Lack of Major Effects on Mouse Brain Adenosine A1 Receptors of Oral Carbamazepine and Calcium Antagonists

Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs.     

Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.

Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.     

Mortality risk factors for listeriosis – A 10 year review of non-pregnancy associated cases in England 2006–2015

Listeriosis

is a foodborne illness that can result in septicaemia, Central Nervous System (CNS) disease, foetal loss and death in high risk patients.

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has been identified in testicular cDNA libraries by two laboratories. The present study examined the expression of wild-type (ERbeta1) and variant (ERbeta2) beta receptors in human testes by 1) RT-PCR with isoform specific primers, and 2) single and double immunohistochemistry using monoclonal antibodies raised against peptides unique to the C termini of hERbeta1 and hERbeta2. PCR products specific for ERbeta1 and ERbeta2 were amplified from cDNA pools prepared from human testes and granulosa cells. On Western blots, the anti-ERbeta1 monoclonal antibody bound to recombinant ERbeta1 and the anti-ERbeta2 monoclonal to recombinant hERbeta2. Neither bound to the other ERbeta isoform nor to recombinant ERalpha. ERbeta1 and ERbeta2 proteins were both detected in human testis. Immunoexpression of ERbeta1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ERbeta2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ERbeta2 than ERbeta1. It is speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ERbeta1 are high. In contrast, expression of ERbeta2, an isoform that may act as a dominant negative inhibitor of ER action, in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.     

Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor

Bacillus anthracis secretes two bipartite toxins thought to be involved in anthrax pathogenesis and resulting death of the host. The current model for intoxication is that protective antigen (PA) toxin subunits bind a single group of cell-surface anthrax toxin receptors (ATRs), encoded by the tumor endothelial marker 8 (TEM8) gene. The ATR/TEM8-PA interaction is mediated by the receptor's extracellular domain related to von Willebrand factor type A or integrin inserted domains (VWA/I domains). A metal ion-dependent adhesion site (MIDAS) located within this domain of the ATR/TEM8 protein chelates a divalent cation critical for PA binding. In this report, we identify a second PA receptor encoded by capillary morphogenesis gene 2 (CMG2), which has 60% amino acid identity to ATR/TEM8 within the VWA/I domain, as well as a conserved MIDAS motif. A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. Binding between the CMG2 VWA/I domain and PA was shown to be direct and metal-dependent, although the cation specificity of this interaction is different than that observed with ATR/TEM8. Northern blot analysis revealed that CMG2 is widely expressed in human tissues, indicating that this receptor is likely to be relevant for disease pathogenesis. Finally, a soluble version of the CMG2 VWA/I domain inhibited intoxication of cells expressing endogenous toxin receptors when it was added to PA at a 3:1 ratio. These studies distinguish CMG2 as a second anthrax toxin receptor and identify a potent antitoxin that may prove useful for the treatment of anthrax.     

Unusual serological response to hepatitis E virus in plasma donors consistent with re‐infection

Hepatitis E virus (HEV)‐positive plasma donations, identified by a plasma mini‐pool screening approach, were analysed using serological methods for the presence of anti‐HEV IgM and IgG. Avidity testing was performed on the IgG‐reactive donations. Anti‐HEV IgG with high avidity was observed in two donors together with high viral loads, but with the absence of anti‐HEV IgM. These data are suggestive of re‐infection in a small proportion of plasma donors, which has not previously been reported.     

Multicenter prospective study of nonruptured abdominal aortic aneurysms. I. Population and operative management

This article describes the patient population and operative management of 666 patients with nonruptured aneurysms of the abdominal aorta. Statistical significance of variables was determined by the chi-square test and logistic regression analysis. There were no statistically significant differences (p greater than 0.05) in mortality rate for abdominal aortic aneurysm (AAA) on the basis of indication for surgery (asymptomatic, 3.9%; asymptomatic but with evidence of enlargement, 4.9%; and symptomatic, 7.2%) or the urgency of operation (elective operation, 4.5%; and urgent operation, 7.1%). Characteristics of the 72 participating surgeons did not influence the operative mortality rate. A family history of AAA was documented in 6.1% of cases and was more common if the patient was female (p = 0.03) and less than 65 years of age (p = 0.04). Patients without clinical evidence of coronary artery disease had a 0.8% mortality rate from cardiac disease compared with 6.2% if any stigmata of coronary disease were present. Prior aortocoronary bypass surgery did not reduce the incidence of postoperative cardiac events or operative mortality rate. Patients having "routine" angiography did not have a less complicated operative course, fewer thrombotic complications, or lower mortality rate than those not having it. Those patients with an inflammatory AAA (4.5%) did not have a significantly higher incidence of pain. Heparin administration (84.8%) did not reduce the complications of graft thrombosis, "trash," distal thrombosis, and/or amputation. The 6.8% of patients requiring suprarenal aortic cross-clamping had a higher incidence of postoperative renal dysfunction (p = 0.02) and intraoperative blood loss (p less than 0.001), but cardiac events were not more frequent. When the aortic cross-clamping time was prolonged (more than 70 minutes), the requirement for crystalloid fluid administration increased (p less than 0.001) and postoperative myocardial infarction was more common (p = 0.004). After ligation of the left renal vein in 7.9%, renal damage or dialysis was more frequent (p = 0.01). Patients having an intra-abdominal graft (tube, 38.5% and biiliac, 30.7%) had fewer wound infections (p = 0.02) and graft thromboses (p less than 0.001) than the patients with a femoral anastomosis. When the internal iliac artery flow was interrupted bilaterally (12%), diarrhea (p = 0.03) and ischemic colitis (p = 0.03) were more frequent complications. Reimplantation of the inferior mesenteric artery was carried out in 4.8%. After renal artery bypass in 2.1%, the mortality rate was not increased, but the incidence of transient renal dysfunction was increased (p = 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)