Defective potassium currents in ataxia telangiectasia fibroblasts

Similarities exist between the progressive cerebellar ataxia in ataxia telangiectasia (AT) patients and a number of neurodegenerative diseases in both mouse and man involving specific mutations in ion channels and/or ion channel activity. These relationships led us to investigate the possibility of defective ion channel activity in AT cells. We examined changes in the membrane potential of AT fibroblasts in response to extracellular cation addition and found that the ability of AT fibroblasts to depolarize in response to increasing concentrations of extracellular K⁺ is significantly reduced when compared with control fibroblasts. Electrophysiological measurements performed with a number of AT cell lines, as well as two matched sets of primary AT fibroblast cultures, reveal that outward rectifier K⁺ currents are largely absent in AT fibroblasts in comparison with control cells. These K⁺ current defects can be corrected in AT fibroblasts transfected with the full-length ATM cDNA. These data implicate, for the first time, a role for ATM in the regulation of K⁺ channel activity and membrane potential.     

Effects of aging on the novelty P3 during attend and ignore oddball tasks

The effects of attention were assessed on novelty P3 amplitude and scalp distribution elicited by environmental sounds in young and elderly volunteers who participated in either actively attended or ignored oddball conditions. For the young, novelty P3 amplitude decreased with time on task during both attend and ignore sequences. Amplitude decrements were greatest at frontal sites during the attend condition, but at all sites during the ignore condition. A reliable amplitude decrement was not observed for the elderly in either the attend or ignore oddball series. The data suggest that attention differentially activates multiple generators that contribute to scalp-recorded novelty P3 activity. The lack of novelty P3 habituation seen in the elderly is consistent with changes in frontal lobe function as age increases.     

HBV-RNA,Quantitative HBsAg,Levels of HBV in Peripheral Lymphocytes and HBV Mutation Profiles in Chronic Hepatitis B

A comprehensive characterization of chronic HBV (CHB) patients is required to guide therapeutic decisions. The cumulative impact of classical and novel biomarkers on the clinical categorization of these patients has not been rigorously assessed. We determined plasma HBV-RNA and HBsAg levels, HBV in peripheral lymphocytes (PBMCs) and HBV mutation profiles in CHB patients. Patient demographics (n = 139) and classical HBV biomarkers were determined during a clinical routine. HBV-RNA in plasma and HBV-DNA in PBMCs were determined by RT-PCR. HBsAg levels were determined using Architect. In samples with HBV-DNA viral load >1000 IU/mL, genotype mutations in precore (PC), basal core promoter (BCP), HBsAg and Pol regions were determined by sequencing. Most patients (n = 126) were HBeAg-negative (HBeAgNeg) with significantly lower levels of HBV-RNA, HBV-DNA and HBsAg compared to HBeAg-positive (HBeAgPos) patients (p < 0.05). HBV genotype D prevailed (61/68), and >95% had BCP/PC mutations. Escape mutations were identified in 22.6% (13/63). HBeAgNeg patients with low levels of HBsAg (log IU ≤ 3) were older and were characterized by undetectable plasma HBV-DNA and undetectable HBV-RNA but not undetectable HBV-DNA in PBMCs compared to those with high HBsAg levels. In >50% of the studied HBeAgNeg patients (66/126), the quantitation of HBsAg and HBV-RNA may impact clinical decisions. In conclusion, the combined assessment of classical and novel serum biomarkers, especially in HBeAgNeg patients, which is the largest group of CHB patients in many regions, may assist in clinical decisions. Prospective studies are required to determine the real-time additive clinical advantage of these biomarkers.     

Spectral monitoring of two-spotted spider mite damage to pepper leaves

Two-spotted spider mites (TSSM; Tetranychus urticae Koch) cause significant damage to crops and yields, in the field as well as in greenhouses. By feeding, TSSM destroy chloroplast-containing cells; this damage can be spectrally detected in the reflectance of the visible and near-infrared regions. This study focuses on hyperspectral reflectance data of greenhouse pepper (Capsicum annuum) leaves, obtained by integrated sphere. The reflectance data were transformed into vegetation indices allowing early TSSM damage detection by separation between leaf damage levels. One-way analysis of variance of coupled damage levels was applied to each of the vegetation indices. We concluded that early identification of TSSM greenhouse pepper leaf damage can be obtained by multispectral means. Furthermore, the proposed methods may identify the damage on the upper side of the leaves although the TSSM feed on the underside of leaves.     

Essential thrombocythemia and leukemic transformation

Alkylating agents and 32P have been widely employed in the treatment of patients with essential thrombocythemia (ET). During a four-month period, we observed 3 cases of ET that had transformed into leukemia. Two patients had been treated with uracil mustard: One developed acute myelogenous leukemia 79 months after institution of therapy, and the other patient developed chronic myelomonocytic leukemia 24 months after the start of therapy. The third patient had been treated with busulfan, and ET evolved into myelofibrosis and eventually into acute undifferentiated leukemia with myelofibrosis. The patient who developed acute myelogenous leukemia was asymptomatic at the time of diagnosis of ET but was treated because his platelet count was greater than 1,000,000/mm3. He died 1 month after leukemic transformation, during induction chemotherapy. The other 2 patients presented with symptoms referable to their thrombocythemia. Review of the English literature revealed 12 other definite or probable cases of ET with leukemic transformation, all but 1 having been treated with alkylating agents and/or 32P. We propose that the natural history of ET may be similar to that of polycythemia vera, with evolution into leukemia being an unusual occurrence except in the setting of previous chemotherapy. Therefore, the current practice of treating asymptomatic patients with ET may not be justified, since administration of alkylating agents or 32P may increase the risk of subsequent development of leukemia.     

Relationship Between Body Composition and Death in Patients with COVID-19 Differs Based on the Presence of Gastrointestinal Symptoms

Digestive Diseases and Sciences - Patients with SARS-CoV-2 who present with gastrointestinal symptoms have a milder clinical course than those who do not. Risk factors for severe COVID-19 disease...     

Tat-dependent adenosine-to-inosine modification of wild-type transactivation response RNA.

Tat is a potent activator of gene expression in human immunodeficiency virus type 1 (HIV-1). Activation by Tat requires a cis-acting element, the transactivation response (TAR) site, located in the viral long terminal repeat and the 5' end of all viral mRNAs. Sequences in TAR RNA can fold into a specific stem-loop structure, and certain features of the stem-loop are essential for Tat-mediated transactivation. In Xenopus oocytes, TAR sequences can inhibit the translation of 3' cis-linked mRNAs. However, coinjection of Tat and the TAR-containing RNA into oocyte nuclei relieves this translational inhibition [Braddock, M., Chambers, A., Wilson, W., Esnout, M. A., Adams, S.E. & Kingsman, S.M. (1989) Cell 58, 269-279]. We report here that the intramolecular TAR stem-loop structure is a substrate for the double-stranded RNA (dsRNA)-modifying activity, which converts adenosines to inosines. This activity is located in the nuclei of Xenopus oocytes. The specificity and extent of modification of adenosines in TAR is dependent on Tat. We propose that the dsRNA-modifying activity may be one of the cellular proteins that interacts with TAR in the nucleus. The possible role of TAR RNA modification in the expression of HIV-1 is discussed.     

Effect of Matrix Metalloproteinase Inhibition by Doxycycline on Myocardial Healing and Remodeling after Myocardial Infarction

Summary The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm² ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm², respectively; p < 0.05). Our work suggest that effective MMPs’ inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.