OBJECTIVES: The objectives of the current study were to define for the first time the roles of the natriuretic peptide (NP) receptors and neutral endopeptidase (NEP) in mediating and modulating the renal actions of Dendroaspis natriuretic peptide (DNP), a new therapeutic synthetic NP. BACKGROUND: Recent reports have advanced the therapeutic potential of a newly described synthetic NP called DNP. Dendroaspis natriuretic peptide is a 38-amino acid peptide recently isolated from the venom of Dendroaspis augusticeps (the green mamba snake). METHODS: Synthetic DNP was administered intra-renally at 5 ng/kg/min to 11 normal anesthetized dogs, 5 of which received the NP receptor antagonist HS-142-1 (3 mg/kg intravenous bolus) while the remaining 6 dogs received an infusion of the NEP inhibitor, candoxatrilat (8 and 80 microg/kg/min) (Pfizer, Sandwich United Kingdom). RESULTS: Intra-renal DNP resulted in marked natriuresis associated with increased urinary cyclic guanosine monophosphate excretion (UcGMPV), glomerular filtration rate (GFR), and renal blood flow (RBF) and decreased distal fractional sodium reabsorption (FNaR) compared with baseline. HS-142-1 attenuated the natriuretic response to DNP, resulting in decreased UcGMPV, GFR, and RBF and increased distal FNaR. In contrast, low and high doses of NEP inhibitor did not potentiate the renal actions of DNP. CONCLUSIONS: We report that the NP receptor blockade attenuated the renal actions of synthetic DNP and that the NEP inhibitor did not alter the renal response to DNP. This latter finding is a unique property of synthetic DNP, as distinguished from other known NPs, supporting its potential as a therapeutic agent. 相似文献
Most Mycobacterium tuberculosis rifampin-resistant strains have been associated with mutations in an 81-bp rifampin resistance-determining region (RRDR) in the gene rpoB. However, if this region alone were targeted, rifampin-resistant strains with mutations outside the RRDR would not be detected. In this study, among 51 rifampin-resistant clinical isolates analyzed by sequencing 1,681-bp-long DNA fragments containing the RRDR, 47 isolates contained mutations within the RRDR, three isolates contained mutations both within and outside the RRDR, and only one isolate had a single missense mutation (Arg548His) located outside the RRDR. A drug susceptibility test of recombinant Mycobacterium smegmatis and M. tuberculosis isolates carrying mutated rpoB (Arg548His) showed an increased MIC for rifampin compared to that of the control strains. Modeling of the Arg548His mutant RpoB-DNA complex revealed that the His548 side chain formed a more stable hydrogen bond structure than did Arg548, reducing the flexibility of the rifampin-resistant cluster II region of RpoB, suggesting that the RpoB Arg548His mutant does not effectively interact with rifampin and results in bacterial resistance to the drug. This is the first report on the relationship between the mutation in codon 548 of RpoB and rifampin resistance in tuberculosis. The novel mutational profile of the rpoB gene described here will contribute to the comprehensive understanding of rifampin resistance patterns and to the development of a useful tool for simple and rapid drug susceptibility tests. 相似文献
Data are limited regarding the real‐world effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) in patients with chronic hepatitis C virus (HCV) infection and severe renal impairment (RI). We aimed to evaluate the performance of GLE/PIB in patients with chronic kidney disease (CKD) stage 4 or 5 in Taiwan. 108 chronic HCV patients with CKD stage 4 (n = 32) or 5 (n = 76) receiving GLE/PIB for 8‐12 weeks were retrospectively recruited at 4 academic centres in Taiwan. The effectiveness was determined by sustained virologic response at off‐therapy week 12 (SVR12) for evaluable (EP) and per‐protocol populations (PP). The safety profiles were also assessed. By EP and PP analyses, the SVR12 rate was 99.1% (107 of 108 patients; 95% confidence interval (CI): 94.9%‐99.8%) and 100% (107 of 107 patients; 95% CI: 96.5%‐100%). The SVR12 rates were 100% (95% CI: 89.3%‐100%) and 98.7% (95% CI: 92.9%‐99.8%) in patients with CKD stage 4 and 5, respectively. One patient, who declined off‐therapy follow‐up after permanently discontinuing GLE/PIB at on‐treatment week 9 due to scheduled cardiac surgery, had nonvirologic failure. Sixteen (14.8%) patients had serious adverse events (AEs), which were judged not related to GLE/PIB. The three most common AEs were pruritus (19.4%), fatigue (15.7%) and nausea (13.9%). None had ≥3‐fold upper limit of normal for total bilirubin and alanine aminotransferase levels. None of the 9 patients with hepatitis B virus (HBV) coinfection developed HBV‐associated hepatitis. In conclusion, GLE/PIB for 8‐12 weeks is effective and well‐tolerated in HCV patients with severe RI. 相似文献
The current study examined correlates, moderators, and mediators of functional impairment in 98 treatment-seeking adults with obsessive–compulsive disorder (OCD). Participants completed or were administered measures assessing obsessive–compulsive symptom severity, functional impairment, resistance against symptoms, interference due to obsessive–compulsive symptoms, depressive symptoms, insight, and anxiety sensitivity. Results indicated that all factors, except insight into symptoms, were significantly correlated with functional impairment. The relationship between obsessive–compulsive symptom severity and functional impairment was not moderated by patient insight, resistance against obsessive–compulsive symptoms, or anxiety sensitivity. Mediational analyses indicated that obsessive–compulsive symptom severity mediated the relationship between anxiety sensitivity and obsessive–compulsive related impairment. Indeed, anxiety sensitivity may play an important contributory role in exacerbating impairment through increases in obsessive–compulsive symptom severity. Depressive symptoms mediated the relationship between obsessive–compulsive symptom severity and obsessive–compulsive related impairment. Implications for assessment and treatment are discussed. 相似文献
Plasmapheresis not only removes circulating antibodies but also modulates cellular immunity, including lymphocyte subsets. To investigate the effect of double‐filtration plasmapheresis (DFPP) on the ratio of lymphocyte subsets in patients with myasthenia gravis (MG), we examined the percentages of B‐cells, T‐cells, T helper (Th) cells, T suppressor (Ts) cells, natural killer (NK) cells, NKT cells, and Th/Ts ratio before and after a single DFPP session and after a course of DFPP. A total of 26 patients were recruited; their peripheral blood lymphocyte subsets were assayed using flow cytometry. After a single session of DFPP treatment, the percentages of T‐cells (P = 0.0200), Th cells (P = 0.0178), and the Th/Ts ratio (P = 0.0309) decreased significantly, whereas the percentage of NK cells (P = 0.0007) increased significantly. More importantly, after one course of DFPP treatment, the reduced clinical quantitative MG (QMG) score was correlated with the decrease of the percentage of T‐cells (r = 0.5005, P = 0.0092). Fourteen thymectomized MG patients had decreased percentages of T‐cells (P = 0.0304) and Th cells (P = 0.0444), whereas they had increased NK cells (P = 0.0197) after a single DFPP session. Here, transiently decreased percentages of T‐cells after the full DFPP course could enhance the effectiveness of plasmapheresis for MG patients. 相似文献
Introduction: Common yew (Taxus baccata) is a common decorative evergreen shrub with potentially fatal toxicity hallmarked by seizure, arrhythmia and cardiovascular collapse if ingested. Taxine B has been identified as one of the most cardiotoxic taxine alkaloids in Taxus spp, and another alkaloid, 3,5-dimethoxyphenol (3,5-DMP), is used as a marker of ingestion. We present a fatal case of ingestion of yew with perimortem serum and gastric taxine B, and 3,5-DMP concentrations.
Case presentation: A 22-year-old woman was brought to the emergency department (ED) from a nearby botanical garden after she was found apneic and pulseless after a witnessed generalized tonic clonic seizure. The patient was found to have a wide complex rhythm with persistent cardiovascular collapse and expired despite maximal supportive care in the ED. A baggie of plant material was found on the patient, identified as Taxus baccata. Perimortem serum and gastric samples were analyzed to quantify serum and gastric taxine B and 3,5-DMP concentrations.
Results: Perimortem serum showed a 3,5-DMP concentration of 86.9 ng/mL, and taxine B of 80.9 ug/mL.
Conclusion: We report a perimortem serum and gastric taxine B and 3,5-DMP concentrations in a fatal case of T. baccata toxicity. 相似文献