Interaction of estrogen receptor‐α ligand binding domain with nuclear proteins of aging mouse brain

After the interaction of estrogen with the ligand binding domain (LBD) of mouse estrogen receptor‐α (mERα) and hormone‐responsive elements of target genes, many nuclear proteins are recruited to regulate the expression of specific genes. Because it is not known which brain proteins interact with LBD or whether these proteins vary with age and sex, we used pull‐down assay and far Western blotting to detect five nuclear proteins of 160, 140, 87, 60, and 46 kD in the mouse brain. These interacting proteins were identified as PELP1, RIP140, PGC1α, BAF60, and ADA3, respectively. The level of PELP1, RIP140, PGC1α, and BAF60 decreased drastically in old compared with adult male mice, whereas the ADA3 level showed no significant change. PELP1, PGC1α, and BAF60 levels were lower in old male compared with female mice. Thus we report the identification and interaction of five nuclear proteins with mERα‐LBD, indicating their role in estrogen signaling and brain functions during aging. © 2009 Wiley‐Liss, Inc.     

Neurotoxicity of Clostridium perfringens Epsilon-Toxin for the Rat Hippocampus via the Glutamatergic System

The neurotoxicity of epsilon-toxin, one of the major lethal toxins produced by Clostridium perfringens type B, was studied by histological examination of the rat brain. When the toxin was injected intravenously at a lethal dose (100 ng/kg), neuronal damage was observed in many areas of the brain. Injection of the toxin at a sublethal dose (50 ng/kg) caused neuronal damage predominantly in the hippocampus: pyramidal cells in the hippocampus showed marked shrinkage and karyopyknosis, or so-called dark cells. The dark cells lost the immunoreactivity to microtubule-associated protein-2, a postsynaptic somal and dendric marker, while acetylcholinesterase-positive fibers were not affected. Timm’s zinc staining revealed that zinc ions were depleted in the mossy layers of the CA3 subfield containing glutamate as a synaptic transmitter. The cerebral blood flow in the hippocampus was not altered significantly before or after administration of the toxin, as measured by laser-Doppler flowmetry, excluding the possibility that the observed histological change was due to a secondary effect of ischemia in the hippocampus. Prior injection of either a glutamate release inhibitor or a glutamate receptor antagonist protected the hippocampus from the neuronal damage caused by epsilon-toxin. These results suggest that epsilon-toxin acts on the glutamatergic system and evokes excessive release of glutamate, leading to neuronal damage.     

Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy

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Diagnosis of visceral leishmaniasis: comparative potential of amastigote antigen,recombinant antigen and PCR

Development of simple, economical and non-invasive tests for the early diagnosis of visceral leishmaniasis (VL) or kala-azar (KA) remains a challenge, and serological studies based on antigen prepared from the amastigote stage of Leishmania donovani, the stage that causes infection, are lacking. In the present study, circulating antibodies to total antigen isolated from the promastigote and amastigote stages of the parasite, as well as to recombinant K39 (rK39) antigen, are measured by enzyme-linked immunosorbent assay (ELISA) and the results compared with a polymerase chain reaction (PCR) test for KA diagnosis. In 116 samples of KA examined, the amastigote antigen gave significantly higher mean absorbance values in ELISA than did the promastigote antigen. The sensitivity for KA detection was significantly higher using the amastigote antigen (94%) than the promastigote antigen (90.5%). Analysis in 91 controls showed that specificity was higher with amastigote antigen (92.3%) than with promastigote antigen (86.8-89.0%). Reliability of ELISA diagnosis with amastigote antigen was only marginally lower than that with rK39 ELISA or with the PCR test. Easy availability and low cost of indigenous amastigote antigen, together with the simplicity of ELISA compared with PCR, make ELISA based on amastigote antigen a promising choice for the diagnosis of KA.     

Hepatitis B virus genotypes and serotypes in western India: lack of clinical significance

To determine hepatitis B virus genotype and subtype distribution among HBV infected individuals with different clinical manifestations in western India, serum samples from 19 asymptomatic hepatitis B surface antigen carriers, 30 chronic hepatitis B patients, 8 acute hepatitis B patients, 5 fulminant hepatitis B patients, and with circulating HBV DNA were genotyped and subtyped on the basis of the nucleotide sequence analysis of S region of the HBV genome. Genotype D was the predominant genotype circulating in western India (57/62; 91.93%). All 19 asymptomatic hepatitis B surface antigen carriers, 8 acute hepatitis B patients, 5 fulminant hepatic failure patients and 25/30 chronic hepatitis B patients were circulating genotype D and ayw3/ayw2 subtypes. HBV genotype A was prevalent in 8% (5/62) of the total number of patients and all belonged to chronic hepatitis B category. Subtyping analysis showed that all genotype A isolates were of subtype adw2. As most of the patients from different clinical categories were infected with HBV genotype D, it is concluded that this genotype did not influence the outcome of HBV infection.     

Selected conditions associated with an increased incidence of incisional hernia: A review of molecular biology

BackgroundIncisional hernias (IH) following a laparotomy, on average, occur in 10–20% of patients, however, little is known about its molecular basis. Thus, a better understanding of the molecular mechanisms could lead to the identification of key target(s) to intervene pre-and post-operatively.MethodsWe examined the current literature describing the molecular mechanisms of IH and overlap these factors with smoking, abdominal aortic aneurysm, obesity, diabetes mellitus, and diverticulitis.ResultsThe expression levels of collagen I and III, matrix metalloproteinases, and tissue inhibitors of metalloproteases are abnormal in the extracellular matrix (ECM) of IH patients and ECM disorganization has an overlap with these comorbid conditions.ConclusionUnderstanding the pathophysiology of IH development and associated risk factors will allow physicians to identify patients that may be at increased risk for IH and to possibly act preemptively to decrease the incidence of IH.     

The burden of cutaneous disease in solid organ transplant recipients of color

Organ transplant recipients (OTRs) are at increased risk of cutaneous malignancy. Skin disorders in OTRs of color (OTRoC) have rarely been systematically assessed. We aimed to ascertain the burden of skin disease encountered in OTRoC by prospectively collecting data from OTRs attending 2 posttransplant skin surveillance clinics: 1 in London, UK and 1 in Philadelphia, USA. Retrospective review of all dermatological diagnoses was performed. Data from 1766 OTRs were analyzed: 1024 (58%) white, 376 (21%) black, 261 (15%) Asian, 57 (3%) Middle Eastern/Mediterranean (ME/M), and 48 (2.7%) Hispanic; and 1128 (64%) male. Viral infections affected 45.1% of OTRs, and were more common in white and ME/M patients (P < .001). Fungal infections affected 28.1% and were more common in ME/M patients (P < .001). Inflammatory skin disease affected 24.5%, and was most common in black patients (P < .001). In addition, 26.4% of patients developed skin cancer. There was an increased risk of skin cancer in white vs nonwhite OTRs (HR 4.4, 95% CI 3.5-5.7, P < .001): keratinocyte cancers were more common in white OTRs (P < .001) and Kaposi sarcoma was more common in black OTRs (P < .001). These data support the need for programs that promote targeted dermatology surveillance for all OTRs, regardless of race/ethnicity or country of origin.     

Pregnant women & vaccines against emerging epidemic threats: Ethics guidance for preparedness,research, and response

Zika virus, influenza, and Ebola have called attention to the ways in which infectious disease outbreaks can severely – and at times uniquely – affect the health interests of pregnant women and their offspring. These examples also highlight the critical need to proactively consider pregnant women and their offspring in vaccine research and response efforts to combat emerging and re-emerging infectious diseases. Historically, pregnant women and their offspring have been largely excluded from research agendas and investment strategies for vaccines against epidemic threats, which in turn can lead to exclusion from future vaccine campaigns amidst outbreaks. This state of affairs is profoundly unjust to pregnant women and their offspring, and deeply problematic from the standpoint of public health. To ensure that the needs of pregnant women and their offspring are fairly addressed, new approaches to public health preparedness, vaccine research and development, and vaccine delivery are required. This Guidance offers 22 concrete recommendations that provide a roadmap for the ethically responsible, socially just, and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens. The Guidance was developed by the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group – a multidisciplinary, international team of 17 experts specializing in bioethics, maternal immunization, maternal-fetal medicine, obstetrics, pediatrics, philosophy, public health, and vaccine research and policy – in consultation with a variety of external experts and stakeholders.     

RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer.

PURPOSE: RRM1 has important functions in the determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non-small-cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. PATIENTS AND METHODS: A retrospective data set of 49 patients and a prospective data set of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. RESULTS: RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue. RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. CONCLUSION: RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.     

Depression of long term potentiation in gerbil hippocampus following postischemic hypothermia

To investigate the mechanism of chronic cell death following postischemic hypothermia, the change of N-methyl- -aspartate receptor (NMDAR) were examined by immunohistochemistry of NMDAR1 and long-term potentiation (LTP) in the CA1 subfield of the gerbil hippocampus. At 1 week following postischemic hypothermia (32°C×4 h), all CA1 neurons survived; however, immunoreactivity of NMDAR1 increased in neuronal perikarya whereas decreased in dendrites in the CA1 neurons. The abnormality was still observed in remaining CA1 neurons at 1 month after hypothermia. LTP was also significantly depressed at 1 week after hypothermia. These results suggest that some abnormalities in the glutamate receptor may be caused by ischemia; such abnormality would persist in spite of hypothermia treatment, resulting in the depression of LTP.