced Defenses in Maize, Rice, Cabbage, and Tomato.
Plant defenses to insect herbivores have been studied in response to several insect behaviors on plants such as feeding, crawling, and oviposition. However, we have only scratched the surface about how insect feces induce plant defenses. In this study, we measured frass-induced plant defenses in maize, rice, cabbage, and tomato by chewing herbivores such as European corn borer (ECB), fall armyworm (FAW), cabbage looper (CL), and tomato fruit worm (TFW). We observed that caterpillar frass induced plant defenses are specific to each host-herbivore system, and they may induce herbivore or pathogen defense responses in the host plant depending on the composition of the frass deposited on the plant, the plant organ where it is deposited, and the species of insect. This study adds another layer of complexity in plant-insect interactions where analysis of frass-induced defenses has been neglected even in host-herbivore systems where naturally frass accumulates in enclosed feeding sites over extended periods of time.


Immunocytochemical identification of T-cells in HIV-1 encephalitis: implications for pathogenesis of CNS disease.
T-lymphocytes enter the brain in viral encephalitides. The monoclonal antibodies UCHL1 and Leu22 are widely used to identify these cells; however, both antibodies cross-react with peripheral blood monocytes, cells ontologically related to brain macrophages and microglia. This study examines the nature of UCHL1- and Leu22-positive cells in HIV-1 encephalitis, and investigates whether they carry the gp41 epitope of HIV-1. Formalin-fixed sections of brain from eight AIDS patients were double-stained using combinations of UCHL1 and Leu22 antibodies with the lectin Ricinus communis agglutinin (RCA), a lectin that binds to microglia, macrophages, and multinucleated giant cells (MNGC), or antibody to the gp41 transmembrane protein of HIV-1 and UCHL1. Some sections were also stained with the OPD4 antibody to helper/inducer T-cells. Small round cells were single-stained for UCHL1 and Leu22 in all cases. A few cells having morphologic characteristics of microglia, macrophages, and MNGC were observed using double stains employing UCHL1 or Leu22 and RCA, or UCHL1 or Leu22 and anti-gp41. Small round cells positive for both UCHL1 or Leu22 and gp41 could represent either macrophages or lymphocytes. The presence of small round cells positive only for UCHL1 or Leu22 in double-stained sections strongly suggests that T-cells are present in the brain in HIV encephalitis. Only a few of these cells were positive with OPD4 antibody for T-helper cells. Inability to demonstrate unequivocally HIV-1-infected T-cells suggests that microglia and macrophages, not T-cells, are the more important reservoirs of retrovirus in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment for posterior fossa dissemination of primary supratentorial glioma.
This study was designed to assess the presentation, management, and outcome of cases involving patients who had a supratentorial glioma that subsequently progressed in the posterior fossa (PF). The authors performed a retrospective chart review of adult patients treated between 1997 and 2005 for supratentorial gliomas that progressed in the PF. The 29 patients with PF progression in this study were relatively young (median age of 34 years at original presentation). Twenty of these patients presented with symptoms. The symptoms were typically nonspecific to this population, at times leading to delays in diagnosis. Overall, these symptoms resolved in eight patients (40%) and progressed or remained unchanged in 12 (60%). Patients treated with more than 5000 cGy of radiation administered to the PF were more likely to have symptom resolution than those who received any other form of treatment, including reduced doses of radiation (p = 0.004). The patients treated with higher doses also survived significantly longer after PF progression (univariate analysis, p = 0.01, and after adjusting for tumor grade, p = 0.04). Patients with PF progression of supratentorial infiltrative gliomas may benefit from treatment, and the authors recommend more than 5000 cGy of radiation to the PF if prior radiotherapy ports and doses allow.


Ocean currents generate large footprints in marine palaeoclimate proxies.
Fossils of marine microorganisms such as planktic foraminifera are among the cornerstones of palaeoclimatological studies. It is often assumed that the proxies derived from their shells represent ocean conditions above the location where they were deposited. Planktic foraminifera, however, are carried by ocean currents and, depending on the life traits of the species, potentially incorporate distant ocean conditions. Here we use high-resolution ocean models to assess the footprint of planktic foraminifera and validate our method with proxy analyses from two locations. Results show that foraminifera, and thus recorded palaeoclimatic conditions, may originate from areas up to several thousands of kilometres away, reflecting an ocean state significantly different from the core site. In the eastern equatorial regions and the western boundary current extensions, the offset may reach 1.5 °C for species living for a month and 3.0 °C for longer-living species. Oceanic transport hence appears to be a crucial aspect in the interpretation of proxy signals.