The surgical management of diverticular disease of the colon complicated by perforation.
Thirty instances of perforating diverticulitis seen at the University of Alabama Hospital were retrospectively reviewed. The correct diagnosis was assumed prior to operation in only 12. A palpable mass located in the lower part of the abdomen was found in 15 patients. All of the patients had a pericolic type of perforation. Seven patients, five with symptoms highly suggestive of a diverticular disease of the colon, were operated upon for suspected gynecologic problems. It appears that the patients in this group could have been treated more appropriately if the diagnosis of a perforating diverticulitis had been considered preoperatively. It is important to determine whether or not the perforation is pericolic, intramesenteric or free, with spreading peritonitis, since the advocated treatment is different for each type of perforation observed.


Anti-Müllerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa.
Few data exist regarding anti-Müllerian hormone, a marker of ovarian reserve, in relation to environmental factors with potential ovarian toxicity. This analysis included 420 women from Limpopo, South Africa studied in 2010-2011. Women were administered comprehensive questionnaires, and plasma concentrations of anti-Müllerian hormone and dichlorodiphenyltrichloroethane were determined. We used separate multivariable models to examine the associations between natural log-transformed anti-Müllerian hormone concentration (ng/ml) and each of the lifestyle, reproductive, and environmental factors of interest, adjusted for age, body mass index, education, and parity. The median age of women was 24 years (interquartile range [IQR] = 22 to 26); the median anti-Müllerian hormone concentration was 3.1 ng/ml (IQR = 2.0 to 6.0). Women who reported indoor residual spraying in homes with painted walls (indicative of exposure to pyrethroids) had 25% lower (95% confidence interval [CI] = -39%, -8%) anti-Müllerian hormone concentrations compared with women who reported no spraying. Little evidence of decreased anti-Müllerian hormone concentrations was observed among women with the highest dichlorodiphenyltrichloroethane levels. Compared with women who used an electric stove, no association was observed among women who cooked indoors over open wood fires. The findings also suggested lower anti-Müllerian hormone concentrations among women who drank coffee (-19% [95% CI = -31%, -5%]) or alcohol (-21% [95% CI = -36%, -3%]). These are among the first data regarding anti-Müllerian hormone concentrations relative to pesticides and indoor air pollution. Our results are suggestive of decreased ovarian reserve associated with exposure to pyrethroid pesticides, which is consistent with laboratory animal data.


Vasopressin V2 receptor mutants that cause X-linked nephrogenic diabetes insipidus: analysis of expression, processing, and function.
We investigated the biochemical and functional properties of five vasopressin V2 receptor mutants (L44F, L44P, W164S, S167L, and S167T) that were recently described in families with a history of X-linked nephrogenic diabetes insipidus. COS.M6 cells transfected with cDNA encoding these mutants acquired < 4% specific [3H]arginine vasopressin (AVP) binding sites on the cell surface in comparison with cells transfected with cDNA coding for the wild-type receptor. Membrane preparations from COS.M6 cells or human embryonic kidney 293 cells expressing these mutants did not respond with an increase in adenylyl cyclase activity in response to AVP, which is in contrast to membranes from cells expressing the wild-type. By analyzing fusion proteins of the V2 receptor and Escherichia coli alkaline phosphatase attached to the carboxyl terminus of the receptor moiety, we found that the mutants L44P, W164S, S167L, and S167T lacked complex glycosylation and were expressed at low levels. The data suggest that the mutants L44P, W164S, S167T, and S167L are misfolded and therefore retained within the endoplasmic reticulum and degraded. In contrast, the fusion proteins carrying the mutant L44F and the in vitro mutant S167A were expressed in their mature form at wild-type levels; however, only the mutant S167A was functionally active. Site-directed mutagenesis of S167 revealed that elimination of the endogenous hydroxyl group (S167A) yielded a protein with properties identical to those of the wild-type receptor, whereas both the introduction of a methyl group (S167T) and the replacement of the hydroxyl group by an isopropyl group (S167L) profoundly disturbed receptor processing. The data show that minute changes at codon 167 nearly abolish expression of a mature protein, thus defining structural requirements of this codon.


Contrasting transcriptional responses of a virulent and an attenuated strain of Mycobacterium tuberculosis infecting macrophages.
H37Rv and H37Ra are well-described laboratory strains of Mycobacterium tuberculosis derived from the same parental strain, H37, that show dramatically different pathogenic phenotypes. In this study, the transcriptomes of the two strains during axenic growth in broth and during intracellular growth within murine bone-marrow macrophages were compared by whole genome expression profiling. We identified and compared adaptations of either strain upon encountering an intracellular environment, and also contrasted the transcriptomes of the two strains while inside macrophages. In the former comparison, both strains induced genes that would facilitate intracellular survival including those involved in mycobactin synthesis and fatty acid metabolism. However, this response was stronger and more extensive for H37Rv than for H37Ra. This was manifested as the differential expression of a greater number of genes and an increased magnitude of expression for these genes in H37Rv. In comparing intracellular transcriptional signatures, fifty genes were found to be differentially expressed between the strains. Of these fifty, twelve were under control of the PhoPR regulon. Further differences between strains included genes whose products were members of the ESAT-6 family of proteins, or were associated with their secretion. Along with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra.


Impact of the COVID-19 pandemic on the incidence of dengue fever in Peru.
Dengue virus and severe acute respiratory syndrome coronavirus 2 coexist in dengue-endemic countries; therefore, the adoption of preventive measures is essential to control the spread of both viruses. We conducted an ecological study to compare the temporal patterns of the incidence of dengue before and during the Coronavirus disease 2019 (COVID-19) pandemic in Peru. A time-series analysis comparing the incidence of dengue using a Student's t test with variance correction was performed. Poisson regression was applied to determine the incidence rate ratio (IRR) of dengue before and during the COVID-19 pandemic. The incidence of dengue was found to be increased in all endemic regions of Peru during the COVID-19 pandemic, with the highest incidences registered in Ica (IRR = 90.14), Huánuco (IRR = 38.6), and Ucayali (IRR = 23.78), with the exception of Piura (IRR = 0.83). The highest increases in the number of dengue cases per million inhabitants were in Ucayali (393.38), Tumbes (233.19), Ica (166.08), and Loreto (129.93). The gradient of dengue cases was positive in all endemic regions during the COVID-19 pandemic. The number of dengue cases per million increased during the COVID-19 pandemic throughout Peru and in several endemic regions, with the exception of Piura.


Mutations in the env gene of human immunodeficiency virus type 1 NDK isolates and the use of African green monkey CXCR4 as a co-receptor in COS-7 cells.
A previous report from this laboratory described the isolation of the first CD4-independent human immunodeficiency virus type 1 isolate, m7NDK. This independence of CD4 is due to seven mutations located in the C2, V3 and C3 regions of the gp120 protein. The present report describes the entry features of the m5NDK virus, which contains five of the seven m7NDK mutations, located in the V3 loop and C3 region. The entry of this virus is strictly CD4-dependent but it can fuse with African green monkey (agm) COS-7 cells bearing human CD4 (h-CD4). This fusion is directly due to the five mutations in the envgene. It has also been shown that entry of m7NDK is CD4-independent in COS-7 cells. Since the wild-type NDK and m7NDK viruses use the human CXCR4 protein as co-receptor, agm-CXCR4 was cloned and used in transfection and fusion inhibition experiments to show that this receptor can be used by the m5 and m7NDK viruses. The wild-type NDK virus, which does not enter COS-7 cells, can use agm-CXCR4, but only when the receptor is transfected into target cells. Although co-receptor nature and expression levels are still major determinants of virus entry, this is the first case where a few mutations in the env gene can overcome this restriction.


SOX2 gene expression and its role in triple negative breast cancer tissues.
The aim of this work was to study the expression of SOX2 gene in triple negative breast cancer and its role. One hundred and twenty specimens of paraffin-embedded triple negative breast cancer (TNBC) tissues were collected from Harbin Medical University Cancer Hospital, Heilongjiang, China between January 2014 and March 2018. The expression of SOX2 was detected using immunohistochemistry, and the relationship between the expression of SOX2 and clinical features was analyzed. Breast cancer cell lines (normal group, SOX2 interference group, SOX2 overexpression group) were cultured in vitro to detect the proliferation and cloning ability of the cell lines. The expression of SOX2 was related to lymph node metastasis and stage of breast cancer (P less than 0.05), but was not related to age, menopause or tumor size (P > 0.05); the expression of SOX2 in the overexpression group was significantly greater than that in the normal group after 72 hours, and no significant difference between the overexpression group and the interference group was observed. The number of clone cells with a diameter of 0.5 mm in the interference group was lower compared to the normal group, and that of the overexpression group was higher, but not significant. SOX2 is associated with the high invasiveness of breast cancer and can be used as a therapeutic target to inhibit the metastasis of cancer cells. SOX2 can promote the proliferation of breast cancer cells and affect the size of clone cells in its involvement in clone.


Inhibition of renin secretion by HCl is related to chloride in both dog and rat.
To determine if inhibition of renin release by HCl is related to acidosis or to Cl-, the effects of peripheral venous infusions of HCl and H2SO4 on plasma renin activity (PRA) were compared in the dog and the rat. In NaCl-deprived, pentobarbital-anesthetized dogs, either 0.15 M HCl (n = 10) or 0.075 M H2SO4 (n = 7) was infused for 60 min. In 5 of the 10 HCl-infused dogs (group A), urine Cl- excretion increased (P less than 0.01) during HCl infusion. In the remaining five dogs (group B), Cl- excretion did not increase. Cl- excretion also did not increase during H2SO4 infusion. Comparable acidosis was produced in all three groups. PRA decreased (P less than 0.01) in response to HCl in group A but did not change (P greater than 0.8) in group B HCl-infused dogs or in H2SO4-infused dogs. In NaCl-deprived, anesthetized rats, PRA was suppressed (P less than 0.05) by HCl (from 40.6 +/- 9.4 to 27.4 +/- 5.3 ng . ml-1 . h-1 (SE)) but not H2SO4 (from 37.1 +/- 4.2 to 37.0 +/- 6.3 ng . ml-1 . h-1), despite comparable acidosis. Cl- excretion increased only in HCl-infused rats. In conclusion, inhibition of PRA by acute infusion of HCl is specifically related to Cl-.


Imaging Flies by Fluorescence Microscopy: Principles, Technologies, and Applications.
The development of fluorescent labels and powerful imaging technologies in the last two decades has revolutionized the field of fluorescence microscopy, which is now widely used in diverse scientific fields from biology to biomedical and materials science. Fluorescence microscopy has also become a standard technique in research laboratories working on Drosophila melanogaster as a model organism. Here, we review the principles of fluorescence microscopy technologies from wide-field to Super-resolution microscopy and its application in the Drosophila research field.


The effect of diabetes on ovaries in a rat model: the role of interleukin-33 and apoptosis.
Interleukin-33 (IL-33) is a novel cytokine involved in diabetes mellitus (DM) but its role in diabetic ovarian injury is unknown. As IL-33 is modulated by apoptosis, we aimed at investigating the effect of diabetes on ovaries in terms of evaluating apoptosis and IL-33 in a rat model. In this prospective experimental study, 16 female, nonpregnant Sprague-Dawley albino rats (12 weeks, 220-240 g) were randomly divided into two groups. Group 1 included eight healthy nondiabetic rats as controls and group 2 included eight rats in which diabetes was induced by intraperitoneal (i.p) injection of streptozotocin (STZ). After overt DM occurred (blood glucose >400 mgr/dl), all animals were euthanized and blood samples were collected by cardiac puncture for biochemical analysis. Bilateral oophorectomy was performed for histopathological examination. Serum levels of IL-33 and ovarian IL-33 and caspase-3 immunoexpressions were assessed. Immunoexpressions of caspase-3 and IL-33 were significantly higher in ovarian stromal cells of the diabetic rats compared to the controls. Also, in diabetic group, serum IL33 levels were significantly higher than the control group. In conclusion, increased IL-33 was observed both in serum and ovaries of STZ-induced diabetic rats as well as increased apoptosis in these diabetic rats. IL-33 may contribute to the apoptosis in diabetic ovarian injury.


Quality of life in normotensives compared to hypertensive men treated with isradipine or methyldopa as monotherapy or in combination with captopril: the LOMIR-MCT-IL study.
Quality of life (QOL) measures were assessed in a multi-center, double-blind, case-controlled trial of 1 year's duration. A total of 368 hypertensive male patients were randomly assigned to monotherapies of either isradipine, methyldopa or placebo. If normotension was not achieved, captopril was added. QOL assessments in the hypertensives and in 155 normotensives included a self-structured scale to measure the subjective perception of QOL, the severity, desirability and controllability of recent critical life events, semantic memory, physical dysfunction, sleep disorders, sexual difficulties, depression and work-related stress. The overall withdrawal rate during the trial was 19%, mainly due to lack of efficacy and adverse experiences. At baseline, and at the end of the trial, the normotensives as compared to hypertensive patients, had significantly better scores in most QOL measures. Patients treated with the combination of isradipine and captopril reported more favorable changes in the subjective measure of QOL (P < 0.03) and in semantic memory (P < 0.001) than patients treated with any of the monotherapies or with methyldopa in combination with captopril. There were no statistically significant differences among treatments for changes of other indices of QOL. In most QOL measurements, normotensives rated better then hypertensives. Patients treated on long-term therapy with the combination of isradipine and captopril showed improvement in self-structured QOL measures and semantic memory, compared to patients treated either with methyldopa or placebo.


Off-target serine/threonine kinase 10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders.
Skin disorders are among the most common adverse events related to treatment with epidermal growth factor receptor (EGFR) kinase inhibitors, and of these, erlotinib is known to cause more frequent and severe skin disease than other agents in this class. Although previous reports have shown that cutaneous manifestations are triggered by the inhibition of multiple EGFR-related homeostatic functions of the skin, this mechanism alone cannot explain the differences in frequency and severity of skin disorders caused by different kinase inhibitors. In this study, we focused on the relationship between the off-target kinase inhibition and aggravation of skin disorders. Based on calculations using reported K(d) values and plasma drug concentrations, serine/threonine kinase 10 (STK10) and Ste20-like kinase (SLK) were selected as candidates preferentially inhibited by erlotinib over gefitinib. In vitro experiments confirmed that STK10 and SLK kinase activity are inhibited by erlotinib at clinical concentrations, whereas only STK10 is slightly inhibited by gefitinib. It was also shown that erlotinib up-regulated lymphocytic responses such as interleukin (IL)-2 secretion and cell migration at clinical concentrations, whereas gefitinib did not affect lymphocyte activity. Moreover, small interfering RNA experiments revealed that STK10 plays a major role in up-regulation of the lymphocytic responses induced by erlotinib treatment. Finally, the role of erlotinib-induced lymphocyte activation was assessed in vivo using irritant hypersensitivity models. The results indicated that erlotinib aggravates cutaneous inflammatory reactions through the activation of lymphocytic responses such as IL-2 secretion and cell migration. These results demonstrated that off-target inhibition of STK10 by erlotinib enhances lymphocytic responses, which lead to the aggravation of skin inflammation.


[Molecular genetic diagnostics. Technology for detecting mutations in DNA].
Analyses of the genetic material in both inherited and acquired diseases such as cancer are already part of the repertoire of many laboratories. Over the last ten to fifteen years research has revealed a very complex human DNA, and shown that the molecular basis for disease is both intricate and variable. Methods for detecting the various categories of genetic changes are needed. These methods should be simple, quick and easy to perform, and cost-effective, and at the same time be both specific and sensitive. No single technology can fulfil all these criteria, and a variety of methods has therefore been introduced. In this overview we describe the different methods and their strengths and limitations.


Time on your hands: Perceived duration of sensory events is biased toward concurrent actions.
Perceptual systems must rapidly generate accurate representations of the world from sensory inputs that are corrupted by internal and external noise. We can typically obtain more veridical representations by integrating information from multiple channels, but this integration can lead to biases when inputs are, in fact, not from the same source. Although a considerable amount is known about how different sources of information are combined to influence what we perceive, it is not known whether temporal features are combined. It is vital to address this question given the divergent predictions made by different models of cue combination and time perception concerning the plausibility of cross-modal temporal integration, and the implications that such integration would have for research programs in action control and social cognition. Here we present four experiments investigating the influence of movement duration on the perceived duration of an auditory tone. Participants either explicitly (Experiments 1-2) or implicitly (Experiments 3-4) produced hand movements of shorter or longer durations, while judging the duration of a concurrently presented tone (500-950 ms in duration). Across all experiments, judgments of tone duration were attracted toward the duration of executed movements (i.e., tones were perceived to be longer when executing a movement of longer duration). Our results demonstrate that temporal information associated with movement biases perceived auditory duration, placing important constraints on theories modeling cue integration for state estimation, as well as models of time perception, action control and social cognition. (PsycINFO Database Record


Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?
Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual's genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP.


IL-27 receptor signaling regulates memory CD4+ T cell populations and suppresses rapid inflammatory responses during secondary malaria infection.
Interleukin-27 (IL-27) is known to control primary CD4(+) T cell responses during a variety of different infections, but its role in regulating memory CD4(+) T responses has not been investigated in any model. In this study, we have examined the functional importance of IL-27 receptor (IL-27R) signaling in regulating the formation and maintenance of memory CD4(+) T cells following malaria infection and in controlling their subsequent reactivation during secondary parasite challenge. We demonstrate that although the primary effector/memory CD4(+) T cell response was greater in IL-27R-deficient (WSX-1(-/-)) mice following Plasmodium berghei NK65 infection than in wild-type (WT) mice, there were no significant differences in the size of the maintained memory CD4(+) T population(s) at 20 weeks postinfection in the spleen, liver, or bone marrow of WSX-1(-/-) mice compared with WT mice. However, the composition of the memory CD4(+) T cell pool was slightly altered in WSX-1(-/-) mice following clearance of primary malaria infection, with elevated numbers of late effector memory CD4(+) T cells in the spleen and liver and increased production of IL-2 in the spleen. Crucially, WSX-1(-/-) mice displayed significantly enhanced parasite control compared with WT mice following rechallenge with homologous malaria parasites. Improved parasite control in WSX-1(-/-) mice during secondary infection was associated with elevated systemic production of multiple inflammatory innate and adaptive cytokines and extremely rapid proliferation of antigen-experienced T cells in the liver. These data are the first to demonstrate that IL-27R signaling plays a role in regulating the magnitude and quality of secondary immune responses during rechallenge infections.


A comparison of three standard methods of identifying mast cells in endobronchial biopsies in normal and asthmatic subjects.
Reported mast-cell counts in endobronchial biopsies from asthmatic subjects are conflicting, with different methodologies often being used. This study compared three standard methods of counting mast cells in endobronchial biopsies from asthmatic and normal subjects. Endobronchial biopsies were obtained from atopic asthmatic subjects (n = 17), atopic nonasthmatic subjects (n = 6), and nonatopic nonasthmatic control subjects (n = 5). After overnight fixation in Carnoy's fixative, mast cells were stained by the short and long toluidine blue methods and antitryptase immunohistochemistry and were counted by light microscopy. Method comparison was made according to Bland & Altman. The limits of agreement were unacceptable for each of the comparisons, suggesting that the methods are not interchangeable. Coefficients of repeatability were excellent, and not different for the individual techniques. These results suggest that some of the reported differences in mast-cell numbers in endobronchial biopsies in asthma may be due to the staining method used, making direct comparisons between studies invalid. Agreement on a standard method is required for counting mast cells in bronchial biopsies, and we recommend the immunohistochemical method, since fixation is less critical and the resultant tissue sections facilitate clear, accurate, and rapid counts.


[Determination of plantar pressure in people who use orthoses of the foot].
To know the transfer of static plantar pressures and body weight distribution through the lower limbs that occur in people with and without the use of orthoses of different densities and influence in other areas of the foot. 32 people participated through non-probability convenience sampling in a quasi-experimental study in which self-reported data were recorded, the determination of plantar pressure, and body weight distribution. 64 feet were studied, showing no difference between the medium pressure and the forefoot without orthoses of 5 mm and 10 mm. Decrease in average pressure and percentage of body weight, both statistically significant, with hindfoot orthoses 10 mm was observed. Given the current evidence for the prescribing and use of foot orthoses is limited, designed to improve the functionality and prevent the onset of disease and foot deformities, these results highlight the need to prescribe orthotics 10 mm when needed to relieve pressure on the backfoot, not seeing the average pressure increased nor diminished in other areas of the foot.


Cytogenetic evidence for the clonal nature of Richter's syndrome.
Sequential chromosome studies were done on a patient who developed diffuse histiocytic lymphoma (DHL) after a long history of untreated chronic T-cell leukemia. During the indolent phase of her disease, a pseudodiploid lymphocyte population with 3q+ and 14q+ chromosome markers gradually replaced the originally diploid tumor cells. The karyotype of the lymphoma was hypertriploid (70--74 chromosomes) with the same 3q+ and 14q+ markers. The findings indicate that DHL in this patient evolved from the leukemic T-cell clone.


Enhancing anti-tumor immune responses through combination therapies: epigenetic drugs and immune checkpoint inhibitors.
Epigenetic mechanisms are processes that affect gene expression and cellular functions without involving changes in the DNA sequence. This abnormal or unstable expression of genes regulated by epigenetics can trigger cancer and other various diseases. The immune cells involved in anti-tumor responses and the immunogenicity of tumors may also be affected by epigenomic changes. This holds significant implications for the development and application of cancer immunotherapy, epigenetic therapy, and their combined treatments in the fight against cancer. We provide an overview of recent research literature focusing on how epigenomic changes in immune cells influence immune cell behavior and function, as well as the immunogenicity of cancer cells. And the combined utilization of epigenetic medications with immune checkpoint inhibitors that focus on immune checkpoint molecules [e.g., Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), T cell Immunoglobulin and Mucin Domain (TIM-3), Lymphocyte Activation Gene-3 (LAG-3)] present in immune cells and stromal cells associated with tumors. We highlight the potential of small-molecule inhibitors targeting epigenetic regulators to amplify anti-tumor immune responses. Moreover, we discuss how to leverage the intricate relationship between cancer epigenetics and cancer immunology to create treatment regimens that integrate epigenetic therapies with immunotherapies.


Sparsity-promoting tomographic fluorescence imaging with simplified spherical harmonics approximation.
Fluorescence molecular tomography has become a promising technique for in vivo small animal imaging and has many potential applications. Due to the ill-posed and the ill-conditioned nature of the problem, Tikhonov regularization is generally adopted to stabilize the solution. However, the result is usually over-smoothed. In this letter, the third-order simplified spherical harmonics approximation to radiative transfer equation is utilized to model the photon propagation within biological tissues. Considering the sparsity of the fluorescent sources, we replace Tikhonov method with an iteratively reweighted scheme. By dynamically updating the weight matrix, L1-norm regularization can be approximated, which can promote the sparsity of the solution. Simulation study shows that this method can preserve the sparsity of the fluorescent sources within heterogeneous medium, even with very limited measurement data.


Simulated inventory and distribution of 137Cs released from multiple sources in the global ocean.
Radioactive cesium (137Cs) is distributed in the world's oceans as a result of global fallout from atmospheric nuclear weapons tests, releases from fuel reprocessing plants, and inputs from nuclear power plant accident. In order to detect future radionuclide contamination, it is necessary to establish a baseline global distribution of radionuclides such as 137Cs and to understand the ocean transport processes that lead to that distribution. In order to aid in the interpretation of the observed database, we have conducted a suite of simulations of the distribution of 137Cs using a global ocean general circulation model (OGCM). Simulated 137Cs radioactivity concentrations agree well with observations, and the results were used to estimate the changes in inventories for each ocean basin. 137Cs activity concentration from atmospheric nuclear weapons tests are expected to be detectable in the world ocean until at least 2030.


Early prediction of a significant patent ductus arteriosus in infants <32 weeks gestational age.
The optimal thresholds for identification of preterm infants at greatest risk for adverse sequelae related to patent ductus arteriosus have not been well delineated. Our aim was to determine hemodynamic parameters in the first 24 hours using continuous non-invasive vital and structural measurements to predict which infants required PDA treatment in our institution. Retrospective secondary analysis of data from infants born 23 to 32 weeks gestational age with cardiac output and stroke volume via electrical cardiometry, cerebral tissue oximetry measurements, mean arterial blood pressure (BP), heart rate, and oxygen saturation and functional echocardiography results at 12 hours of life were recorded when available (93 percent of subjects). A total of 292 infants, of which 55 (26±2 weeks, 862±268 grams) were treated for PDA. Treated infants demonstrated increased left ventricular output (p < 0.001) and lower mean BP (p = 0.010). The optimal area under the receiver operating characteristic curve (AUC) for predicting PDA treatment in our all gestations cohort is a mean BP at 15 hours of life of <33 mm Hg (AUC = 0.854, p < 0.001, 95% CI 0.792, 0.916). For infants <28 weeks a mean BP at 13 hours of life of <33 mm Hg (AUC = 0.741, p < 0.050, 95% CI 0.642, 0.839). In our cohort increased left ventricular output and lower mean BP predicted a clinically significant PDA requiring treatment.


Stimulation of ATP hydrolysis by ssDNA provides the necessary mechanochemical energy for G4 unfolding.
The G-quadruplex (G4) is a distinct geometric and electrophysical structure compared to classical double-stranded DNA, and its stability can impede essential cellular processes such as replication, transcription, and translation. This study focuses on the BsPif1 helicase, revealing its ability to bind independently to both single-stranded DNA (ssDNA) and G4 structures. The unfolding activity of BsPif1 on G4 relies on the presence of a single tail chain, and the covalent continuity between the single tail chain and the G4's main chain is necessary for efficient G4 unwinding. This suggests that ATP hydrolysis-driven ssDNA translocation exerts a pull force on G4 unwinding. Molecular dynamics simulations identified a specific region within BsPif1 that contains five crucial amino acid sites responsible for G4 binding and unwinding. A "molecular wire stripper" model is proposed to explain BsPif1's mechanism of G4 unwinding. These findings provide a new theoretical foundation for further exploration of the G4 development mechanism in Pif1 family helicases.


Inactivation of membrane transport in Escherichia coli by near-ultraviolet light.
Evidence is presented that near-ultraviolet (near-UV) light can alter galactoside transport in Escherichia coli in several independent ways. It can inactivate the permease system per se, it can interfere with metabolic energy production or transfer, and it can cause an increase in the generalized permeability of the membrane. Earlier publications suggested that near-UV destroys cofactors needed for electron transport and thus places a limitation on energy reserves. In agreement, we found that the active accumulation of [14C]thiomethyl-beta-D-galactopyranoside is decreased after irradiation by a larger factor than that due to action directly on the permease system. The effect on the latter was measured by the decrease in the rate of o-nitrophenyl-beta-D-galactopyranoside (ONPG) transport. As evidence that energy supplies for this "downhill" process did not become rate limiting after irradiation, we found that carbonylcyanide-m-chlorophenyl-hydrazone did not stimulate ONPG transport of irradiated cells. Cells genetically deficient in functional permease or cells treated with formaldehyde still transport ONPG passively, although at much lower rates. With the use of such cells, it was found that high fluences (doses) made the cells leaky. Further evidence that the permease system and the metabolic energy system can be inactivated independently is also presented. It is shown that a photoproduct from the irradiation of chloramphenicol inactivates the permease system much more efficiently than the energy system. In addition, it is shown that thio-beta-D-digalactopyranoside protects the permease system, but not the energy system, both against direct inactivation by near-UV and against photosensitized inactivation in the presence of chloramphenicol.


Microbiology of carious lesions.
Dental caries is a process in which the enamel, and later the dentine, is demineralized by acids produced by bacterial fermentation of carbohydrates. The main indicator bacteria in this process are mutans streptococci and lactobacilli. This article discusses how monitoring of patients' salivary levels of these organisms can help in prevention and treatment of caries in different patient populations.


[Effect of antioxidants on radical-initiated peroxidation of retinal homogenate].
To compare the effect of antioxidants on radical-initiated peroxidation of retinal homogenate. Lipid peroxides in bovine retinal homogenate were induced by 5 mM FeNO3 (Fe), 25 mM 2, 2'-azobis(2,4'-dimethylvaleronitrile) (lipid-soluble, AMVN) or 50 mM 2,2'-azobis (2-amidinoprpane) dihydrochloride (water-soluble, AAPH) and the preventive effects of antioxidants were measured. Phosphatidylcholine hydroperoxide (PC-OOH) was analyzed with high performance liquid chromatography (HPLC) as the endpoint biomarker. Troglitazone, an oral hypoglycemic agent, inhibited PC-OOH production by Fe and AMVN. Therefore, it may be effective for protecting against oxidative stress on the inner surface plasma membranes and subcellular organelle. Quercetin has radical scavenging effects on both sides of the membrane, because it prevents PC-OOH production by AMVN or AAPH. These results demonstrate the usefulness of an in vitro screening test that can accurately and rapidly determine the capacity of an antioxidant against lipid peroxidation or oxidative stress.


ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC). LCCS is genetically heterogeneous with mutations in five genes identified to date, all with a role in the innervation or contractile apparatus of skeletal muscles. In a consanguineous Saudi family with multiple stillbirths presenting with LCCS, we excluded linkage to all known LCCS loci and combined autozygome analysis and whole-exome sequencing to identify a novel homozygous variant in ZBTB42, which had been shown to be enriched in skeletal muscles, especially at the neuromuscular junction. Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level. This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change. Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation.


Ambulance location and relocation problems with time-dependent travel times.
EMERGENCY SERVICE PROVIDERS ARE FACING THE FOLLOWING PROBLEM: how and where to locate vehicles in order to cover potential future demand effectively. Ambulances are supposed to be located at designated locations such that in case of an emergency the patients can be reached in a time-efficient manner. A patient is said to be covered by a vehicle if (s)he can be reached by an ambulance within a predefined time limit. Due to variations in speed and the resulting travel times it is not sufficient to solve the static ambulance location problem once using fixed average travel times, as the coverage areas themselves change throughout the day. Hence we developed a multi-period version, taking into account time-varying coverage areas, where we allow vehicles to be repositioned in order to maintain a certain coverage standard throughout the planning horizon. We have formulated a mixed integer program for the problem at hand, which tries to optimize coverage at various points in time simultaneously. The problem is solved metaheuristically using variable neighborhood search. We show that it is essential to consider time-dependent variations in travel times and coverage respectively. When ignoring them the resulting objective will be overestimated by more than 24%. By taking into account these variations explicitly the solution on average can be improved by more than 10%.


An analog CMOS central pattern generator for interlimb coordination in quadruped locomotion.
This paper proposes a neuromorphic analog CMOS controller for interlimb coordination in quadruped locomotion. Animal locomotion, such as walking, running, swimming, and flying, is based on periodic rhythmic movements. These rhythmic movements are driven by the biological neural network, called the central pattern generator (CPG). In recent years, many researchers have applied CPG to locomotion controllers in robotics. However, most of these have been developed with digital processors and, thus, have several problems, such as high power consumption. In order to overcome such problems, a CPG controller with analog CMOS circuit is proposed. Since the CMOS transistors in the circuit operate in their subthreshold region and under low supply voltage, the controller can reduce power consumption. Moreover, low-cost production and miniaturization of controllers are expected. We have shown through computer simulation, such circuit has the capability to generate several periodic rhythmic patterns and transitions between their patterns promptly.


Molecular background of leak K+ currents: two-pore domain potassium channels.
Two-pore domain K(+) (K(2P)) channels give rise to leak (also called background) K(+) currents. The well-known role of background K(+) currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K(2P) channel types) that this primary hyperpolarizing action is not performed passively. The K(2P) channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K(2P) channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K(2P) channel family into the spotlight. In this review, we focus on the physiological roles of K(2P) channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.


Statistical prediction and molecular dynamics simulation.
We describe a statistical approach to the validation and improvement of molecular dynamics simulations of macromolecules. We emphasize the use of molecular dynamics simulations to calculate thermodynamic quantities that may be compared to experimental measurements, and the use of a common set of energetic parameters across multiple distinct molecules. We briefly review relevant results from the theory of stochastic processes and discuss the monitoring of convergence to equilibrium, the obtaining of confidence intervals for summary statistics corresponding to measured quantities, and an approach to validation and improvement of simulations based on out-of-sample prediction. We apply these methods to replica exchange molecular dynamics simulations of a set of eight helical peptides under the AMBER potential using implicit solvent. We evaluate the ability of these simulations to quantitatively reproduce experimental helicity measurements obtained by circular dichroism. In addition, we introduce notions of statistical predictive estimation for force-field parameter refinement. We perform a sensitivity analysis to identify key parameters of the potential, and introduce Bayesian updating of these parameters. We demonstrate the effect of parameter updating applied to the internal dielectric constant parameter on the out-of-sample prediction accuracy as measured by cross-validation.


Evolution of environmental epidemiologic risk assessment.
Epidemiology has historically played an important role in the recognition of causes for diseases affecting the health of the public. Initially, epidemiology was concerned with infectious diseases. Later it became involved in metabolic and dietary deficiency diseases. Most recently, epidemiology has addressed the question of the public health effects of chemicals from production facilities, accidental spills, and chemical waste disposal sites. Concurrent improvements in the sensitivity of chemical analyses have enabled the identification of chemicals arising from waste disposal sites in the soil, air, drinking water, and food supplies of neighboring residential areas, albeit usually at very low concentrations. This knowledge has created great concerns among the affected populations and their public health agencies. The responsibility for interpreting the potential severity of the health effects of these environmental contaminants has fallen to those scientists experienced in epidemiology. This has led to a subdiscipline, reactive epidemiology, which describes investigations focused on specific events, usually under emotion-laden circumstances, rather than scientific merit. The reactive epidemiologist is rigidly constrained as to the size, timing, and location of the study. There is a strong requirement for public communication skills. New data bases are needed including "sentinel" diseases that are linked to exposure to chemicals, records of land use, and residency data for the population at risk.


Fast and Reversible Quasi-Solid-State Anion Exchange in Highly Luminescent CsPbX3 Perovskite Nanocrystals for Dual-Mode Encryption-Decryption.
Solid-state anion exchange method is easy to handle and beneficial to improve stability of CsPbX3 (X = Cl, Br, I) perovskites nanocrystals (NCs) with respect to anion exchange in liquid phase. However, the corresponding exchange rate is rather slow due to the limited diffusion rate of anions from solid phases, resulting in mixed-halide perovskite NCs. Herein, a fast and reversible post-synthetic quasi-solid-state anion exchange method in CsPbX3 NCs with inorganic potassium halide KX salts/polyvinylpyrrolidone (PVP) thin film is firstly reported. Original morphology of the exchanged NCs is well-preserved for all samples. Complete anion exchange from Br- to Cl- or I- is successfully achieved in CsPbX3 NCs within ≈20 min through possible vacancies-assisted ion exchange mechanism, under ambient conditions and vice versa. Particularly, Br- -exchanged CsPbCl3 and CsPbI3 NCs exhibit improved optical properties. Encouraged by the attractive fluorescence and persistent luminescence as well as good stability of the resulted CsPbX3 NCs, an effective dual-mode information storage-reading application is demonstrated. It is believed that this method can open a new avenue for the synthesis of other direct-synthesis challenging quantum-confined perovskite NCs/nanoplates/nanodisks or CsSnX3 NCs/thin film and provide an opportunity for advanced information storage compatible for practical applications.


Combined pre-operative irradiation and surgery for advanced cancer of the larynx and laryngopharynx. (A 14 year correlative statistical and histopathological study).
A carefully planned clinical program of combined pre-operative radiation and surgery has been conducted by the Department of Otolaryngology at The Mount Sinai Hospital for 14 years in an effort to improve the survival rate for advanced cancer of the larynx and laryngopharynx. An extensive histopathological study of resected larynges and radical neck specimens was undertaken in 1961 in order to determine the effects of pre-operative radiation. A very careful statistical analysis has been made of the survival experience of this series of cases. The three and five year survival rates have been computed by the actuarial method. The histopathological study entailed a serial section study of 26 larynges and 21 radical neck dissection specimens. These studies have been most informative as to the nature of the radiobiologic process involved in the destruction of laryngeal cancer. In addition, the study has been revealing as to the ability of radiation to sterilize cancer in the neck specimens. The clinical correlate of this histologic finding has been the observation of reduced cervical recurrences in patients treated with combined therapy. In conclusion, our statistics seem to indicate that our combined therapy method has improved the survival rates of patients with advanced cancer of the larynx and laryngopharynx.


Is tobacco a drug? Administrative agencies as common law courts.
Professor Cass Sunstein argues that the FDA has the authority to regulate tobacco products. He considers the text of the Federal Food, Drug, and Cosmetic Act, which supports the FDA assertion, and the context of its enactment, which argues against the FDA. He resolves the tension between text and context in favor of FDA jurisdiction by turning to the emerging role of administrative agencies. In modern government, he contends, administrative agencies have become America's common law courts, with the power to adapt statutory regimes to new facts and new values when the underlying statute is ambiguous. Professor Sunstein's Article, like the other pieces in this volume, was written after the United States District Court for the Middle District of North Carolina decided Coyne Beahm v. FDA, but before a three judge panel of the United States Court of Appeals for the Fourth Circuit reversed that decision in Brown & Williamson Tobacco Corp. v. FDA. In Coyne Beahm, the District Court held that the Federal Food, Drug, and Cosmetic Act authorized the FDA to regulate tobacco products, but not tobacco advertising. The Fourth Circuit rejected the District Court's jurisdictional ruling and invalidated the FDA's regulations in their entirety. The Clinton Administration has since requested an en banc rehearing before the Fourth Circuit.


Host cell-derived lactate functions as an effector molecule in Neisseria meningitidis microcolony dispersal.
The development of meningococcal disease, caused by the human pathogen Neisseria meningitidis, is preceded by the colonization of the epithelial layer in the nasopharynx. After initial adhesion to host cells meningococci form aggregates, through pilus-pilus interactions, termed microcolonies from which the bacteria later detach. Dispersal from microcolonies enables access to new colonization sites and facilitates the crossing of the cell barrier; however, this process is poorly understood. In this study, we used live-cell imaging to investigate the process of N. meningitidis microcolony dispersal. We show that direct contact with host cells is not required for microcolony dispersal, instead accumulation of a host-derived effector molecule induces microcolony dispersal. By using a host-cell free approach, we demonstrated that lactate, secreted from host cells, initiate rapid dispersal of microcolonies. Interestingly, metabolic utilization of lactate by the bacteria was not required for induction of dispersal, suggesting that lactate plays a role as a signaling molecule. Furthermore, Neisseria gonorrhoeae microcolony dispersal could also be induced by lactate. These findings reveal a role of host-secreted lactate in microcolony dispersal and virulence of pathogenic Neisseria.


Determination of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxyethylamphetamine, and 3,4-methylenedioxymethamphetamine in urine by online solid-phase extraction and ion-pairing liquid chromatography with detection by electrospray tandem mass spectrometry.
A method using an online solid-phase extraction (SPE) and ion-pairing liquid chromatography with electrospray tandem mass spectrometry (LC/ES-MS/MS) was developed for determination of amphetamine (Amp), methamphetamine (mAmp), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), and 3,4-methylenedioxymethamphetamine (MDMA) in urine samples. A SPE cartridge column with both hydrophilic and lipophilic functions was utilized for online extraction. A reversed-phase C18 LC column was employed for LC separation and MS/MS was used for detection. Trifluoroacetic acid was added to the mobile phase as an ion-pairing reagent. This method was fully automated and the extraction and analysis procedures were controlled by a six-port switch valve. Recoveries ranging from 85-101% were measured. Good linear ranges (10-500 ng/mL) for Amp and mAmp were determined. For MDA, MDMA and MDEA, dual linear ranges were obtained from 5-100 and 100-500 ng/mL, respectively. The detection limit of each analytical compound, based on a signal-to-noise ratio of 3, ranged from 1-3 ng/mL. The applicability of this newly developed method was examined by analyzing several urine samples from drug users. Good agreement was obtained between the results from this method and a literature GC/MS method.


Turtle embryos move to optimal thermal environments within the egg.
A recent study demonstrated that the embryos of soft-shelled turtles can reposition themselves within their eggs to exploit locally warm conditions. In this paper, we ask whether turtle embryos actively seek out optimal thermal environments for their development, as do post-hatching individuals. Specifically, (i) do reptile embryos move away from dangerously high temperatures as well as towards warm temperatures? and (ii) is such embryonic movement due to active thermoregulation, or (more simply) to passive embryonic repositioning caused by local heat-induced changes in viscosity of fluids within the egg? Our experiments with an emydid turtle (Chinemys reevesii) show that embryos avoid dangerously high temperatures by moving to cooler regions of the egg. The repositioning of embryos is an active rather than passive process: live embryos move towards a heat source, whereas dead ones do not. Overall, our results suggest that behavioural thermoregulation by turtle embryos is genuinely analogous to the thermoregulatory behaviour exhibited by post-hatching ectotherms.


Amino acid patterns around disulfide bonds.
Disulfide bonds provide an inexhaustible source of information on molecular evolution and biological specificity. In this work, we described the amino acid composition around disulfide bonds in a set of disulfide-rich proteins using appropriate descriptors, based on ANOVA (for all twenty natural amino acids or classes of amino acids clustered according to their chemical similarities) and Scheffé (for the disulfide-rich proteins superfamilies) statistics. We found that weakly hydrophilic and aromatic amino acids are quite abundant in the regions around disulfide bonds, contrary to aliphatic and hydrophobic amino acids. The density distributions (as a function of the distance to the center of the disulfide bonds) for all defined entities presented an overall unimodal behavior: the densities are null at short distances, have maxima at intermediate distances and decrease for long distances. In the end, the amino acid environment around the disulfide bonds was found to be different for different superfamilies, allowing the clustering of proteins in a biologically relevant way, suggesting that this type of chemical information might be used as a tool to assess the relationship between very divergent sets of disulfide-rich proteins.


Swine H1N1 infection in a renal transplant recipient.
Influenza pandemics have been observed in several periods throughout history. The first influenza pandemic of the 21st century began in Mexico in 2009 and has spread rapidly all over the world. Swine H1N1 has been officially declared a pandemic by the World Health Organization in June 2009. As has been observed in previous pandemics, pregnant women, adolescents, and immunosuppressed individuals are affected more severely in this pandemic. Despite several reports about the pandemic, there have not been any reports of swine H1N1 infection in individuals who underwent renal transplant. The aim of the current study was to present oseltamivir therapy in a swine H1N1-infected patient who underwent renal transplant 10 months earlier, and was thus under immunosuppressive treatment. To the best of our knowledge, this is the first case report of a swine H1N1 infection in a renal transplant recipient.


Mass spectrometric study of dirhenium biscarboxylate:purine dinucleotide complexes.
Dirhenium adducts of purine dinucleotides were identified by mass spectrometry. In consecutive studies, Re(2)(O(2)C(2)H(3))(2)Cl(4) . 2H(2)O was reacted with 2'-deoxyguanylyl(3'-->5')-2'-deoxyguanosine (dGpG) and 2'-deoxyadenylyl(3'-->5')-2'-deoxyguanosine (dApG) in H(2)O or D(2)O. These reactions were monitored to identify novel dinuclear rhenium:dinucleotide complexes as confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS), electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (CID MS/MS) experiments. However, the most abundant adducts detected by ES-MS were dirhenium:nucleotide species. Of these, guanine-containing ions were observed with highest ion counts suggesting a preference for guanine coordination. Dimetal adducts showed coordination of the purine bases and common metalated fragments were observed for both dGpG and dApG reactions.


An overview of the effects of dioxins and dioxin-like compounds on vertebrates, as documented in human and ecological epidemiology.
Dioxins and dioxin-like compounds are primary examples of persistent organic pollutants that induce toxicity in both wildlife and humans. Over the past 200 years these compounds have been almost exclusively generated by human activity and have left a string of disasters in the wake of their accidental release. Most recently, the contamination of the Irish pork supply with dioxins resulted in an international recall of all Irish pork products. Epidemiologic data on human and ecological dioxin exposures have revealed a common pattern of biological response among vertebrate species, which is mediated through activation of the Aryl hydrocarbon Receptor (AhR). These AhR-mediated effects include profound consequences on the vertebrate individual exposed in early life with respect to myriad developmental endpoints including neurologic, immunologic, and reproductive parameters. Humans appear to be susceptible to these effects in a manner similar to that of the laboratory and wildlife species, which have demonstrated such outcomes. Furthermore, epidemiologic data suggest that there is little or no margin of exposure for humans with respect to these developmental effects. Given these concerns, prudent public health policy should include the continued reduction of exposures.


Binding and spreading of ParB on DNA determine its biological function in Pseudomonas aeruginosa.
ParB protein of Pseudomonas aeruginosa belongs to a widely represented ParB family of chromosomally and plasmid-encoded partitioning type IA proteins. Ten putative parS sites are dispersed in the P. aeruginosa chromosome, with eight of them localizing in the oriC domain. After binding to parS, ParB spreads on the DNA, causing transcriptional silencing of nearby genes (A. A. Bartosik et al., J. Bacteriol. 186:6983-6998, 2004). We have studied ParB derivatives impaired in spreading either due to loss of DNA-binding ability or oligomerization. We defined specific determinants outside of the helix-turn-helix motif responsible for DNA binding. Analysis confirmed the localization of the main dimerization domain in the C terminus of ParB but also mapped another self-interactive domain in the N-terminal domain. Reverse genetics were used to introduce five parB alleles impaired in spreading into the P. aeruginosa chromosome. The single amino acid substitutions in ParB causing a defect in oligomerization but not in DNA binding caused a chromosome segregation defect, slowed the growth rate, and impaired motilities, similarly to the pleiotropic phenotype of parB-null mutants, indicating that the ability to spread is vital for ParB function in the cell. The toxicity of ParB overproduction in Pseudomonas spp. is not due to the spreading since several ParB derivatives defective in oligomerization were still toxic for P. aeruginosa when provided in excess.


Thin-film microfabricated nanofluidic arrays for size-selective protein fractionation.
Size-selective fractionation and quantitation of biostructures in the sub-hundred nanometer size range is an important research area. Unfortunately, current methods for size fractionation are complex, time consuming, or offer poor resolution. Using standard microfabrication technology, we developed a nanofluidic sieving system to address these limitations. Our setup consists of an array of parallel nanochannels with a height step in each channel, an injection reservoir, and a waste reservoir. The height steps can size fractionate a protein mixture as a solution flows through the nanochannels via capillary action. We tested this system with different sizes and concentrations of five proteins to understand protein size and height step effects on trapping. Our results clearly show size-dependent trapping of proteins at nanometer-scale height steps in nanochannels. We also developed a model that predicts the observed size-dependent trapping of proteins. This work is a key step towards scalable nanofluidic methods for molecular fractionation.


Dendritic cells: nature and classification.
Dendritic cells (DCs) are antigen (Ag)-presenting cells (APCs) characterized by a unique capacity to stimulate naive T cells and initiate primary immune responses. Recent studies suggest that DCs also play critical roles in the induction of central and peripheral immunological tolerance, regulate the types of T cell immune responses, and function as sentinels in innate immunity against microbes. The diverse functions of DCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here we review recent progress in our understanding of the nature and classification of DCs.


Real-world reporting rates of administration-site reactions with on-demand treatment of hereditary angioedema attacks.
Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/ or submucosal swelling. To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzedadministration-site adverse drug reactions (ADR) associated with approved on-demand HAE therapies reported in the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS). We searched the FAERS database from October 1, 2009, to March 31, 2022, for reports of all FDA-approved on-demandtherapies for HAE: plasma-derived C1-inhibitor (pdC1-INH), ecallantide, icatibant, and recombinant C1-inhibitor (rhC1-INH). ADRs in which the drug was listed as the "primary suspect" were recorded for each drug. ADR preferred terms were grouped into 18 ADR domains based on semantic and/or clinical similarity, and the number of reports for each drug was calculated per year from the time of approval through March 2022, and descriptive results were presented. Preferred terms associated with administration-site ADRs identified from clinical trials and denoted on approved HAE drug U.S. package inserts were examined in a complementary analysis. The highest reported rates of administration-site ADRs per year were site pain (17.9 reports per year), site erythema(7.4 per year), and site swelling (6.7 per year). RhC1-INH was the only drug for which access-site complications and/or malfunctions were reported (9.5 per year). PdC1-INH had the highest rate of incorrect route of product administration (3.7 per year). PdC1-INH showed statistically significant elevated reporting rate of injection-site reactions (reporting odds ratio [ROR] 3.59 [2.36-5.46]; empirical Bayesian geometric mean [EBGM] 1.97 [1.39]). Icatibant and rhC1-INH showed a statistical trend toward an increased reporting rate of administration-site reactions. Real-world data from FAERS were generally consistent with adverse events reported in clinical trials and suggest that patients experience substantial treatment burden associated with FDA-approved parenteral on-demand therapies for HAE attacks. It should be noted that ADR rates are not exposure adjusted and are based on spontaneous reporting.


[Diet of the tropical fish Gobioides broussonnetii (Pisces: Gobiidae) at Laguna de Unare, Venezuela].
Unare Lagoon is one of the most important fishery coastal ecosystems in Venezuela. For the past 10 years, changes in its hydrological regime have affected the physiochemical characteristics of the water with important consequences on its faunal composition and abundance. An example of such variation is the abundant presence ofa fish species, Gobioides broussonnetii, recently registered in this ecosystem. The ecology of this species must be studied to identify new ecological processes occurring in the lagoon. Detritus is the most important component of the G. broussonnetii diet, followed by plant and animal items. The species is a primary detritivorous consumer and this may be associated with its activity pattern (morning): It may be an occasional visitor because it was not captured regularly in the monthly samplings.


Involvement of thio-, peroxi-, and glutaredoxins in cellular redox-dependent processes.
Among the key antioxidant enzymes, thioredoxin and glutaredoxin systems play an important role in cell defense against oxidative stress and maintenance of redox homeostasis owing to the regulation of thiol-disulfide exchange. The thioredoxin isoforms Trx1 (cytoplasmic form) and Trx2 (mitochondrial form) can reduce inter- and intramolecular disulfide bonds in proteins, in particular, in oxidized peroxiredoxins, which disrupt organic hydroperoxides, H2O2, and peroxynitrite. NADPH-dependent thioredoxin reductase, which reduces a broad range of substrates including oxidized form of thioredoxin, can also directly reduce lipid hydroperoxides, H2O2, and dehydroascorbic and lipoic acids. Glutaredoxin, whose major isoforms in mammals are Grx1, Grx2, and Grx5, as well as thioredoxin, catalyzes S-glutathionylation and deglutathionylation of proteins to protect SH-groups from oxidation and restore functionally active thiols. However, in contrast to thioredoxin, glutaredoxin reduces GSH-mixed disulfides and catalyzes the reaction not only via a dithiol mechanism but also via monothiol reduction. In addition to the role in cellular antioxidant defense, all of the reviewed redox proteins (thioredoxin, thioredoxin reductase, peroxiredoxin, and glutaredoxin) have a number of significant functions required for cell viability: they regulate transcription factor activities, play the role of growth factors, serve as enzyme cofactors, take part in regulation of cell cycle, and are involved in antiapoptotic mechanisms.


Complementation of physiological and behavioral defects by a slowpoke Ca(2+) -activated K(+) channel transgene.
The Drosophila slowpoke gene encodes a large conductance calcium-activated potassium channel used in neurons, muscle, and some epithelial cells. Tissue-specific transcriptional promoters and alternative mRNA splicing generate a large array of transcripts. These distinct transcripts are thought to tailor the properties of the channel to the requirements of the cell. Presumably, a single splice variant cannot satisfy the specific needs of all cell types. To test this, we examined whether a single slowpoke splice variant was capable of complementing all slowpoke behavioral phenotypes. Null mutations in slowpoke cause animals to be semiflightless and to manifest an inducible "sticky-feet" phenotype. The well-characterized slowpoke transcriptional control region was used to direct the expression of a single slowpoke splice variant (cDNA H13) in transgenic flies. The endogenous gene in these flies had been inactivated by the slo(4) mutation. Action-potential recordings and voltage-clamp recordings demonstrated the production of functional channels from the transgene. The transgene completely complemented the flight defect, but not the sticky-feet phenotype. We conclude that distinct slowpoke channel isoforms, produced by alternative splicing, are not interchangeable and are required for proper function of different cell types.


An early intensive intervention for inducing inactive asthma in adults--a one-year follow-up observation study.
Treatment strategy that reduces dependence on long-term medication for chronic asthma is preferable. The purpose of the study is to investigate the efficacy of an early intensive intervention for inducing inactive asthma in adults and identify factors that affect the efficacy. A prospective study was conducted on subjects who had asthma for two years or less. An intensive intervention consisting of systemic corticosteroid treatment for two weeks followed by inhaled corticosteroid for further 16 weeks with concomitant administration of bronchodilator(s) was administrated on 109 subjects. As a control group, 33 subjects were treated according to the current asthma treatment guidelines for 18 weeks. The primary outcome of the intervention was assessed with symptomatology and use of medication during 12 months after the cessation of treatment period. At one year after the intervention, significantly more patients in the intensive intervention group (41%) than in the control group (24%) had no respiratory symptoms and were medication-free or had experienced minor upper respiratory symptoms (inactive asthma) (P = 0.01). The intensive intervention maintained a significant factor associated with one-year inactive asthma (adjusted odds ratio: 3.61, 95% confidence interval: 1.20-10.84; P = 0.02). Infection as onset cause, asthma duration and pre-treatment %FEV(1.0) were also identified independently associated with inactive asthma. As the limitation, the study was not randomized trial. Intensive therapy in the early stage is very likely to contribute to increasing one-year asthma inactivity, which may reduce patients' dependence on long-term management by medical treatment.


Ag nanoframes: controllable reduction of AgClxBr1-x nanocubes.
The synthesis of Ag nanoframes is a great challenge due to the high reactivity of Ag. Here, we present a facile and simple method to synthesize Ag nanoframes using silver halide as the template. Our method to fine-tune the reduction rate allows us to control the morphologies from Ag nanoframes to nanocages and hollow nanoshells. These Ag nanoframes exhibited an excellent catalytic activity for methylene blue reduction.


Dendritic Morphology of an Inhibitory Retinal Interneuron Enables Simultaneous Local and Global Synaptic Integration.
Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multielectrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regions. Local integration occurs within spatially restricted dendritic subunits and narrow time windows and is largely unaffected by the strength of electrical coupling. In contrast, global integration across the dendritic tree occurs over longer time periods and is markedly influenced by the strength of electrical coupling. These integrative properties enable AII amacrines to combine local control of synaptic plasticity with location-independent global integration. Dynamic inhibitory control of dendritic subunits is likely to be of general importance for amacrine cells, including cells with small dendritic trees, as well as for inhibitory interneurons in other regions of the CNS.SIGNIFICANCE STATEMENT Our understanding of synaptic integration is based on the prototypical morphology of a neuron with multiple dendrites and a single axon at opposing ends of a cell body. Many neurons, notably retinal amacrine cells, are exceptions to this arrangement, and display input and output synapses interspersed along their dendritic branches. In the large dendritic trees of some amacrine cells, such arrangements can give rise to multiple computational subunits. Other amacrine cells, with small dendritic trees, have been assumed to operate as single computational units. Here, we report the surprising result that despite a small dendritic tree, the AII amacrine cell simultaneously performs local integration of synaptic inputs (over smaller dendritic subregions) and global integration across the entire cell.


Nutrient digestibility, rumen parameters, and (cannabinoid) residues in sheep fed a pelleted diet containing green hemp (Cannabis sativa L.) biomass.
The feeding value for ruminants of green hemp biomass, from the low Δ9-tetrahydrocannabinol (Δ9-THC) variety of Cannabis sativa L., is unknown. Twelve Merino ewes were individually penned and randomly allocated on a stratified liveweight basis to one of two pelleted dietary treatments, control (0% hemp, n = 6) or hemp (42% green hemp biomass, n = 6) that delivered a diet meeting the nutrient requirements of the animals. The experimental period consisted of 17 d dietary and housing adaptation, followed by 7 d total urine and feces collection for determination of apparent nutrient digestibility. A ruminal fluid sample was collected on day 27 and assessed for pH, ammonia, volatile fatty acid (VFA), and cannabinoid concentrations. A blood sample from the jugular vein and incisional subcutaneous fat biopsy from an area around the base of the tail were collected on day 28 with additional fat biopsies taken 35 d and 140 d post-feeding to measure cannabinoids. The dry matter (DM), organic matter (OM), and crude protein (CP) digestibilities, along with total VFA concentration did not differ (P = 0.713) between the two diets; however, acid detergent fiber (ADF) and neutral detergent fiber (NDF) digestibilities (P < 0.001), water intake (P = 0.023), and fecal water output (P < 0.001) were significantly lower for the sheep-fed Hemp. Rumen pH did not vary (P = 0.256) between diets, but ruminal ammonia concentration was significantly lower (P = 0.024) for sheep consuming Hemp. Sheep-fed Hemp had significantly greater molar proportions of butyric (P = 0.039) and hexanoic (P = 0.012) acids and lower molar proportions of propionic acid (P = 0.003). There were no differences between diets for N intake (P = 0.175), fecal N output (P = 0.253), and N balance (P = 0.695), with all sheep in positive N balance; however, there was significantly lower (P = 0.001) urinary N output for sheep-fed Hemp. Cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA) were detected in plasma of all sheep-fed Hemp. ∆9-tetrahydrocannabinol was present in the subcutaneous fat of four of the six sheep on the final day of being fed Hemp, and in all (six) sheep 35 d post-feeding and one sheep 140 d post-feeding Hemp. No cannabinoids were detected in the corresponding samples taken from the sheep-fed Control. Thus, despite green hemp biomass being nutritionally a suitable feed for ruminants, under current Food Standards in Australia, the presence of these cannabinoid residues restricts its use in ruminant diets.


Roles and Modalities of Ectonucleotidases in Remodeling the Multiple Myeloma Niche.
Ectoenzymes are cell surface molecules, which represent functional bridges between the environment and the cytoplasm. One set of ectoenzymes-CD39, CD38, CD203a, and CD73-leads to the generation of adenosine (ADO) by metabolizing ATP and NAD+. While ADO is known to control inflammation and suppress immune responses, other aspects of ADO function are still obscure, mainly due to its short half-life in biological fluids. Human multiple myeloma (MM) grows in the closed system of the bone marrow (BM) niche representing an ideal setting for studying ectoenzymes and their products. Another source of information on ectoenzyme function may derive from in vivo results of anti-CD38 antibody therapy in MM. Current results, obtained from in vitro models and from preliminary in vivo findings, indicate that ectoenzymes produce ADO locally in the BM niche. Furthermore, MM cells release microvesicles (MV), which thanks to their molecular cargo and surface ectoenzymes may function as particulate communicators outside of the niche. During anti-CD38 antibody therapy, the MV carry therapeutic IgG, determining that the prevalent orientation of MV will be toward cells and tissues expressing receptors for the IgG Fc domain. The resulting picture is one where MM adopts an immune escape strategy based on reshaping the environmental niche. This adaptation is followed by actions of MV that are exerted in biological fluids and circulating immune cells. By coating FcRs+ cells, MV modify pericellular spaces, reproducing the metabolic halo generated by ectoenzymes within closed systems.


Coronary heart disease in Indians: implications of the INTERHEART study.
Coronary heart diseases (CHD) have reached epidemic proportions among Indians. The recently concluded INTERHEART study emphasizes the role of behavioural and conventional risk factors in the prediction of CHD risk among Indians. These findings have implication for the health care providers and policy makers in the country due to the fact that all these conventional risk factors are potentially modifiable and are good starting points for prevention. The policy measures by means of legislation and regulatory approaches on agriculture and food industry or tobacco or physical activity will have large impact on CHD risk factor reduction in the population. In addition, the health system needs to focus on: (i) providing information for increasing awareness and an enabling environment for adoption of healthy living habits by the community; (ii) early detection of persons with risk factors and cost-effective interventions for reducing risk; and (iii) early detection of persons with clinical disease and cost-effective secondary prevention measures to prevent complications. The evidence from INTERHEART provides rationale for developing treatment algorithms and treatment guidelines for CHD at various levels of health care. In addition, INTERHEART provides answer for the quest for a single reliable biomarker, Apo B/ApoA 1 ratio that can predict the future CHD risk among individuals. Further to this, the INTERHEART study also opens up several unanswered questions on the pathobiology of the premature onset of myocardial infarction among Indians and calls for the need to developing capacity in clinical research in CHD in India.


Increased use of antihypertensive medications after partial nephrectomy vs. radical nephrectomy.
A prospective study of partial vs. radical nephrectomy demonstrated worse overall survival in patients undergoing partial nephrectomy which appeared to be driven by cardiovascular outcomes. We sought to determine if the blood pressures or use of antihypertensive medications differed between patients who underwent partial or radical nephrectomy. A tertiary-referral institutional renal mass database was queried for patients between 2006 and 2012 undergoing partial or radical nephrectomy. Serial blood pressure follow-up, clinicopathologic variables, and changes in medications were collected. Patients were excluded for inadequate data, noncurative-intent surgery, noncancer surgical indication, and absence of medication information. Time-dependent hemodynamic changes were compared by split-plot analysis of variance and addition to antihypertensive regimen was studied as time-to-event survival analyses with Kaplan-Meier curves and a Cox proportional hazards model. A final cohort of 264 partial nephrectomy and 130 radical nephrectomy cases were identified. Patients undergoing partial nephrectomy were younger, more likely to have T1 tumors, and had lower preoperative creatinine (P<0.001 for all). No differences were noted on postoperative hemodynamics (P>0.05). Significantly more patients who underwent partial nephrectomy added antihypertensive medications postoperatively (P≤0.001) and surgical treatment remained as a significant independent predictor on Cox regression (hazard ratio = 2.51, P = 0.002). Limitations include the retrospective nature of the study and potential for unidentified confounders. Hemodynamic parameters after radical or partial nephrectomy may be different. The etiology of this observation, is currently unexplored. Additional prospective mechanistic investigations are warranted.


[Cystatin C: current step and future prospects].
Cystatin C is a low molecular weight-protein, which may replace creatinine for the evaluation of renal function, particularly in the clinical settings where the relationship between creatinine production and muscular mass impairs the clinical performance of creatinine. This paper intends to summarize the current knowledge about the physiology of cystatin C and about its use as a renal marker, alone or within formulas developed to estimate the glomerular filtration rate. Moreover, this paper reviews the recent data about potential other applications of cystatin C, especially in cardiology, in oncology and in clinical pharmacology.


Synthesis and characterization of novel substituted thiophene derivatives and discovery of their carbonic anhydrase and acetylcholinesterase inhibition effects.
Novel substituted thiophene derivatives (1, 2a-e, 3, and 4) were synthesized and their structures were characterized by infrared radiation, nuclear magnetic resonance, and mass analysis. These novel substituted thiophene derivatives were effective inhibitor compounds of the carbonic anhydrase I and II isozymes (hCA I and II), and acetylcholinesterase (AChE) enzyme with K i values in the range of 447.28 to 1004.65 nM for hCA I, 309.44 to 935.93 nM for hCA II, and 0.28 to 4.01 nM for AChE, respectively. Novel substituted thiophene derivatives can be good candidate drugs for the treatment of some diseases like neurological disorders, epilepsy, glaucoma, gastric and duodenal ulcers, mountain sickness, or osteoporosis as carbonic anhydrase isozymes inhibitors, and for the treatment of Alzheimer's and Parkinson's diseases as acetylcholinesterase inhibitors.


In vitro effects of Italian Lavandula multifida L. leaf extracts on gilthead seabream (Sparus aurata) leucocytes and SAF-1 cells.
Lavandula multifida is very appreciated by pharmaceutical and cosmetic industries. In Italy is only found in Calabria and Sicily and, at present, urge its valorization due to its high extinction and genetic erosion risks. Possible applications of L. multifida extracts as immunostimulant in fish aquaculture were assayed by using gilthead seabream (Sparus aurata) as a marine fish model, due to its importance in fish aquaculture. The in vitro effects of both aqueous and ethanolic leaf extracts obtained from two Italian populations of L. multifida on head kidney leucocyte activities (viability, phagocytosis, respiratory burst and peroxidase content) were assessed. Furthermore, the possible cytotoxic effects of the extracts on SAF-1 cells and their bactericidal effects on three fish pathogenic bacteria (Vibrio harveyi, Vibrio anguillarum, Aeromonas salmonicida) were also evaluated. All the assays were performed in comparison with leaf extracts obtained from a widely-distributed species as L. angustifolia. Results showed that water and ethanolic leaf extracts obtained from L. multifida enhanced innate immune activities of S. aurata HK leucocytes. Furthermore, SAF-1 cell viability was not affected significantly after being incubated with the extracts. These extracts did not exert any bactericidal activity on the pathogenic bacterial strains tested in the present study. Results obtained in the present work suggested the possibility of use such extracts in in vivo studies in order to corroborate the possibility of their use in aquaculture. Their use could prevent to improve fish defense against pathogenic infections through enhancement of the fish immune status.


Mayo Adhesive Probability Score Is Associated With Localized Renal Cell Carcinoma Progression-free Survival.
To assess the association of the Mayo Adhesive Probability (MAP) score and progression-free survival (PFS) in patients with renal cell carcinoma (RCC). The MAP score is derived from cross-sectional imaging measurements of perinephric fat thickness and stranding. We identified 456 patients from a prospective registry who were treated surgically for localized RCC between 2002 and 2014. One reviewer calculated a preoperative MAP score (0-5) for each patient. Kaplan-Meier curves were utilized to estimate PFS. Cox proportional hazard models were used to estimate the association of MAP score with risk of progression univariately and after adjusting for covariates such as age, body mass index (BMI), and size, stage, grade, necrosis scores. Patients with higher MAP scores (4-5) were more likely to be male, to be older, to have higher BMI, and to have larger tumors (all P <.01). Of our total cohort, 405 patients had MAP scores and follow-up data to assess PFS. Dichotomizing MAP scores into high (MAP 4-5) and low (MAP 0-3) yields a hazard ratio of 2.16 for the 4-5 group vs 0-3 (95% confidence interval: 1.15-4.06, P = .017). Adjustment for BMI did not alter the association (BMI-adjusted hazard ratio [HR] = 2.20 [1.07-4.52], P = .032). Of interest, the association with MAP and PFS remains for pT1 RCC patients (n = 287, HR = 3.46 [1.06-11.24], P = .039). High MAP scores (4-5) are associated with decreased PFS in patients surgically treated for clinically localized RCC compared with patients with lower MAP scores (0-3). RCC aggressiveness may be associated with perinephric fat thickness and stranding.


Influence of chromium tripicolinate on glucose metabolism and nutrient partitioning in growing lambs.
Twenty-four Suffolk lambs (average BW 38 +/- 2.7 kg; 16 ewes and 8 wethers) were fed either a corn-cottonseed hull-based control diet (CON) or CON plus 250 ppb of Cr as chromium tripicolinate (CrPic). Lambs were penned in groups of three and ADG and DMI were measured through d 85 of the experiment. Jugular blood samples were obtained during wk 2, 7, and 11. An i.v. glucose tolerance test (IVGTT; 500 mg of glucose/kg BW) and an i.v. insulin challenge test (IVICT; .1 IU of ovine insulin/kg BW) were performed during wk 2 and 10 of the trial. This was followed by a N balance trial during wk 3 and 11. Wethers were slaughtered at the end of the experiment and carcass characteristics determined. No differences (P > .10) were observed between dietary treatments in DMI, ADG, or N balance; however, the CrPic-fed wethers had 18% less fat over the 10th rib (P = .082) and a lower yield grade (P = .014). Plasma NEFA was lower throughout the trial (P < .03) and cholesterol was 17% lower during wk 2 (P < .02) in lambs fed CrPic. There were no differences due to diet (P > .10) in plasma concentrations of urea N, glucose, albumin, total protein, insulin, glucagon, triiodothyronine, or thyroxine. Glucose clearance rate and half-life during the IVGTT and IVICT did not differ (P > .10) between CON and CrPic groups; however, during the IVGTT on wk 2, plasma insulin was elevated (P < .05) and glucose reduced (P = .067) in the lambs fed CrPic. Supplemental CrPic seems to influence metabolic measurements that may affect performance of growing lambs.


OCCURRENCE OF COAGULASE-POSITIVE STAPHYLOCOCCI IN CHEDDAR CHEESE.
Samples (13) from several lots of cheddar cheese incriminated in staphylococcal food poisoning and 343 samples of cheddar cheese purchased over a 3-year period in retail markets were examined quantitatively for coagulase-positive staphylococci with the smear plate technique. Of the food-poisoning samples, 11 contained coagulase-positive staphylococci in numbers that ranged from 50 to several million per g. Of the 343 market cheese samples, 20% contained coagulase-positive staphylococci in concentrations ranging from less than 50 to more than 200,000 per g. The phage patterns of 64 of 89 cultures isolated from the food-poisoning samples placed them in the miscellaneous phage group (44A) or in phage group IV and the miscellaneous group (42D/44A); 14 had phage patterns that involved group III, the group with which food poisoning has usually been associated. In contrast, over 50% of 104 cultures from the market cheese, which were typed at 100 times the critical test dilution, had phage patterns that involved group III. Of nine selected cultures isolated from the food-poisoning cheese, three (all in phage group III) were positive for enterotoxin by intravenous injection test of cats.


Screening for depression in Andean Latin America: Factor structure and reliability of the CES-D short form and the PHQ-8 among Bolivian public hospital patients.
Objective We assessed the validity and reliability of the Center for Epidemiologic Studies-Depression scale (CES-D) short form and the Patient Health Questionnaire-8 (PHQ-8) (two measures of depressive symptoms) among urban, low-income patients from a heavily indigenous area of Andean Latin America. This is a patient population that is in many ways culturally distinct from the populations that have been included in previous Spanish language validation studies of these instruments. Methods We administered the CES-D Yale version short form and the PHQ-8 to 107 outpatients at public hospitals in La Paz and El Alto, Bolivia. We conducted exploratory factor analysis, checked internal reliability, and examined concordance between the two measures in identifying patients with clinically significant depressive symptoms. Results Internal reliability was high for both scales: PHQ-8 (Cronbach's α = 0.808) and CES-D (α = 0.825). A one-factor solution for the PHQ-8 was maintained after the removal of one poorly loading item. The CES-D showed a two-factor solution, with items for somatic symptoms and interpersonal problems loading on the same factor as negative affect. Using both the cutoff for depression recommended in prior studies and a sample specific cutoff of ≥1 standard deviation above the mean, the two scales demonstrated only moderate agreement (κ = 0.481-0.486). Conclusions The PHQ may be more appropriate for clinical use in the Andean region, given its greater specificity; however, lower than expected agreement between the scales suggests that they also measure different elements of depression. Irregularities with the factor structure of both scales suggest that further research with this population is needed to better understand depressive symptomology and improve screening in the region.


Mechanisms of fatigue differ after low- and high-force fatiguing contractions in men and women.
The magnitude of failure in voluntary drive after fatiguing contractions of different intensities in men and women is not known. The purpose of this study was to compare the time to task failure and voluntary activation of men and women for a sustained isometric contraction performed at a low and high intensity with the elbow flexor muscles. Nine men and nine women sustained an isometric contraction at 20% and 80% of maximal voluntary contraction (MVC) force until task failure during separate sessions. The men had a shorter time to failure than women for the 20% but not the 80% MVC task. Voluntary activation was reduced to similar levels for the men and women at the end of the fatiguing contractions but was reduced less after the 80% MVC task than the 20% MVC contraction. Twitch amplitude was reduced similarly at task failure for both sexes and to similar levels at termination of the 20% and 80% MVC tasks. The rate of change in mean arterial pressure was the main predictor of time to failure for the low-force sustained contraction. These results suggest that women experienced greater muscle perfusion, less peripheral fatigue, and a longer time to task failure than men during the low-force fatiguing contraction. However, the low-force task induced greater central fatigue than the high-force contraction for both men and women. Thus, low-force, long-duration fatiguing contractions can be used in rehabilitation to induce significant fatigue within the central nervous system and potentially greater neural adaptations in men and women.


Interleukin-1beta induces complement component C3 and IL-6 production at the basolateral and apical membranes in a human intestinal epithelial cell line.
In previous studies, stimulation of cultured enterocytes with IL-1beta resulted in production of IL-6 and complement component C3. The cellular mechanisms of these responses in the enterocyte are not fully understood. We tested the hypothesis that IL-1beta-induced C3 and IL-6 production is differentially regulated at the apical and basolateral membranes of the enterocyte. Caco-2 cells (a transformed human colonic carcinoma cell line) were grown in a 2-chamber system to full differentiation. The cells were treated with IL-1beta either at the apical or basolateral membrane, and C3 and IL-6 mRNA levels and release of C3 and IL-6 into the apical and basal chambers were determined. The release of C3 was greatest into the basal chamber regardless of whether the cells were stimulated at the apical or basolateral membrane. In contrast, the production of IL-6 was greatest at the cell membrane that was stimulated with IL-1beta. Stimulation of the Caco-2 cells with IL-1beta resulted in increased mRNA levels for C3 and IL-6 with no major differences noted when the cells were treated at the apical or basolateral membrane. The results suggest that enterocyte production and release of at least some acute phase proteins and cytokines are differentially regulated at the apical and basolateral membrane of the enterocyte after stimulation with IL-1beta.


Monitoring of antitumor immunity in patients with larynx cancer by tube leukocyte adherence inhibition assay.
The presence of specific antitumor immunity was examined by the tube leukocyte adherence inhibition (LAI) assay in patients with carcinomas of the larynx. Peripheral blood leukocytes (PBL) from patients with larynx cancer gave positive reactions in the LAI assay with the antigen prepared from the carcinoma of the larynx but not with antigen from normal larynx tissue. Adherence of PBL from normal donors did not differ significantly irrespective of whether antigens from tumor or normal larynx tissue were used. With a panel of tumor extracts tested, PBL of some patients reacted to only one antigen, wheras PBL of other patients reacted to several antigens. LAI reactivity disappeared after surgery, reappeared at 4 weeks after surgery, and then declined when patients were tumor free. These results show that the tube LAI assay may be of value in diagnosing larynx cancer and in following up its treatment.


Effects of sealers and liners on marginal leakage of amalgam and gallium alloy restorations.
In an in vitro study, the use of sealers and liners (Fuji varnish, Vitrabond, Vitremer, Paama 2, All-Bond 2, or Resinomer) significantly reduced the amount of marginal leakage around amalgam (Permite C or Lojic Plus) and gallium (Galloy) alloy restorations. This reduction in marginal leakage was produced by all sealers and liners tested, and there were no statistically significant differences between these materials. Unlined restorations of Permite C had significantly less marginal leakage than Galloy or Lojic Plus. Unlined Lojic Plus restorations had the greatest amount of marginal leakage. The experimental method used in the present study proved to be suitable for quantitative comparison of marginal leakage of different dental materials.


Environmental triggers of acute myocardial infarction: results of a nationwide multiple-factorial population study.
The objective of this study was to study the independent environmental triggers of ST-elevation myocardial infarction (STEMI) in a multifactorial environmental population model. Daily counts of all STEMI patients who underwent urgent percutaneous coronary intervention over the period 2006-2009 in Belgium were associated with average daily meteorological data and influenza-like illness incidence data. The following meteorological measures were investigated: particulate matter less than 10 μM (PM10) and less than 2.5 μM (PM(2.5)), ozone, black smoke, temperature and relative humidity. During the study period a total of 15,964 STEMI patients (mean age 63, 75% male) were admitted with a daily average admission rate of 11 ± 4 patients. A multivariate Poisson regression analysis showed that only the temperature was significantly correlated with STEMI, with an 8% increase in the risk of STEMI for each 10°C decrease in temperature (adjusted incidence risk ratio (IRR) 0.92, 95% CI 0.89-0.96). The effects of temperature were consistent among several subpopulations but the strongest effect was seen in diabetic patients (IRR 0.85, 95% CI 0.78 -0.95). There was a trend for an incremental risk of STEMI for each 10 μg/m³ PM(2.5) increase and during influenza epidemics with IRR of 1.02 (95% CI 1.00-1.04) and 1.07 (95% CI 0.98-1.16), respectively. In a global environmental model, low temperature is the most important environmental trigger for STEMI, whereas air pollution and influenza epidemics only seem to have a modest effect.


Atomic/molecular layer deposited thin-film alloys of Ti-4,4'-oxydianiline hybrid-TiO2 with tunable properties.
By combining atomic layer deposition (ALD) and molecular layer deposition (MLD) thin-film techniques, the latter being a variant of the former in which organic precursors are used, it is possible to deposit thin films containing precisely controlled portions of inorganic and organic constituents. This in turn enables the adjustment of material properties by changing the number of ALD and MLD cycles applied during the deposition. In this work, the properties of such thin-film "alloys" prepared by varying the portions of Ti-4,4'-oxydianiline (Ti-ODA) inorganic-organic hybrid and TiO(2) in the structure were investigated. The films were deposited at 280 °C using TiCl(4) and water as precursors for TiO(2), and TiCl(4) and ODA for the Ti-ODA hybrid. The results demonstrate excellent tunability of the film properties such as degree of crystallinity, roughness, refractive index, and hardness depending on the relative number of TiO(2) and Ti-ODA cycles employed.