Biotin Deficiency in Telogen Effluvium: Fact or Fiction?
BACKGROUND: Biotin is popular in hair loss treatment supplements, although the frequency of its deficiency in patients with hair loss has not been established. OBJECTIVES: This work sought to assess the serum levels of biotin in patients with telogen effluvium. METHODS: This case-control study included 60 patients with telogen effluvium and 20 control subjects. Subjects who were on biotin therapy three months prior to the study and those reporting other causes of hair loss were excluded. The scalp of each patient was clinically and dermoscopically examined. Serum biotin levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: Serum levels of biotin were optimal in patients and control groups with no significant difference between the groups. Insignificantly lower biotin levels in elderly patients, smokers, athletes, those with a history of recurrent infections, and women who were pregnant and/or lactating were observed. There was also an insignificant positive correlation between the serum level of biotin and patient age and an insignificant negative correlation between disease duration and patient body mass index. Serum biotin has a weak specificity and sensitivity in differentiating between cases and control subjects or between acute and chronic telogen effluvium. CONCLUSION: There was no significant difference in serum biotin levels between cases and controls or between those with acute or chronic telogen effluvium.


An RBM10 and NF-κB interacting host lncRNA promotes JEV replication and neuronal cell death.
Central nervous system infection by flaviviruses such as Japanese encephalitis virus, Dengue virus, and West Nile virus results in neuroinflammation and neuronal damage. However, little is known about the role of long non-coding RNAs (lncRNAs) in flavivirus-induced neuroinflammation and neuronal cell death. Here, we characterized the role of a flavivirus-induced lncRNA named JINR1 during the infection of neuronal cells. Depletion of JINR1 during virus infection reduces viral replication and cell death. An increase in GRP78 expression by JINR1 is responsible for promoting virus replication. Flavivirus infection induces the expression of a cellular protein RBM10, which interacts with JINR1. RBM10 and JINR1 promote the proinflammatory transcription factor NF-κB activity, which is detrimental to cell survival.


Localisation of Cannabinoid and Cannabinoid-Related Receptors in the Horse Ileum.
Colic is a common digestive disorder in horses and one of the most urgent problems in equine medicine. A growing body of literature has indicated that the activation of cannabinoid receptors could exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity. The localisation of cannabinoid and cannabinoid-related receptors in the intestine of the horse has not yet been investigated. The purpose of this study was to immunohistochemically localise the cellular distribution of canonical and putative cannabinoid receptors in the ileum of healthy horses. Distal ileum specimens were collected from six horses at the slaughterhouse. The tissues were fixed and processed to obtain cryosections which were used to investigate the immunoreactivity of canonical cannabinoid receptors 1 (CB1R) and 2 (CB2R), and three putative cannabinoid-related receptors: nuclear peroxisome proliferator-activated receptor-alpha (PPARα), transient receptor potential ankyrin 1 and serotonin 5-HT1a receptor (5-HT1aR). Cannabinoid and cannabinoid-related receptors showed a wide distribution in the ileum of the horse. The epithelial cells showed immunoreactivity for CB1R, CB2R and 5-HT1aR. Lamina propria inflammatory cells showed immunoreactivity for CB2R and 5-HT1aR. The enteric neurons showed immunoreactivity for CB1R, transient receptor potential ankyrin 1 and PPARα. The enteric glial cells showed immunoreactivity for CB1R and PPARα. The smooth muscle cells of the tunica muscularis and the blood vessels showed immunoreactivity for PPARα. The present study represents a histological basis which could support additional studies regarding the distribution of cannabinoid receptors during gastrointestinal inflammatory diseases as well as studies assessing the effects of non-psychotic cannabis-derived molecules in horses for the management of intestinal diseases.


Deviations from Michaelis-Menten kinetics. The possibility of complicated curves for simple kinetic schemes and the computer fitting of experimental data for acetylcholinesterase, acid phosphatase, adenosine deaminase, arylsulphatase, benzylamine oxidase, chymotrypsin, fumarase, galactose dehydrogenase, beta-galactosidase, lactate dehydrogenase, peroxidase and xanthine oxidase.
The possible graph shapes for one-site/two-state and substrate-modifier models are discussed. The two-state model is a version of the Monod-Wyman-Changeux model and gives a rate equation with 240 denominator terms. Discussion in terms of K and V effects is not possible. A simplified version of the mechanism can be shown to give v-versus-[S] curves that are either sigmoid or non-sigmoid. They may show substrate inhibition or no final maximum, and the double-reciprocal plots can be concave up or down. The corresponding binding model is determined by only two constants and gives a linear double-reciprocal plot. The substrate-modifier mechanism is a simple example of a mechanism where inclusion of catalytic steps leads to a genuine increase in degree of the rate equation. The v-versus-[S] curve can show such complexities as two maxima and a minimum, and the double-reciprocal plot can cross its asymptote twice, proving the rate equation to be 4:4. A simplified version is 3:3, and analysis shows that at least 18 of the 27 double-reciprocal plots that can arise with 3:3 functions are possible with this particular mechanism. Representative double-reciprocal and Scatchard plots are presented for several sets of rate-constant values. It is concluded that relatively simple mechanisms give pseudo-steady-state rate equations of high degree and considerable complexity. With extended ranges of substrate concentrations there is every reason to believe that experimental data would show the sort of deviations from Michaelis-Menten kinetics seen with calculated curves for such simple mechanisms. Narrow ranges of substrate concentration, on the other hand, would lead to inflexions and curvature being overlooked. It is not possible to discuss such deviations from Michaelis-Menten kinetics in terms of kinetic constants such as Km and V, and, in general, it is also difficult to see any simple way to explain intuitively such features as sigmoidicity, substrate inhibition, double-reciprocal convexity and decrease in degree by cancellation of common factors between numerator and denominator of rate equations. These conclusions apply with even more force when catalytic steps are included, for then the rate equations, are for multi-site mechanisms, of higher degree, allowing increasingly complex curve shapes. A number of enzymes were studied and initial-rate data were fitted by computer.(ABSTRACT TRUNCATED AT 400 WORDS)


Chronic Allergen Exposure Contributes to Steroid Resistance via Increased Phosphorylation of Glucocorticoid Receptors S226 and p38 MAPK in a Mouse Model of Asthma.
Chronic allergen exposure can significantly induce p38 mitogen-activated protein kinase (MAPK) activation in asthma. p38 MAPK is involved in steroid resistance through phosphorylation of glucocorticoid receptors (GR) at S226. This study aims to investigate whether chronic allergen exposure can induce steroid resistance and whether it is associated with p38 MAPK activation in asthma. A mouse model of asthma was prepared by sensitizing and challenging mice with chronic ovalbumin (OVA) exposure. Key features of allergic asthma, encompassing bronchial hyperresponsiveness, pathology of lung tissues, cytokine profiles of inflammation in bronchoalveolar lavage fluid (BALF), and serum immunoglobulin (Ig)E concentration were evaluated. Furthermore, suppressive effects of corticosteroid on the splenocytes under stimulation of lipopolysaccharides, glucocorticoid receptor (GR) DNA binding ability of splenocytes, expression of GRα and phosphorylation of GR s226 in splenocytes, and p38 MAPK phosphorylation in splenocytes and lung tissues were determined. Chronic OVA exposure substantially induced airway hypersensitivity, leading to increased inflammatory infiltration in lung tissues. Additionally, it resulted in elevated levels of interleukin (IL)-4, IL-5, and IL-6 in BALF, as well as heightened levels of IgE in serum. Furthermore, OVA exposure substantially enhanced p38 MAPK phosphorylation in lung tissues. It also weakened the suppressive impacts of corticosteroids on splenocytes, impaired the GR DNA binding ability, and led to an enhanced phosphorylated state of GR S226 and p38 MAPK in splenocytes. Taken together, chronic allergen exposure contributes to steroid resistance in asthma, which is linked to an increased phosphorylated state of GR S226 and p38 MAPK.


[The survivability time of central nervous system cells].
Our investigations show that vital functions of some neurons and glial cells may survive for 4-8 hours after death and disappear in parallel with destructive changes in cells. Up-to-date morphological techniques demonstrate that neurons and other cells of the CNS preserve biological activity not for several minutes as believed so far but up to 4-8 hours. It is too early to judge about functional importance of this phenomenon and further investigations into this problem are necessary. Temporal parameters of RNA synthesis in the brain cells give additional knowledge about CNS cells survival and this may be of interest for reanimatology and transplantology.


Applications of physiologically based absorption models in drug discovery and development.
This article describes the use of physiologically based models of intestinal drug absorption to guide the research and development of new drugs. Applications range from lead optimization in the drug discovery phase through clinical candidate selection and extrapolation to human to phase 2 formulation development. Early simulations in preclinical species integrate multiple screening data and add value by transforming these individual properties into a prediction of in vivo absorption. Comparison of simulations to plasma levels measured after oral dosing in animals highlights unexpected behavior, and parameter sensitivity analysis can explore the impact of uncertainties in key properties, point toward factors which are limiting absorption and contribute to assessment of compound developability. Physiological models provide reliable prediction of human absorption and with refinement based on phase 1 data are useful guides to further market formulation development. Improvements in the accuracy of simulations are expected as better in vitro methods generate more in vivo relevant solubility and permeability data, and modeling will play a central role in the development of more predictive methods for transporter-related effects on drug absorption.


The effects of 2-methoxy oestrogens and their sulphamoylated derivatives in conjunction with TNF-alpha on endothelial and fibroblast cell growth, morphology and apoptosis.
2-methoxyoestradiol (2-MeOE2) is a potent anti-angiogenic agent. Its 3- and 17-sulphamoylated derivatives have been demonstrated to induce G2-M cell cycle arrest and apoptosis in breast cancer cells in vitro as well as tumour regression in rats in vivo with greater potency than the parent oestrogen. To determine whether the anti-cancer properties of these derivatives can be synergistically enhanced with low-dose TNF-alpha co-treatment, we investigated the effects of these treatments in adult human fibroblasts and human umbilical vein endothelial cells (HUVECs). Treatment of fibroblasts with 0.1 microM 2-methoxyoestradiol-3,17-bis sulphamate (2-MeOE2bisMATE) but not 2-MeOE2 caused a reversible morphology change and induced G2-M arrest (from 12 to 33%) but not subsequent apoptosis. In contrast, treatment of HUVECs did not induce morphology change or G2-M arrest. Using a nucleosomal ELISA assay, we showed that TNF-alpha (20 ng/ml) combination treatment synergistically increases 0.1 microM 2-MeOE2bisMATE-induced but not 0.1 microM 2-MeOE2-induced apoptosis in HUVECs. These results suggest that TNF-alpha co-treatment may be a beneficial method of increasing the potency of 2-substituted oestrogens as anti-angiogenic agents through synergistic induction of apoptosis in endothelial cells while maintaining low cytotoxicity to fibroblasts.


Hydroxychloroquine Increased Anxiety-Like Behaviors and Disrupted the Expression of Some Related Genes in the Mouse Brain.
Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for COVID-19, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta, corticotropin-releasing hormone (Crh), a serotonin transporter (Slc6a4), and a microglia maker (Aif1) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Lots of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.


Long-term effects of intensive glucose lowering on cardiovascular outcomes.
Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).


Disparities in built and natural features of urban parks: comparisons by neighborhood level race/ethnicity and income.
Known associations between the built environment and health outcomes have accelerated research examining racial/ethnic and income disparities in access to parks and other community features that support physical activity. Currently, it cannot be concluded that park characteristics are equal in quantity or condition across areas of disparate race/ethnicity and income composition. This study examined natural and built park characteristics across areas of different race/ethnicity and income composition to identify potential disparities. Twenty-one parks in Greensboro, NC (USA), located in minority or non-minority areas and in low or medium-high income areas were inventoried using a park audit tool and GIS. Parks were compared on number of activity areas, features, amenities, size, percent tree canopy, cleanliness, and condition. Independent sample t tests and Mann-Whitney tests were used to compare means of outcome variables. Fisher's exact tests were applied for categorical variables. Fewer wooded areas and more trash cans were found in low-income and minority areas as compared to medium-high income and non-minority areas. Low-income areas were found to have more picnic areas than their counterparts. Sitting and resting features in non-minority areas were found to be cleaner than those in minority areas. Results showed some evidence of disparities in park characteristics. Findings can inform park policy and design as well as renovations and maintenance procedures, particularly in specific areas where existing disparities were identified.


Induction of apoptosis by idarubicin: how important is the plasma peak?
It is still not clear whether a high plasma peak or a prolonged plasma presence of the drug is optimal for chemotherapy with anthracyclines. A high plasma peak seems to correlate with the liberation of oxygen radicals and cumulative delayed cardiotoxicity, and therefore, should be avoided. On the other hand, its role in attaining the desired therapeutic effect, i.e. induction of apoptosis in tumor cells, has not been clearly elucidated. Idarubicin is the only anthracycline that can be applied orally. We measured the DNA-binding of idarubicin and idarubicinol and the induced apoptosis in the human promyelocytic HL-60 leukemia cell line. Various pharmacokinetic profiles, with and without clinically relevant peak concentrations, were simulated in vitro. The concentration necessary for maximal DNA-binding and subsequent induction of apoptosis was 1.5 microg/ml for 20 minutes which is well above the plasma concentration achievable in therapy. A plateau of apoptosis was observed after 90 minutes of incubation; a prolongation above 90 minutes did not increase the rate of apoptosis. We simulated a bolus application and a continuous infusion using two different pharmacokinetic profiles of idarubicin with comparable AUCs (area under the time curve). After 48 hours of total incubation, the viability of HL-60 cells was 56.88% with profile 1 (50 ng/ml idarubicin for 2 hours) and 83.00% with profile 2 (4.25 ng/ml for 24 hours). Although these in vitro experiments are not directly applicable to the clinical situation, they do indicate that a prolongation of the application time up to at least 90 minutes, either by continuous infusion or by oral application, may be acceptable as a method of increasing apoptosis. On the other hand, the plasma peak seems to be an important factor for the induction of apoptosis. Further studies are in progress to define the minimal plasma peak necessary to induce a maximum of apoptosis.


The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas.
KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca(2+)/calmodulin promote PI3Kα/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3Kα through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3Kα at the membrane, and that this is the likely reason for Ca(2+)/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3Kα/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Kα binding in a K-Ras4B/calmodulin/PI3Kα trimer could be a promising adenocarcinoma-specific therapeutic strategy.


Expression of Fgf23 in activated dendritic cells and macrophages in response to immunological stimuli in mice.
Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.


Mechanism of ATPase-mediated Cu+ export and delivery to periplasmic chaperones: the interaction of Escherichia coli CopA and CusF.
Cellular copper homeostasis requires transmembrane transport and compartmental trafficking while maintaining the cell essentially free of uncomplexed Cu(2+/+). In bacteria, soluble cytoplasmic and periplasmic chaperones bind and deliver Cu(+) to target transporters or metalloenzymes. Transmembrane Cu(+)-ATPases couple the hydrolysis of ATP to the efflux of cytoplasmic Cu(+). Cytosolic Cu(+) chaperones (CopZ) interact with a structural platform in Cu(+)-ATPases (CopA) and deliver copper into the ion permeation path. CusF is a periplasmic Cu(+) chaperone that supplies Cu(+) to the CusCBA system for efflux to the extracellular milieu. In this report, using Escherichia coli CopA and CusF, direct Cu(+) transfer from the ATPase to the periplasmic chaperone was observed. This required the specific interaction of the Cu(+)-bound form of CopA with apo-CusF for subsequent metal transfer upon ATP hydrolysis. As expected, the reverse Cu(+) transfer from CusF to CopA was not observed. Mutation of CopA extracellular loops or the electropositive surface of CusF led to a decrease in Cu(+) transfer efficiency. On the other hand, mutation of Met and Glu residues proposed to be part of the metal exit site in the ATPase yielded enzymes with lower turnover rates, although Cu(+) transfer was minimally affected. These results show how soluble chaperones obtain Cu(+) from transmembrane transporters. Furthermore, by explaining the movement of Cu(+) from the cytoplasmic pool to the extracellular milieu, these data support a mechanism by which cytoplasmic Cu(+) can be precisely directed to periplasmic targets via specific transporter-chaperone interactions.


[Postanastomotic renal-artery stenosis after renal transplantation].
A particular kind of renal-artery stenosis was observed in three of 60 renal transplantations performed between 1969 and 1974. It was always 1.0-1.5 cm distal to the anastomosis and, as histological examination demonstrated, was definitely due to vessel injury after removal of the transplant. To avoid it the proximal arterial stump should be cut off before transplantation. The postanastomotic region must be dissected free during the operation and an extended graft venoplasty or sleeve resection performed.


Changes in the Intestinal Microbiota in Patients with Stage 5 Chronic Kidney Disease on a Low-Protein Diet and the Effects of Human to Rat Fecal Microbiota Transplantation.
BACKGROUND Dietary protein restriction is recommended for patients with stage 5 chronic kidney disease (CKD), or end-stage renal disease (ESRD). This study aimed to investigate the changes in the intestinal microbiota due to different dietary regimens in patients with stage 5 CKD and the effects of human to rat fecal microbiota transplantation. MATERIAL AND METHODS Second-generation high-throughput sequencing was used to analyze the amplifiers in the 16S rRNA V4 region in the intestinal microbiota of patients with stage 5 CKD and healthy individuals. The intestinal microbiota of patients with stage 5 CKD in the low-protein group and the healthy individual group was transferred by human to rat fecal microbiota transplantation using Sprague-Dawley rats. Data underwent meta-analysis using Meta-Stat. RESULTS Patients with CKD on a very low-protein diet showed an increase in intestinal Escherichia, Shigella, and Klebsiella, a decrease in Blautia, heat map analysis showed that Christensenellaceae R-7 group rs1 were significantly increased, and MetaStat analysis showed that Bacteroides, Prevotella, and Mitsuokella were significantly increased. Following human to rat fecal microbiota transplantation from patients with stage 5 CKD, the profile of the rat intestinal microbiota became similar to the human donors. The weight of the rats fed a very low-protein diet after fecal microbiota transplantation significantly decreased after six weeks compared with normal rats and rats that received normal fecal microbiota transplantation. CONCLUSIONS Patients with stage 5 CKD on a very low-protein diet showed changes in the intestinal microbiota that could be transferred from humans to rats by fecal microbiota transplantation.


VIP and PACAP induce shift to a Th2 response by upregulating B7.2 expression.
VIP and PACAP, two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunological functions. Although primarily anti-inflammatory in nature, VIP and PACAP also affect resting macrophages. In this study, we report on the role of VIP and PACAP on macrophage B7 expression and costimulatory function for antigen-primed CD4+ T cells, and on the macrophage-induced regulation of Th1/Th2 differentiation in vitro and in vivo. VIP and PACAP upregulate B7.2, but not B7.1, MHC class II, or ICAM-1 expression, and activate macrophages to stimulate the proliferation of naïve T cells in response to soluble anti-CD3 or allogeneic stimulation. The stimulatory effect is mediated through the specific receptor VPAC1, and involves the cAMP/PKA pathway as second messengers. The enhancement in B7.2 expression occurs at both mRNA and protein levels, and correlates with the VIP/PACAP induced upregulation of the costimulatory activity of macrophages for antigen-primed CD4+ T cells. VIP/PACAP-treated macrophages gain the ability to induce Th2-type cytokines such as IL-4 and IL-5, and to reduce Th1-type cytokines such as IFN gamma and IL-2. In vivo administration of VIP or PACAP in antigen-immunized mice reduces the numbers of IFN gamma-secreting cells, enhances the numbers of IL-4-secreting cells, and affects the pattern of antigen-specific Ig isotypes. The preferential differentiation into Th2 effector cells induced by VIP/PACAP-treated macrophages is mediated through the upregulation of B7.2 expression. Since Th1-dominated responses are associated with some autoimmune diseases and inflammatory reactions typical of cell-mediated immunity, the VIP/PACAP inhibition of Th1 development may represent an additional mechanism for the general anti-inflammatory activity of the two neuropeptides.


Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.
We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer. Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil-based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry. Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001). High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse.


Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis.
Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs. Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis. One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001). Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.


Computer-aided detection of intracranial aneurysms in MR angiography.
Intracranial aneurysms represent a significant cause of morbidity and mortality. While the risk factors for aneurysm formation are known, the detection of aneurysms remains challenging. Magnetic resonance angiography (MRA) has recently emerged as a useful non-invasive method for aneurysm detection. However, even for experienced neuroradiologists, the sensitivity to small (<5 mm) aneurysms in MRA images is poor, on the order of 30~60% in recent, large series. We describe a fully automated computer-aided detection (CAD) scheme for detecting aneurysms on 3D time-of-flight (TOF) MRA images. The scheme locates points of interest (POIs) on individual MRA datasets by combining two complementary techniques. The first technique segments the intracranial arteries automatically and finds POIs from the segmented vessels. The second technique identifies POIs directly from the raw, unsegmented image dataset. This latter technique is useful in cases of incomplete segmentation. Following a series of feature calculations, a small fraction of POIs are retained as candidate aneurysms from the collected POIs according to predetermined rules. The CAD scheme was evaluated on 287 datasets containing 147 aneurysms that were verified with digital subtraction angiography, the accepted standard of reference for aneurysm detection. For two different operating points, the CAD scheme achieved a sensitivity of 80% (71% for aneurysms less than 5 mm) with three mean false positives per case, and 95% (91% for aneurysms less than 5 mm) with nine mean false positives per case. In conclusion, the CAD scheme showed good accuracy and may have application in improving the sensitivity of aneurysm detection on MR images.


Bacterial vaginosis and cervical dilation and effacement at 24-29 weeks' gestation.
The purpose of this study was to investigate the association between bacterial vaginosis (BV) and cervical dilation and effacement, as measures of impending preterm delivery. The Pregnancy, Infection, and Nutrition Study collected genital tract specimens and documented cervical change from 807 eligible women between 24 and 29 weeks' gestation. BV was assessed with Nugent-scored vaginal smears, and analyzed in relation to cervical measurements. At 24-29 weeks' gestation, <7% of women had a dilated cervix, 31% had a cervix < or =2 cm, and 17.3% had BV. Unadjusted analyses found no associations between BV and cervical measurements. Adjusted logistic regression suggested an association between BV and cervical effacement among women with a sexually transmitted disease (STD) earlier in pregnancy (odds ratio = 1.9, 95% CI 0.8-4.3). Stratified analyses for BV/dilation also suggested interaction with STDs. Overall, BV was not association with cervical dilation or effacement at 24-29 weeks' gestation.


Diabetes duration, perceived comfort with self-management and glycaemic control in adolescents with type 1 diabetes: A cross-sectional study.
Evidence is lacking on whether diabetes duration is associated with type 1 diabetes (T1D) self-management during late adolescence before transfer from paediatric to adult care. We examined associations of diabetes duration with dimensions of perceived comfort with diabetes self-management (self-efficacy, transition readiness, diabetes distress) and glycaemic control in late adolescence. Using a cross-sectional design, we conducted a secondary analysis of baseline data of adolescents (ages 16-17 years) with T1D followed at paediatric diabetes academic hospitals in Montreal and enrolled in the Group Education Trial to Improve Transition (GET-IT-T1D). Participants completed validated questionnaires on self-efficacy (Self-Efficacy for Diabetes Self-Management Measure [SEDM], score 1 to 10), diabetes distress and transition readiness, as well as a haemoglobin (HbA1c) capillary blood test. Our primary outcome was self-efficacy. We examined associations of diabetes duration with self-efficacy, diabetes distress, transition readiness and HbA1c using linear and logistic regression models adjusted for sex, socioeconomic status, insulin pump use, glucose sensor use and psychiatric comorbidity. Of 203 adolescents with T1D, mean diabetes duration (SD) was 7.57 (4.44) years. Mean SEDM score was 6.83 (SD 1.62). Diabetes duration was not associated with self-efficacy, diabetes distress or transition readiness. Each additional year of diabetes duration was associated with 0.11% (95% CI, 0.05 to 0.16) higher HbA1c. Although diabetes duration is not associated with dimensions of perceived comfort with diabetes self-management, adolescents with longer diabetes duration are at risk for higher HbA1c and may need additional support to improve glycaemic control before transition to adult care.


A New Method for Deriving Global Estimates of Maternal Mortality.
Maternal mortality is widely regarded as a key indicator of population health and of social and economic development. Its levels and trends are monitored closely by the United Nations and others, inspired in part by the UN's Millennium Development Goals (MDGs), which call for a three-fourths reduction in the maternal mortality ratio between 1990 and 2015. Unfortunately, the empirical basis for such monitoring remains quite weak, requiring the use of statistical models to obtain estimates for most countries. In this paper we describe a new method for estimating global levels and trends in maternal mortality. For countries lacking adequate data for direct calculation of estimates, we employed a parametric model that separates maternal deaths related to HIV/AIDS from all others. For maternal deaths unrelated to HIV/AIDS, the model consists of a hierarchical linear regression with three predictors and variable intercepts for both countries and regions. The uncertainty of estimates was assessed by simulating the estimation process, accounting for variability both in the data and in other model inputs. The method was used to obtain the most recent set of UN estimates, published in September 2010. Here, we provide a concise description and explanation of the approach, including a new analysis of the components of variability reflected in the uncertainty intervals. Final estimates provide evidence of a more rapid decline in the global maternal mortality ratio than suggested by previous work, including another study published in April 2010. We compare findings from the two recent studies and discuss topics for further research to help resolve differences.


Characteristics and interpretation of subgroup analyses based on tumour characteristics in randomised trials testing target-specific anticancer drugs: design of a systematic survey.
Target-specific anticancer drugs are under rapid development. Little is known, however, about the risk of administering target-specific drugs to patients who have tumours with molecular alterations or other characteristics that can make the drug ineffective or even harmful. An increasing number of randomised clinical trials (RCTs) investigating target-specific anticancer drugs include subgroup analyses based on tumour characteristics. Such subgroup analyses have the potential to be more credible and influential than subgroup analyses based on traditional factors such as sex or tumour stage. In addition, they may more frequently lead to qualitative subgroup effects, that is, show benefit in one but harm in another subgroup of patients (eg, if the tumour characteristic makes the drug ineffective or even enhance tumour growth). If so, subgroup analyses based on tumour characteristics would be highly relevant for patient safety. The aim of this study is to systematically assess the frequency and characteristics of subgroup analyses based on tumour characteristics, the frequency of qualitative subgroup effects, their credibility, and the interpretations that investigators and guidelines developers report. We will perform a systematic survey of 433 RCTs testing the effect of target-specific anticancer drugs. Teams of methodologically trained investigators and oncologists will identify eligible studies, extract relevant data and assess the credibility of putative subgroup effects using a recently developed formal instrument. We will systematically assess how trial investigators interpret apparent subgroup effects based on tumour characteristics and the extent to which they influence subsequent practice guidelines. Our results will provide empirical data characterising an increasingly used type of subgroup analysis in cancer trials and its potential impact on precision medicine to predict benefit or harm. Formal ethical approval is not required for this study. We will disseminate the findings in a peer-reviewed and open-access journal publication.


Pentraxin 3 as a new indicator of cardiovascular‑related death in patients with advanced chronic kidney disease.
INTRODUCTION Pentraxin3 (PTX3) play an important role in the inflammatory response, taking part in recognizing pathogens and damaged tissues. OBJECTIVES The aim of the study was to assess the relationship between PTX3 levels and all-cause and cardiovascular (CV) mortality in chronic kidney disease (CKD) patients during five-year observation period. PATIENTS AND METHODS The study comprised 78 patients (51 hemodialyzed, 27 predialysis). The examined parameters included PTX3, calcium, phosphate, iPTH, interleukin-6 (IL-6), fibroblast growth factor 23 (FGF-23), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin, tumor necrosis factor receptor II (TNF-R II), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), stromal cell-derived factor α (SDF1α), and thrombomodulin (TM). In a subgroup of 45 patients, fragments of radial artery obtained during creation of hemodialysis access were stained for calcifications. In 51 patients, ultrasonography was performed to assess intima-media thickness (CCA-IMT). RESULTS Median serum concentration of PTX3 was 1.43 (0.74-2.50) ng/ml. Higher concentrations of fibrinogen, CRP, IL-6, TNF-R II, TGFβ1, HGF, OPN, OPG, FGF-23, TM, SDF1α, lower albumin and uric acid levels were observed in patients with PTX3 above the median. During follow-up, 27 patients (35%) died, including 25 due to CV causes. In contrast to CRP, baseline PTX3 predicted CV mortality independently of classical CV risk factors. Also, PTX3 concentrations significantly predicted mortality after adjustment for age, baseline dialysis status, serum OPG and CRP, radial artery calcifications, and CCA-IMT. CONCLUSIONS We postulate that PTX3 might be an early marker of CV mortality in patients with advanced CKD yet before the increase of specific marker for systemic inflammation like hsCRP.


Effect of treated-sewage contamination upon bacterial energy charge, adenine nucleotides, and DNA content in a sandy aquifer on Cape Cod.
Changes in adenylate energy charge (ECA) and in total adenine nucleotides (A(T) and DNA content (both normalized to the abundance of free-living, groundwater bacteria) in response to carbon loading were determined for a laboratory-grown culture and for a contaminated aquifer. The latter study involved a 3-km-long transect through a contaminant plume resulting from continued on-land discharge of secondary sewage to a shallow, sandy aquifer on Cape Cod, Mass. With the exception of the most contaminated groundwater immediately downgradient from the contaminant source, DNA and adenylate levels correlated strongly with bacterial abundance and decreased exponentially with increasing distance downgradient. ECAS (0.53 to 0.60) and the ratios of ATP to DNA (0.001 to 0.003) were consistently low, suggesting that the unattached bacteria in this groundwater study are metabolically stressed, despite any eutrophication that might have occurred. Elevated ECAS (up to 0.74) were observed in glucose-amended groundwater, confirming that the metabolic state of this microbial community could be altered. In general, per-bacterium DNA and ATP contents were approximately twofold higher in the plume than in surrounding groundwater, although ECA and per-bacterium levels of A(T) differed little in the plume and the surrounding uncontaminated groundwater. However, per-bacterium levels of DNA and A(T) varied six- and threefold, respectively, during a 6-h period of decreasing growth rate for an unidentified pseudomonad isolated from contaminated groundwater and grown in batch culture.(ABSTRACT TRUNCATED AT 250 WORDS)


Sepsis.
Essential facts Sepsis, a clinical syndrome caused by the body's immune and coagulation systems being switched on by an infection, is believed to cause about 44,000 deaths a year. If not recognised early and treated promptly, sepsis can lead to shock, multiple organ failure and death. Major reports (UK parliamentary and health service ombudsman enquiry in 2013 and the UK National Confidential Enquiry into Patient Outcome and Death in 2015) have highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined.


Autologous costal chondral transplantation and costa-derived chondrocyte implantation: emerging surgical techniques.
It is a great challenge to cure symptomatic lesions and considerable defects of hyaline cartilage due to its complex structure and poor self-repair capacity. If left untreated, unmatured degeneration will cause significant complications. Surgical intervention to repair cartilage may prevent progressive joint degeneration. A series of surgical techniques, including biological augmentation, microfracture and bone marrow stimulation, autologous chondrocyte implantation (ACI), and allogenic and autogenic chondral/osteochondral transplantation, have been used for various indications. However, the limited repairing capacity and the potential pitfalls of these techniques cannot be ignored. Increasing evidence has shown promising outcomes from ACI and cartilage transplantation. Nevertheless, the morbidity of autologous donor sites and limited resource of allogeneic bone have considerably restricted the wide application of these surgical techniques. Costal cartilage, which preserves permanent chondrocytes and the natural osteochondral junction, is an ideal candidate for the restoration of cartilage defects. Several in vitro and in vivo studies have shown good performance of costal cartilage transplantation. Although costal cartilage is a classic donor in plastic and cosmetic surgery, it is rarely used in skeletal cartilage restoration. In this review, we introduce the fundamental properties of costal cartilage and summarize costa-derived chondrocyte implantation and costal chondral/osteochondral transplantation. We will also discuss the pitfalls and pearls of costal cartilage transplantation. Costal chondral/osteochondral transplantation and costa-based chondrocytotherapy might be up-and-coming surgical techniques for recalcitrant cartilage lesions.


Use of long acting antipsychotics and relationship to newly diagnosed bipolar disorder: a pragmatic longitudinal study based on a Canadian health registry.
There is limited data from large naturalistic studies to inform prescribing of long-acting injectable medication (LAIs). Guidance is particularly rare in the case of primary mood disorders. This study describes prescribing trends of LAIs in 3879 patients in Quebec, Canada, over a period of 4 years. Health register data from the Quebec provincial health plan were reviewed. In this specific registry, 32% of patients who received LAIs drugs for schizophrenia had a confirmed diagnosis of bipolar disorder and 17% had a diagnosis of major depressive disorder. Non-schizophrenia syndromes were preferentially prescribed risperidone long-acting antipsychotic, whereas patients with schizophrenia were prescribed an excess of haloperidol decanoate. Patients with non-schizophrenia disorders prescribed long-acting antipsychotics were more frequently treated in primary care compared with patients with schizophrenia. Data from a large number of patients treated naturalistically in Quebec with long-acting antipsychotics suggests that these compounds, prescribed to treat symptoms of schizophrenia and schizoaffective disorders, were maintained when mood symptoms emerged, even in cases when the diagnosis changed to bipolar disorder. This pragmatic study supports the need to explore this intervention as potential treatment for affective disorders.


Changes of hypothalamus-pituitary hormones in patients after total removal of craniopharyngiomas.
This paper aimed to elucidate the changes of hypothalamus-pituitary hormones in patients after total removal of craniopharyngiomas. A total of 40 patients with craniopharyngiomas received surgery. The levels of triiodothyronine (T3), thyroxine (T4), thyrotropic hormone (TSH), antidiuretic hormone (ADH), and adrenocorticotropin (ACTH) were measured in the 40 patients before surgery and one week after surgery respectively. Twenty-eight patients (70%) had hypothyroidism before surgery, but 38 (95%) had hypothyroidism after surgery (P < 0.01). Twenty-three patients (57.5%) had diabetes insipidus (DI) before surgery and 38 (95%) had DI after surgery (P < 0.001). The pre- and post-operative levels of ADH were (2.49 +/- 0.30) pg/ml and (2.80 +/- 0.29) pg/ml respectively (P > 0.05), whereas those of ACTH were (23.97 +/- 2.69) pg/ml and (15.60 +/- 1.91) pg/ml respectively (P < 0.05). Hormone deficits after total removal of craniopharyngioma appear to be the common complication of surgery. Hypothyroidism and diabetes insipidus are more frequent after surgery than before surgery. Thyroxine and glucocorticoids should be administered routinely after total removal of craniopharyngioma.


Palpebral edema as a cutaneous manifestation of hyperthyroidism.
Three cases of palpebral edema associated with Graves' disease are described. These patients had unilateral edema and minimal erythema of the upper eyelid. Notable was that, histologically, dermal edema and dilation of lymphatic vessels were observed, but deposition of mucopolysaccharides was not. In 2 cases, edema of the eyelid was resistant to treatment with an antithyroid drug. Unilateral edema of the upper eyelid is an important cutaneous manifestation that indicates the presence of hyperthyroidism.


Monitoring of glomerulonephritis.
In addition to the standard biochemical measures we need better methods for monitoring of glomerulonephritides. A variety of new tests are now available. One has to be selective in one's choice. Attention has to be paid to means of assessing interstitial fibrosis and damage to the tubules of the kidneys.


Functional site of bukatoxin, an alpha-type sodium channel neurotoxin from the Chinese scorpion (Buthus martensi Karsch) venom: probable role of the (52)PDKVP(56) loop.
Alpha-toxins from scorpion venoms prolong the action potential of excitable cells by blocking sodium channel inactivation. We have purified bukatoxin, an alpha-toxin from scorpion (Buthus martensi Karsch) venom, to homogeneity. Bukatoxin produced marked relaxant responses in the carbachol-precontracted rat anococcygeus muscle (ACM), which were mediated through the L-arginine-nitric oxide synthase-nitric oxide pathway, consequent to a neuronal release of nitric oxide. Based on the presence of proline residues in the flanking segments of protein-protein interaction sites, we predicted the site between (52)PP(56) to be the potential interaction site of bukatoxin. A homology model of bukatoxin indicated the presence of this site on the surface. Buka11, a synthetic peptide designed based on this predicted site, produced a concentration-dependent nitric oxide-mediated relaxant response in ACM. Using alanine-substituted peptides, we have shown the importance (53)DKV(55) flanked by proline residues in the functional site of bukatoxin.


Semiparametric frailty models for clustered failure time data.
We consider frailty models with additive semiparametric covariate effects for clustered failure time data. We propose a doubly penalized partial likelihood (DPPL) procedure to estimate the nonparametric functions using smoothing splines. We show that the DPPL estimators could be obtained from fitting an augmented working frailty model with parametric covariate effects, whereas the nonparametric functions being estimated as linear combinations of fixed and random effects, and the smoothing parameters being estimated as extra variance components. This approach allows us to conveniently estimate all model components within a unified frailty model framework. We evaluate the finite sample performance of the proposed method via a simulation study, and apply the method to analyze data from a study of sexually transmitted infections (STI).


Intracerebral Hemorrhage Caused by Thrombosis of a Developmental Venous Anomaly with an Unusual Structure: A Case Report.
Developmental venous anomalies (DVAs) are common intracranial vascular malformations and they are generally do not cause clinical complications. In cases showing DVA and hemorrhage, the hemorrhage is usually associated with adjacent cavernous malformations. Very few cases of intracerebral hemorrhage (ICH) caused by thrombosis in DVA have been reported in the literature. In this case report, we present an interesting case of a large ICH caused by thrombosis within a DVA with an unusual structure that may have potentiated the thrombosis.


Imaging factors influencing spine and cord measurements by CT: a phantom study.
Metrizamide computed tomography (CT) of the spine allows evaluation of the contents and measurement of the size of intracanalicular structures. The relative size (linear and area measurements) of spinal structures can be changed by varying imaging factors or the density of intrathecal contrast material. Two phantoms, one consisting of rods embedded in a plastic cylinder and the other of a vertebral body with a central rod simulating spinal cord, were evaluated with varying imaging factors (window width and window level) and different contrast concentrations within the surround. It was found that wide window widths allowed the most consistent measurements independent of window level, that a window level midway between the CT number of rod and surround would facilitate uniform measurements independent of window width, and that the use of high concentrations of contrast material (high CT number) in the surround, in combination with a wide window width, was most effective in establishing consistent measurements.


[Pathomorphology of West Nile fever].
8 patients, aged from 61 to 70 years, died from serous meningoencephalitis during the outburst of the West Nile fever in Volgograd in 1999-2001, were studied morphologically. Serous meningoencephalitis with necrotic vasculitis is a characteristic feature of this fever with degenerative changes and destructive foci in the brain. Proteinic and fatty inflammatory and lymphomacrophageal reactions were observed in the liver, serous productive myocarditis and cardiomyocytic necrosis dystrophy. Desquamative pneumonia, intracapillary nephritis were also seen. Immunohistochemical reaction against virus of this fever was positive in the vascular endothelium of parenchymal organs, hepatocytes, neurons of the brain.


Survey for zoonotic rickettsial pathogens in northern flying squirrels, Glaucomys sabrinus, in California.
Epidemic typhus, caused by Rickettsia prowazekii, is maintained in a southern flying squirrel (Glaucomys volans) sylvatic cycle in the southeastern United States. The northern flying squirrel (Glaucomys sabrinus) has not been previously associated with R. prowazekii transmission. A second rickettsial pathogen, Anaplasma phagocytophilum, infects dusky-footed woodrats (Neotoma fuscipes) and tree squirrels in northern California. Because northern flying squirrels or their ectoparasites have not been tested for these rickettsial pathogens, serology and polymerase chain reaction (PCR) were used to test 24 northern flying squirrels for R. prowazekii and A. phagocytophilum infection or antibodies. Although there was no evidence of exposure to R. prowazekii, we provide molecular evidence of A. phagocytophilum infection in one flying squirrel; two flying squirrels also were seropositive for this pathogen. Fleas and ticks removed from the squirrels included Ceratophyllus ciliatus mononis, Opisodasys vesperalis, Ixodes hearlei, Ixodes pacificus, and Dermacentor paramapertus.


Experimental evidence for resonant tunneling in a luttinger liquid
We have measured the low-temperature conductance of a one-dimensional island embedded in a single mode quantum wire. The quantum wire is fabricated using the cleaved edge overgrowth technique and the tunneling is through a single state of the island. Our results show that while the resonance line shape fits the derivative of the Fermi function the intrinsic linewidth decreases in a power law fashion as the temperature is reduced. This behavior agrees quantitatively with Furusaki's model for resonant tunneling in a Luttinger liquid.


A dexamethasone-loaded PLGA microspheres/collagen scaffold composite for implantable glucose sensors.
We have developed a new dexamethasone (Dex)-loaded poly(lactic-co-glycolic acid) microspheres/porous collagen scaffold composite for implantable glucose sensors. The scaffolds were fabricated around the sensing element of the sensors and crosslinked using nordihydroguaiaretic acid (NDGA). The microspheres containing Dex were incorporated into the NDGA-crosslinked collagen scaffold by dipping in microsphere suspension in either water or Pluronic. The loading efficiencies of Dex in the microspheres and the scaffold were determined using high performance liquid chromatography. The microspheres/scaffold composite fabricated using microspheres in the hydrogel solution had a better loading efficiency than when microspheres were in water suspension. The composite fabricated using the hydrogel also showed a slower and more sustained drug release than the standard microspheres in vitro during a 4 week study and did not significantly affect the function of the sensors in vitro. The sensors with the composite that were still functional retained above 50% of their original sensitivity at 2 weeks. Histology showed that the inflammatory response to the Dex-loaded composite was much lower than for the control scaffold at 2 and 4 weeks after implantation. The Dex-loaded composite system might be useful to reduce inflammation to implanted glucose sensors and therefore extend their function and lifetime.


Takotsubo cardiomyopathy after elective mitral valve replacement.
Takotsubo cardiomyopathy is a syndrome characterized by transient acute left ventricular dysfunction, electrocardiographic changes that can mimic acute myocardial infarction and minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. Reports of Takotsubo syndrome after cardiac surgery are exceptional. We describe a case of Takotsubo cardiomyopathy in a 68-year-old woman after elective mitral valve replacement. Takotsubo syndrome should be considered in the differential diagnosis of patients presenting cardiogenic shock after cardiac surgery.


Tar pollution event (2021) at the Southeastern Levantine oligotrophic basin, short-term impacts and operational oceanography perspectives.
The Levantine basin (LB) in the Southeastern Mediterranean Sea is a high-risk oil pollution hot spot owing to its dense maritime traffic and intense oil and gas exploration and exploitation activities. In February 2021 the Israeli LB shorelines were impacted by an exceptional tar pollution event (~550 tons; average distribution: ~3 kg tar m-1 front beach) of an unknown oil spill source. Here we report on the immediate numerical modelling assessment of the oil spill propagation and tar distribution; operational use of underwater gliders for tracking water column anomalies of dissolved polycyclic aromatic hydrocarbons (PAHs) and turbidity signals; the beached tar composition and amounts and the short-term response of the microbial population along the ~180 km shoreline. This pollution event emphasizes the need for improving the early warning systems for oil spills and implementing continuous operational monitoring at high-risk, ecologically sensitive and valuable resource areas like the Israeli LB waters.


Implementing successful residential alternatives to acute in-patient psychiatric services: lessons from a multi-centre study of alternatives in England.
Standard acute psychiatric care in the UK is costly but problematic. Alternatives to standard in-patient wards exist, but little is known about their effectiveness, implementation and sustainability. This paper explores successful features and limitations of five residential alternative services in England and factors that facilitate or impede their initial and sustained implementation and success. Semi-structured interviews about the functioning of six alternative services were conducted with 36 mental health professionals with good working knowledge of, and various connections with these services. A group interview with study researchers was also conducted. Data were analysed using thematic analysis. One service did not show evidence of operating as an alternative and was excluded from further analysis. The remaining five alternatives are valued for providing a more holistic style of care than standard services that confers many perceived benefits. However, they are seen as less appropriate for compulsorily detained or highly disturbed patients, and as providing less comprehensive treatment packages than hospital settings. Factors identified as important to successful implementation and sustainability are: responding to known shortcomings in local acute care systems; balancing role clarity and adaptability; integration with other services; and awareness of the alternative among relevant local health-care providers. Residential alternatives can play an important role in managing mental health crises. Their successful implementation and endurance depend on establishing and maintaining a valued position within local service systems. Findings contribute to bridging the gap between research evidence on the problems of standard acute care and delivering improved crisis management services.


Granulocyte colony-stimulating factor in neutropenic, pediatric solid tumor patients following chemotherapy.
Granulocyte colony-stimulating factor (G-CSF) has been used to reduce the duration and/or degree of neutropenia of different etiologies in recent years. In this study, experience with the use of G-CSF (Neupogen, Roche) after 123 courses of highly myelosuppressive chemotherapy administered to 31 (20 female, 11 male) patients with pediatric solid tumors is reported. G-CSF was initiated at a white blood cell (WBC) count of 918 +/- 452/microL (100-2000), at a dose of 7.6 +/- 2.3 micrograms/kg/d (5-14) subcutaneously for 5.2 +/- 2.4 days (2-18). G-CSF was given for afebrile neutropenia after 82 and for febrile neutropenia after 41 courses. Only in two episodes where G-CSF was given for afebrile neutropenia, fever developed. The average hospitalization period for febrile neutropenia was 9.8 +/- 3.3 days (5-20). Chemotherapy could be given on scheduled time and dosage in 90% of the courses in which G-CSF was used for afebrile neutropenia. G-CSF was well tolerated. Bone pain was observed in two patients and urticaria in one patient. In conclusion, G-CSF increased the WBC count effectively, there were only two febrile episodes in 82 courses in children receiving G-CSF for afebrile neutropenia, it was well tolerated, and it was found to be feasible for use in a developing country.


DropConnected neural networks trained on time-frequency and inter-beat features for classifying heart sounds.
Automatic heart sound analysis has the potential to improve the diagnosis of valvular heart diseases in the primary care phase, as well as in countries where there is neither the expertise nor the equipment to perform echocardiograms. An algorithm has been trained, on the PhysioNet open-access heart sounds database, to classify heart sounds as normal or abnormal. The heart sounds are segmented using an open-source algorithm based on a hidden semi-Markov model. Following this, the time-frequency behaviour of a single heartbeat is characterized by using a novel implementation of the continuous wavelet transform, mel-frequency cepstral coefficients, and certain complexity measures. These features help detect the presence of any murmurs. A number of other features are also extracted to characterise the inter-beat behaviour of the heart sounds, which helps to recognize diseases such as arrhythmia. The extracted features are normalized and their dimensionality is reduced using principal component analysis. They are then used as the input to a fully-connected, two-hidden-layer neural network, trained by error backpropagation, and regularized with DropConnect. This algorithm achieved an accuracy of 85.2% on the test data, which placed third in the PhysioNet/Computing in Cardiology Challenge (first place scored 86.0%). However, this is unrealistic of real-world performance, as the test data contained a dataset (dataset-e) in which normal and abnormal heart sounds were recorded with different stethoscopes. A 10-fold cross-validation study on the training data (excluding dataset-e) gives a mean score of 74.8%, which is a more realistic estimate of accuracy. With dataset-e excluded from training, the algorithm scored only 58.1% on the test data.


A neural learning approach for adaptive image restoration using a fuzzy model-based network architecture.
We address the problem of adaptive regularization in image restoration by adopting a neural-network learning approach. Instead of explicitly specifying the local regularization parameter values, they are regarded as network weights which are then modified through the supply of appropriate training examples. The desired response of the network is in the form of a gray level value estimate of the current pixel using weighted order statistic (WOS) filter. However, instead of replacing the previous value with this estimate, this is used to modify the network weights, or equivalently, the regularization parameters such that the restored gray level value produced by the network is closer to this desired response. In this way, the single WOS estimation scheme can allow appropriate parameter values to emerge under different noise conditions, rather than requiring their explicit selection in each occasion. In addition, we also consider the separate regularization of edges and textures due to their different noise masking capabilities. This in turn requires discriminating between these two feature types. Due to the inability of conventional local variance measures to distinguish these two high variance features, we propose the new edge-texture characterization (ETC) measure which performs this discrimination based on a scalar value only. This is then incorporated into a fuzzified form of the previous neural network which determines the degree of membership of each high variance pixel in two fuzzy sets, the EDGE and TEXTURE fuzzy sets, from the local ETC value, and then evaluates the appropriate regularization parameter by appropriately combining these two membership function values.


Sphincter of Oddi motility disorders in patients with idiopathic recurrent pancreatitis.
Motor disorders of the sphincter of Oddi (SO) may play a role in the pathogenesis of idiopathic recurrent pancreatitis. We have compared manometric records from the SO in 28 patients with idiopathic recurrent pancreatitis with those from 10 control subjects. Patients with idiopathic recurrent pancreatitis had presented with episodes of upper abdominal pain associated with abnormal serum levels of amylase on at least two occasions, in the absence of alcohol abuse and biliary disease. Retrograde pancreatography was either normal or showed only minor changes in pancreatic ducts. A triple lumen low compliance manometric system was used to obtain a 5 min recording of spontaneous SO motor activity. From this recording were determined the SO basal pressure, SO phasic contraction amplitude, SO wave frequency and direction of wave propagation. The SO response to intravenous cholecystokinin-octapeptide (CCK-OP) 20 ng/kg was then recorded for at least 3 min. Twenty-five of the twenty-eight patients demonstrated one or more manometric abnormality when compared with data from the ten controls. The most frequent abnormality was an elevated SO basal pressure in 16 patients. In addition, excess of retrograde contractions in nine patients, high frequency of SO phasic contractions in nine patients, absence of phasic contractions in three patients, and paradoxical response to CCK-OP administration in two patients were recorded. This study has demonstrated a spectrum of sphincter of Oddi manometric disorders in patients with idiopathic recurrent pancreatitis and suggests that motility disorders of the sphincter of Oddi may be associated with episodes of pancreatitis.


Accumulation of Glassy Poly(ethylene oxide) Anchored in a Covalent Organic Framework as a Solid-State Li+ Electrolyte.
Design of molecular structures showing fast ion conductive/transport pathways in the solid state has been a significant challenge. The amorphous or glassy phase in organic polymers works well for fast ion conductivity because of their dynamic and random structure. However, the main issue with these polymers has been the difficulty in elucidating the mechanisms of ion conduction and thus low designability. Furthermore, the amorphous or glassy state of ion conductive polymers often confronts the problems of structural/mechanical stabilities. Covalent organic frameworks (COFs) are an emerging class of crystalline organic polymers with periodic structure and tunable functionality, which exhibit potential as a unique ion conductor/transporter. Here, we describe the use of a COF as a medium for all-solid-state Li+ conductivity. A bottom-up self-assembly approach was applied to covalently reticulate the flexible, bulky, and glassy poly(ethylene oxide) (PEO) moieties that can solvate Li+ for fast transport by their segmental motion in the rigid two-dimensional COF architectures. Temperature-dependent powder X-ray diffraction and thermogravimetric analysis showed that the periodic structures are intact even above 300 °C, and differential scanning calorimetry and solid-state NMR revealed that the accumulated PEO chains are highly dynamic and exhibit a glassy state. Li+ conductivity was found to depend on the dynamics and length of PEO chains in the crystalline states, and solid-state Li+ conductivity of 1.33 × 10-3 S cm-1 was achieved at 200 °C after LiTFSI doping. The high conductivity at the specified temperature remains intact for extended periods of time as a result of the structure's robustness. Furthermore, we demonstrated the first application of a COF electrolyte in an all-solid-state Li battery at 100 °C.


Mitochondrial phylogenomics of the Bivalvia (Mollusca): searching for the origin and mitogenomic correlates of doubly uniparental inheritance of mtDNA.
Doubly uniparental inheritance (DUI) is an atypical system of animal mtDNA inheritance found only in some bivalves. Under DUI, maternally (F genome) and paternally (M genome) transmitted mtDNAs yield two distinct gender-associated mtDNA lineages. The oldest distinct M and F genomes are found in freshwater mussels (order Unionoida). Comparative analyses of unionoid mitochondrial genomes and a robust phylogenetic framework are necessary to elucidate the origin, function and molecular evolutionary consequences of DUI. Herein, F and M genomes from three unionoid species, Venustaconcha ellipsiformis, Pyganodon grandis and Quadrula quadrula have been sequenced. Comparative genomic analyses were carried out on these six genomes along with two F and one M unionoid genomes from GenBank (F and M genomes of Inversidens japanensis and F genome of Lampsilis ornata). Compared to their unionoid F counterparts, the M genomes contain some unique features including a novel localization of the trnH gene, an inversion of the atp8-trnD genes and a unique 3'coding extension of the cytochrome c oxidase subunit II gene. One or more of these unique M genome features could be causally associated with paternal transmission. Unionoid bivalves are characterized by extreme intraspecific sequence divergences between gender-associated mtDNAs with an average of 50% for V. ellipsiformis, 50% for I. japanensis, 51% for P. grandis and 52% for Q. quadrula (uncorrected amino acid p-distances). Phylogenetic analyses of 12 protein-coding genes from 29 bivalve and five outgroup mt genomes robustly indicate bivalve monophyly and the following branching order within the autolamellibranch bivalves: ((Pteriomorphia, Veneroida) Unionoida). The basal nature of the Unionoida within the autolamellibranch bivalves and the previously hypothesized single origin of DUI suggest that (1) DUI arose in the ancestral autolamellibranch bivalve lineage and was subsequently lost in multiple descendant lineages and (2) the mitochondrial genome characteristics observed in unionoid bivalves could more closely resemble the DUI ancestral condition. Descriptions and comparisons presented in this paper are fundamental to a more complete understanding regarding the origins and consequences of DUI.


Vaccination for invasive canine meningioma induces in situ production of antibodies capable of antibody-dependent cell-mediated cytotoxicity.
Malignant and atypical meningiomas are resistant to standard therapies and associated with poor prognosis. Despite progress in the treatment of other tumors with therapeutic vaccines, this approach has not been tested preclinically or clinically in these tumors. Spontaneous canine meningioma is a clinically meaningful but underutilized model for preclinical testing of novel strategies for aggressive human meningioma. We treated 11 meningioma-bearing dogs with surgery and vaccine immunotherapy consisting of autologous tumor cell lysate combined with toll-like receptor ligands. Therapy was well tolerated, and only one dog had tumor growth that required intervention, with a mean follow up of 585 days. IFN-γ-elaborating T cells were detected in the peripheral blood of 2 cases, but vaccine-induced tumor-reactive antibody responses developed in all dogs. Antibody responses were polyclonal, recognizing both intracellular and cell surface antigens, and HSP60 was identified as one common antigen. Tumor-reactive antibodies bound allogeneic canine and human meningiomas, showing common antigens across breed and species. Histologic analysis revealed robust infiltration of antibody-secreting plasma cells into the brain around the tumor in posttreatment compared with pretreatment samples. Tumor-reactive antibodies were capable of inducing antibody-dependent cell-mediated cytotoxicity to autologous and allogeneic tumor cells. These data show the feasibility and immunologic efficacy of vaccine immunotherapy for a large animal model of human meningioma and warrant further development toward human trials.


Development of bioadhesive amino-pegylated poly(anhydride) nanoparticles designed for oral DNA delivery.
Amino-pegylated poly(methyl vinyl ether-co-maleic anhydride) nanoparticles were prepared applying a solvent displacement method. The surface charge of the resulting pegylated particles was considerably higher (-2.7 mV) than that of the non-pegylated (-33.5 mV). After oral administration to rats the amino-pegylated nanoparticles exhibited great ability for bioadhesive interactions with the gastrointestinal mucosa. Furthermore, fluorescence microscopy revealed that the amino-pegylated were able to cross the cellular membrane of the absorptive enterocytes. Genomic salmon testes DNA was associated to the amino-pegylated poly(anhydride) particles by applying two procedures: (i) incubation of aqueous DNA solution with the freshly formed amino-pegylated particles; and (ii) initial incubation of DNA and DAP-PEG simultaneously, followed by blending with preformed non-pegylated particles. Gel electrophoresis showed that both methods were safe and DNA integrity was not affected. Based on the results describing their adhesive properties and intracellular transport, the amino-pegylated nanoparticles were considered as a suitable carrier for DNA.


Risk factors for healthcare professionals' mental health during the COVID-19 pandemic: a systematic review.
The aim of the present study was to map the available evidence on the mental health risk factors of frontline health professionals during the COVID-19 pandemic. This is a systematic review that followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The search was independently carried out by four researchers, following the selection criteria in the electronic databases: PubMed Central, Ovid Technologies, GALE Academic Onefile, Science Citation Index Expanded. The data processing used Zotero software, responsible for creating and importing items according to the criteria established by the research. A total of 18,733 articles were found, of which 2,722 were excluded by the Zotero software because they were in duplicate, and another 366 were manually excluded. After applying the selection criteria, 43 articles entered the final analysis of this review. It is recommended that new scientific research be carried out, especially focusing on the analysis of health workers' mental health, aiming at providing the basis to create and implement public mental health programs and policies for workers.


Characteristics of uninsured Americans with chronic kidney disease.
In the United States, public health insurance is available for nearly all persons with end-stage renal disease (ESRD). Little is known about the extent of health insurance coverage for persons with non-dialysis dependent chronic kidney disease (CKD). To describe patterns of health insurance coverage for adults with non-dialysis dependent CKD and to examine risk factors for progression of CKD to ESRD and management of hypertension among those lacking insurance. Cross-sectional analysis of data from a nationally representative sample of 16,148 US adults aged 20 years or older who participated in the National Health and Nutrition Examination Survey 1999-2006. National prevalence estimates of health insurance coverage, ESRD risk factors, and treatment of hypertension. An estimated 10.0% (95% CI, 8.3%-12.0%) of US adults with non-dialysis dependent CKD were uninsured, 60.9% (95% CI, 58.2%-63.7%) had private insurance and 28.7% (95% CI, 26.4%-31.1%) had public insurance alone. Uninsured persons with non-dialysis dependent CKD were more likely to be under the age of 50 (62.8% vs. 23.0%, P < 0.001) and nonwhite (58.7%, vs. 21.8%, P < 0.001) compared with their insured counterparts. Approximately two-thirds of uninsured adults with non-dialysis dependent CKD had at least one modifiable risk factor for CKD progression, including 57% with hypertension, 40% who were obese, 22% with diabetes, and 13% with overt albuminuria. In adjusted analyses, uninsured persons with non-dialysis dependent CKD were less likely to be treated for their hypertension (OR, 0.59; 95% CI, 0.40-0.85) and less likely to be receiving recommended therapy with angiotensin inhibitors (OR, 0.45; 95% CI, 0.26-0.77) compared with those with insurance coverage. Uninsured persons with non-dialysis dependent CKD are at higher risk for progression to ESRD than their insured counterparts but are less likely to receive recommended interventions to slow disease progression. Lack of public health insurance for patients with non-dialysis dependent CKD may result in missed opportunities to slow disease progression and thereby reduce the public burden of ESRD.


The basolateral complex of the amygdala is necessary for acquisition but not expression of CS motivational value in appetitive Pavlovian second-order conditioning.
The basolateral complex of the amygdala (ABL) is involved in processing information about stimulus motivational value. However, it is not clear whether the ABL is critical for acquisition, maintenance, or expression of this information. Our previous work has shown that ABL lesions made prior to training, block acquisition of an appetitive Pavlovian second-order conditioning task, in which performance is thought to depend on the acquisition of motivational (conditioned reinforcement) value by the first-order conditioned stimulus (CS). The present experiments examined the effects of ABL lesions made after first-order conditioning, when the CS acquires motivational value, but before second-order conditioning, the test for acquired value of that CS. Rats received pairings of a visual CS with a food reinforcer. They then received bilateral sham or excitotoxic lesions of the ABL. After recovery, they received pairings of a second-order auditory CS with the previously conditioned visual CS. In two experiments, both sham and lesioned rats acquired normal second-order conditioned behaviours. Some of the same rats were then given another round of second-order conditioning with novel CSs. In this case, when first-order training occurred after surgery, some second-order conditioned behaviours were impaired in lesioned rats. Tests of the associative underpinnings of second-order conditioned behaviours showed that those behaviours impaired by ABL lesions were based on stimulus-response associations. The results show that although the ABL is critical for second-order conditioning, this role is limited to acquisition of information about the motivational value of the first-order CS, and it is not critical for maintenance of this information or for its use in forming second-order associations.


Monocyte functional capacity in chronic neutropenia.
The bactericidal activity of monocytes from a child with chronic benign granulocytopenia who has had virtual absence of neutrophils yet minimal infections since birth was examined against Escherichia coli and Staphylococcus aureus and compared with that of monocyte and neutrophils from 20 control subjects. Studies on monocyte function in this patient with no neutrophils revealed normal monocyte kill of both organisms when compared with control monocytes. Monocyte and neutrophil killing of both organisms was similar in control subjects at bacteria to phagocyte ratios of 1:1. When ratios of 3:1 were employed, however, control neutrophils were more effective than control and patient monocytes in reducing the number of viable organisms. These findings support the neutrophil as the more effective blood phagocyte but stress the importance of monocyte functional capacity in patients compromised by granulocytopenia or neutrophil functional defects.


Unexplained health inequality--is it unfair?
Accurate measurement of health inequities is indispensable to track progress or to identify needs for health equity policy interventions. A key empirical task is to measure the extent to which observed inequality in health - a difference in health - is inequitable. Empirically operationalizing definitions of health inequity has generated an important question not considered in the conceptual literature on health inequity. Empirical analysis can explain only a portion of observed health inequality. This paper demonstrates that the treatment of unexplained inequality is not only a methodological but ethical question and that the answer to the ethical question - whether unexplained health inequality is unfair - determines the appropriate standardization method for health inequity analysis and can lead to potentially divergent estimates of health inequity. We use the American sample of the 2002-03 Joint Canada/United States Survey of Health and measure health by the Health Utilities Index (HUI). We model variation in the observed HUI by demographic, socioeconomic, health behaviour, and health care variables using Ordinary Least Squares. We estimate unfair HUI by standardizing fairness, removing the fair component from the observed HUI. We consider health inequality due to factors amenable to policy intervention as unfair. We contrast estimates of inequity using two fairness-standardization methods: direct (considering unexplained inequality as ethically acceptable) and indirect (considering unexplained inequality as unfair). We use the Gini coefficient to quantify inequity. Our analysis shows that about 75% of the variation in the observed HUI is unexplained by the model. The direct standardization results in a smaller inequity estimate (about 60% of health inequality is inequitable) than the indirect standardization (almost all inequality is inequitable). The choice of the fairness-standardization method is ethical and influences the empirical health inequity results considerably. More debate and analysis is necessary regarding which treatment of the unexplained inequality has the stronger foundation in equity considerations.


Survival and predictors of death in people with HIV-associated lymphoma compared to those with a diagnosis of lymphoma in general population.
to compare overall survival in HIV-associated lymphoma (HIV-L) and lymphoma raising in HIV-negative population (nHIV-L) and to identify predictors of increased risk of death. All HIV+ patients with HIV-associated lymphoma (Hodgkin lymphoma, HL; non-Hodgkin Lymphoma, NHL) observed between 1.2000 and 12.2013 in the ICONA Foundation Study cohort or in three collaborating centres, and, as control group, nHIV-L individuals followed in one of the four collaborating centres over the same time period, were included. Survival estimates were calculated by use of Kaplan-Meier (KM) and multivariable Cox regression models. 1,331 pts were included (465 HIV-L, 866 nHIV-L): 909 (68%) NHL, 422 (32%) HL. 3 years-cumulative probability (95% confidence interval, CI) of death was higher in HIV-L compared to nHIV-L in NHL (38% (33-44) vs. 22% (19-26); p<0.001), and HL (22% [15-29] vs. 10% (6-13), p<0.001). Among HL, HIV was associated with an increased risk of death (hazard ratio [HR] = 2.37 [95% CI: 1.24-4.55], p = 0.009) independently of calendar year, age, gender, type of chemotherapy and stage; in NHL, HIV was no longer an independent predictor of death after controlling for rituximab use and IPI (HR = 1.26 (0.97-1.63), p = 0.08). Our analysis shows a reduced overall survival in HIV+ patients diagnosed with lymphoma compared to HIV-negative controls. Whereas in HIV people with HL, the increased risk of death was confirmed even after adjustment for main confounders, the association between HIV status and survival in NHL appears to be somewhat attenuated after controlling for more aggressive presentation and lower frequency of rituximab use in HIV-+ people.


Automated synthesis of arabinoxylan-oligosaccharides enables characterization of antibodies that recognize plant cell wall glycans.
Monoclonal antibodies that recognize plant cell wall glycans are used for high-resolution imaging, providing important information about the structure and function of cell wall polysaccharides. To characterize the binding epitopes of these powerful molecular probes a library of eleven plant arabinoxylan oligosaccharides was produced by automated solid-phase synthesis. Modular assembly of oligoarabinoxylans from few building blocks was enabled by adding (2-naphthyl)methyl (Nap) to the toolbox of orthogonal protecting groups for solid-phase synthesis. Conjugation-ready oligosaccharides were obtained and the binding specificities of xylan-directed antibodies were determined on microarrays.


Functional recovery and alterations in the expression and localization of protein kinase C following voluntary exercise in rat with cerebral infarction.
Recently, it has become widely known that rehabilitative training after stroke brings about some improvement of paralysis and disability; however, not much is known about the relationship between paralysis recovery and the participation of plasticity-related molecules. Hence, the localization and level of expression of several proteins in the cerebral cortex of rat groups with/without voluntary exercise using a running wheel after photo thrombotic infarction were examined in this study. In behavioral evaluation, the mean latency until falling from a rotating rod in the group with voluntary exercise at 6 days after infarction was significantly longer than that in the group without exercise. Immunohistochemical localization of c-Fos protein after behavioral test occurred in the area surrounding the infarction core in the exercise group. In protein expression analysis, protein kinase C (PKC), growth-associated protein 43 (GAP43) and phosphorylated at serine 41 GAP43 (p-GAP43) were significantly increased after voluntary exercise compared with those in rats without exercise. Expression of PKC immunoreactivity was observed in layer III of the perilesional cortex in rats with exercise, and the intracellular localization in the pyramidal neurons was mainly translocated to the plasma membrane. The expression and localization of these proteins may be related to the underlying mechanisms of exercise-induced paralysis recovery, that is, neuronal plasticity and remodeling of cortical connections through the phosphorylation of GAP43 by interaction with PKC. In the present study, the participation of at least some of the modulators associated with the improvement of motor deficit adjacent to the brain lesion might have been detected.


A highly sensitive ELISA D-dimer increases testing but not diagnosis of pulmonary embolism.
To determine the effect of introducing a rapid enzyme-linked immunosorbent assay (ELISA) D-dimer on the percentage of emergency department (ED) patients evaluated for pulmonary embolism (PE), the use of associated laboratory testing, pulmonary vascular imaging, and the diagnoses of PE. Patients evaluated for PE during three 120-day periods were enrolled: immediately before (period 1), immediately after (period 2), and one year after the introduction of a rapid ELISA D-dimer in the hospital. The frequency of ED patients evaluated for PE with any test, with D-dimer testing, and with pulmonary vascular imaging and the frequency of PE diagnosis during each time period were determined. The percentage of patients evaluated for PE nearly doubled; from 1.36% (328/24,101) in period 1 to 2.58% (654/25,318) in period 2 and 2.42% (583/24,093) in period 3. The percentage of patients who underwent D-dimer testing increased more than fourfold; from 0.39% (93/24,101) in period 1 to 1.83% (464/25,318) in period 2 and 1.77% (427/24,093) in period 3. The percentage of patients who underwent pulmonary vascular imaging increased from 1.02% (247/24,101) in period 1 to 1.36% (344/25,318) in period 2 and to 1.39% (334/24,093) in period 3. There was no difference in the percentage of patients diagnosed as having PE in period 1 (0.20% [47/24,101]), period 2 (0.27% [69/25,318]), and period 3 (0.24% [58/24,093]). In the study's academic ED, introduction of ELISA D-dimer testing was accompanied by an increase in PE evaluations, D-dimer testing, and pulmonary vascular imaging; there was no observed change in the rate of PE diagnosis.


Bilateral radial agenesis with absent thumbs, complex heart defect, short stature, and facial dysmorphism in a patient with pure distal microduplication of 5q35.2-5q35.3.
A partial duplication of the distal long arm of chromosome 5 (5q35-->qter) is known to be associated with a distinct phenotype referred to as Hunter-McAlpine syndrome. Clinical spectrum of this disorder mainly consists of mental retardation, microcephaly, short stature, skeletal anomalies, and craniofacial dysmorphism featuring flat facies, micrognathia, large, low-set dysplastic ears, hypertelorism, almond-shaped, down-slanted palpebral fissures, epicanthal folds, small nose, long philtrum, small mouth, and thin upper lip. Less frequent remarkable findings include craniosynostosis, heart defect, hypoplastic phalanges, preaxial polydactyly, hypospadias, cryptorchidism, and inguinal hernia. In most patients with a partial duplication of 5q the aberration occurred due to an inherited unbalanced translocation, therefore the phenotype was not reflective of pure trisomy 5q. We report on a 9.5-year-old boy with some feature of Hunter-McAlpine syndrome including short stature, complex heart defect (dextrocardia, dextroversion, PFO), bilateral cryptorchidism, hypothyroidism, and craniofacial dysmorphism. Additionally, bilateral radial agenesis with complete absence of Ist digital rays, ulnar hypoplasia with bowing, choroidal and retinal coloboma, abnormal biliary vesicle were identified, which have never been noted in 5q trisomy patients. Karyotype analysis, sequencing and MLPA for TBX5 and SALL4 genes were unremarkable. Array comparative genomic hybridization detected a duplication on 5q35.2-5q35.3, resulting from a de novo chromosomal rearrangement. Our proband carried the smallest of all previously reported pure distal 5q trisomies encompassing terminal 5.4-5.6 Mb and presented with the most severe limb malformation attributed to the increased number of distal 5q copies. We postulate that a terminal distal trisomy of 5q35.2-5q35.3, which maps 1.1 Mb telomeric to the MSX2 gene is causative for both radial agenesis and complex heart defect in our proband. A potential candidate gene causative for limb malformation in our proband could be FGFR4, which maps relatively in the closest position to the chromosomal breakage site (about 1.3 Mb) from all known 5q duplications. Since the limb malformation as well as the underlying genetic defect are distinct from other 5q trisomy patient we propose that a position effect resulting in altered long-range regulation of the FGFR4 (alternatively MSX2) may be responsible for the limb malformation in our proband.


The ethics and science of medicating children.
Prescriptions for psychiatric drugs to children and adolescents have skyrocketed in the past 10 years. This article presents evidence that the superior effectiveness of stimulants and antidepressants is largely a presumption based on an empirical house of cards, driven by an industry that has no conscience about the implications of its ever growing, and disturbingly younger, list of consumers. Recognizing that most mental health professionals do not have the time, and sometimes feel ill-equipped to explore the controversy regarding pharmacological treatment of children, this article discusses the four fatal flaws of drug studies to enable critical examination of research addressing the drugging of children. The four flaws are illustrated by the Emslie studies of Prozac and children, which offer not only a strident example of marketing masquerading as science, but also, given the recent FDA approval of Prozac for children, a brutal reminder of the danger inherent in not knowing how to distinguish science from science fiction. The authors argue that an ethical path requires the challenge of the automatic medical response to medicate children, with an accompanying demand for untainted science and balanced information to inform critical decisions by child caretakers.


[Pulmonary complications of large, type 4 hiatal hernias].
Three patients, 63, 76 and 56-years-old, presented with pulmonary symptoms caused by a large, type 4 hiatal hernia. A woman was examined for dyspnoea, and CT scan revealed an intrathoracically herniated stomach and colon. A man with progressive dyspnoea and a lung function disorder seen during spirometry was found to have herniation of the stomach, omentum and transverse colon. The third patient, a man, was hospitalised with bilateral pneumonia and found to have a herniated stomach, transverse colon, and pancreas. Repair by laparoscopy was successful in the second patient, but was not possible and required conversion to laparotomy in the other two patients. In addition, re-laparotomy for gastric ischaemia was necessary in the first patient, and for significant stenosis of the distal oesophagus in the third patient. After surgery, pulmonary symptoms and lung function improved in all three patients. Although surgical reduction of large hiatal hernias improves pulmonary symptoms, this can be at the cost of substantial morbidity.