Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the ␥-aminobutyric acid (GABA) binding site of GABA A receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors. Patch-clamp studies using human embryonic kidney cells transiently transfected with recombinant GABA A receptors composed of ␣12␥2 subunits showed that TAMCA did not activate these receptors but dose dependently blocked GABA-induced chloride ion flux with an IC 50 of 7.1 Ϯ 3.1 mM. Application of TAMCA to the lumbar spinal cord of rats resulted in dose-dependent hyperexcitability, which was completely blocked by coapplication of the GABA A receptor agonist muscimol. These results indicate that TAMCA may induce hyperexcitability by blocking GABA-driven inhibition of the CNS.
Hepatitis C virus (HCV) NS3 polymorphism Q80K is mainly found in patients with HCV genotype (G) 1a, and has been associated with a reduced treatment response to simeprevir with pegylated interferon (P) and ribavirin (R). Prevalence of Q80K among G1 patients may vary geographically. Q80K prevalence in the North-American G1 population in a recent study was 34%. We conducted a post hoc meta-analysis of Q80K polymorphism prevalence among HCV G1-infected patients enrolled in simeprevir and telaprevir Phase II/III studies. Baseline HCV NS3/4A protease sequences were analysed by population sequencing to determine Q80K prevalence. Overall, of 3349 patients from 25 countries in the European region analysed, 35.8%, 63.8% and 0.3% of patients had G1a, G1b and other/unknown HCV G1 subtypes, respectively. Q80K was detected at baseline in 7.5% of HCV G1 patients overall. Examination by subtype showed that 19.8%, 0.5% and 18.2% of patients with G1a, G1b and other/unknown HCV G1 subtypes had the Q80K polymorphism, respectively. Among countries in the European region with sequencing data available for either ⩾20 patients with G1a and/or ⩾40 G1 patients overall, the Q80K prevalence in G1 ranged from 0% in Bulgaria to 18.2% in the UK. Q80K prevalence also varied within G1a across different countries. HCV subtype 1a was correctly determined in 99% of patients by the LiPA v2 assay. A low overall prevalence of Q80K was observed in HCV G1-infected patients in the European region, compared with North America. However, the prevalence varied by country, due to differing ratios of G1a/G1b and differing Q80K prevalence within the G1a populations.
We tested the hypothesis that ischemic preconditioning (PC) of skeletal muscle provided tolerance to a subsequent ischemic event 24 h later, and that such protection was due to nitric oxide (NO). Male Wistar rats, anesthetized with halothane, were randomly assigned to groups: ischemic (no PC; n = 11), PC ( n = 11), PC + N-nitro-l-arginine methyl ester (l-NAME; 100 μmol/l; n = 5), PC + N-nitro-d-arginine methyl ester (100 μmol/l; n= 4), PC + aminoguanidine (AMG; 100 μmol/l; n = 4), ischemic +l-NAME ( n= 4), or ischemic + AMG ( n = 4). PC consisted of 5× 10 min of ischemia and reperfusion, and, 24 h later, 2 h of ischemia were induced by a tourniquet applied to the limb. With the use of intravital microscopy, the number of perfused capillaries ( N pc) in the extensor digitorum longus (EDL) muscle was measured over a 90-min reperfusion period. The ratio of ethidium bromide- to bisbenzimide-labeled nuclei was used to estimate tissue injury. PC preserved N pc(23.6 ± 2.5) following 2 h of ischemia compared with sham muscles (11.5 ± 5.1), significantly elevating inducible NO synthase (iNOS) activity (81% increase), but did not afford protection to the parenchyma.l-NAME and AMG prevented ischemia-reperfusion-induced reduction in N pc in muscles without PC. However, after 90 min of reperfusion,l-NAME ( N pc = 15.0 ± 1.7), but not AMG ( N pc = 22.8 ± 3.1), significantly reduced the microvascular protection afforded by PC. We conclude that PC of the EDL muscle resulted, 24 h later, in protection to microvascular perfusion only, and that such protection was due to NO from sources other than iNOS.
Tranexamic acid may cause severe complications when used in the central nervous system. Thus, fibrin sealants containing t-AMCA should not be used in neurosurgery.
Study design: Experimental laboratory investigation of the eect of anesthesia on evoked potentials in rats. Objectives: To de®ne the optimal ketamine/xylazine anesthesia levels for the recording of dierent evoked potentials. Setting: BioSurgery Preclinical Department, Baxter BioScience, Vienna, Austria. Methods: Rats were implanted with cranial screws that allow stimulation and recording of evoked potentials. Somatosensory evoked potentials (SEPs), brainstem-derived motor evoked potentials (BMEPs) and corticomotor evoked potential (CMEPs) were recorded under dierent levels of anesthesia. The recorded signals were evaluated by measuring their latencies and amplitudes. The level of anesthesia was assessed by scoring the hind limb withdrawal re¯ex. Results: All three signals showed a strong dependency on the level of anesthesia. The observed eects, however, diered between the three signals. SEP amplitudes and latencies declined as animals slowly transgressed from deep to light anesthesia. In contrast, BMEP amplitudes were larger and latencies shorter in light anesthesia than in deep anesthesia. CMEPs ®nally were hard to record under deep anesthesia, but were easily recorded in light anesthesia. BMEPs that were recorded during light anesthesia also showed a signi®cant change in con®guration that was coupled with a notable increase in the variability of its amplitudes. Conclusions: The level of ketamine/xylazine anesthesia aects evoked potentials and thus should be controlled during electrophysiological recording. Our results suggest that SEPs should be best recorded during deep anesthesia, while BMEPs and CMEPs are best recorded during intermediate and light anesthesia.
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