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11.
12.
Host answers to pathogen attacks define the course of pathogenic events and decide about the fate of the host organism. Infection with coxsackievirus B3 (CVB3) can induce severe myocarditis and pancreatitis. The interplay between host factors and virus components is crucial for the fate of the infected host. As we have shown before, expression of the pro-apoptotic host protein Siva is significantly increased after CVB3 infection, and infected cells are removed by programmed cell death. Analysis of Siva expressed in Escherichia coli revealed that this protein binds three zinc ions, suggesting a rather complex three-dimensional structure. By screening a human heart cDNA library we found a new interaction partner of Siva. The peroxisomal membrane protein PMP22 may be involved in the host response against CVB3. Previous investigations showed that Siva interacts with the cytoplasmic C-terminus of CD27, a member of the tumor necrosis factor receptor group, and transmits an apoptotic signal. With the help of directed two-hybrid assays we determined the N-terminal part of Siva as the binding region for CD27.  相似文献   
13.
To examine the time course and relative extent of proteolysis of neurofilament and tubulin proteins after traumatic axonal injury (TAI), anesthetized mice were subjected to optic nerve stretch injury. Immunohistochemistry confirmed neurofilament accumulation within axonal swellings at 4, 24, and 72 h postinjury (n = 4 injured and 2 sham per time point). Immunoblotting of optic nerve homogenates (n = 5 injured and 1 sham at 0.5, 4, 24 or 72 h) revealed calpain-mediated spectrin proteolytic fragments after injury. Protein levels for NF68 progressively decreased from 0.5 h to 24 h postinjury, while NF200 and α-tubulin levels decreased acutely (0.5–4 h), with a secondary decline at 72 h postinjury. These data demonstrate that diffusely distributed TAI is associated not only with a localized accumulation of neurofilament proteins, but also significant decreases in total cytoskeletal protein levels which may be mediated, in part, by calpains. Protection of the axonal cytoskeleton represents a potential therapeutic target for axonal damage associated with injury or neurodegenerative diseases. Special issue in honor of Naren Banik.  相似文献   
14.
The activation of poly(ADP-ribose) polymerase, a DNA base excision repair enzyme, is indicative of DNA damage. This enzyme also undergoes site-specific proteolysis during apoptosis. Because both DNA fragmentation and apoptosis are known to occur following experimental brain injury, we investigated the effect of lateral fluid percussion brain injury on poly(ADP-ribose) polymerase activity and cleavage. Male Sprague-Dawley rats (n = 52) were anesthetized, subjected to fluid percussion brain injury of moderate severity (2.5-2.8 atm), and killed at 30 min, 2 h, 6 h, 24 h, 3 days, or 7 days postinjury. Genomic DNA from injured cortex at 24 h, but not at 30 min, was both fragmented and able to stimulate exogenous poly(ADP-ribose) polymerase. Endogenous poly(ADP-ribose) polymerase activity, however, was enhanced in the injured cortex at 30 min but subsequently returned to baseline levels. Slight fragmentation of poly(ADP-ribose) polymerase was detected in the injured cortex in the first 3 days following injury, but significant cleavage was detected at 7 days postinjury. Taken together, these data suggest that poly(ADP-ribose) polymerase-mediated DNA repair is initiated in the acute posttraumatic period but that subsequent poly(ADP-ribose) polymerase activation does not occur, possibly owing to delayed apoptosis-associated proteolysis, which may impair the repair of damaged DNA.  相似文献   
15.

Setting

Seven districts in Andhra Pradesh, South India

Objectives

To a) determine treatment outcomes of patients who fail first line anti-TB treatment and are not placed on an multi-drug resistant TB (MDR-TB) regimen, and b) relate the treatment outcomes to culture and drug susceptibility patterns (C&DST).

Design

Retrospective cohort study using routine programme data and Mycobacterium TB Culture C&DST between July 2008 and December 2009.

Results

There were 202 individuals given a re-treatment regimen and included in the study. Overall treatment outcomes were: 68 (34%) with treatment success, 84 (42%) failed, 36 (18%) died, 13 (6.5%) defaulted and 1 transferred out. Treatment success for category I and II failures was low at 37%. In those with positive cultures, 81 had pan-sensitive strains with 31 (38%) showing treatment success, while 61 had drug-resistance strains with 9 (15%) showing treatment success. In 58 patients with negative cultures, 28 (48%) showed treatment success.

Conclusion

Treatment outcomes of patients who fail a first-line anti-TB treatment and who are not placed on an MDR-TB regimen are unacceptably poor. The worst outcomes are seen among category II failures and those with negative cultures or drug-resistance. There are important programmatic implications which need to be addressed.  相似文献   
16.
The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine–proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only ornithine aminotransferase (OAT), the rate-limiting enzyme in the conversion of ornithine to proline, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total OAT activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in OAT activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes.  相似文献   
17.
DNA fragmentation, an early event in neuronal death following traumatic brain injury, may be triggered by the 40-kDa subunit of DNA fragmentation factor (DFF40). DFF40 is typically bound to the 45-kDa subunit of DFF (DFF45), and activation of DFF40 may occur as a result of caspase-3-mediated cleavage of DFF45 into 30- and 11-kDa fragments. In this study, the intracellular distribution of DFF45 and DFF40 was examined following lateral fluid percussion brain injury of moderate severity (2.4-2.7 atm) in male Sprague-Dawley rats. In the cytosolic fraction (S1) of the injured cortex at 2 and 24 h postinjury, significant decreases in the intensities of DFF45-like proteins at 45- and 32-kDa bands and a concomitant increase in the 11-kDa bands were observed (p < 0.05 vs. uninjured controls). A significant decrease in the intensities of the 32-kDa band in the nuclear (P1) fraction of the injured cortex was observed at 30 min and 2 h postinjury (p < 0.01). Concomitantly, a decrease in DFF40 was observed in the cortical S1 fraction at 2 and 24 h (p < 0.05) and in the P1 fraction at 30 min and 2 h postinjury (p < 0.01). In the hippocampus, DFF45 decreased at 30 min in the P1 and 2 h in the S1 fraction (p < 0.05) and recovered by 24 h postinjury, whereas DFF40 was significantly decreased in the S1 and increased in the P1 fraction at both 2 and 24 h (p < 0.01), which indicated a translocation of DFF40 from cytosol to nucleus. These data are the first to demonstrate that changes in DFF proteins occur after brain trauma and suggest that these changes may play a role in apoptotic cell death via caspase-3-DFF45/DFF40-DNA cleavage observed following traumatic brain injury.  相似文献   
18.
Abstract

Unbound drug concentration in the brain would be the true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate the clinical dose projection. With the application of mass spectrometry, the current work proposes a definite measure of test drug exposures at serotonin-2A occupancy. The 5-HT2A occupancy of antagonist in the rat brain has determined with non-radiolabeled tracer MDL-100,907 at an optimized dose (3?µg/kg) and treatment time (30?min). Equilibrium dialysis method determines the in vitro free fraction of the test antagonist in untreated rat brain homogenates and plasma. Drug-free fractions derived the unbound concentration (EC50) in plasma and brain at test doses. The corresponding binding affinities (Ki) correlated with the unbound concentrations. Except for quetiapine, the ED50 values in the dose-occupancy curves of antagonists are close and ranged from 1 to 3?mg/kg. The test drug quetiapine, eplivanserin, and clozapine showed high free fractions in plasma, but for ketanserin and olanzapine, the brain free fraction was higher. The correlation between the unbound EC50 of the antagonists and corresponding Ki values was good (r2=0.828). The improved EC50 accuracy with unbound concentrations was 10–250 folds in plasma and 10–170 folds in the brain. Further, the free fractions (fu, plasma/fu, brain) of test drugs had shown a correlation of ~83% with brain permeability (Ctotal brain/Ctotal plasma), a limiting factor. Thus, correlating the occupancy with unbound exposure and pharmacology would result in an accurate measurement of drug potency and optimizes in selecting the clinical dose.  相似文献   
19.
Abstract

The use of liquid chromatography coupled with mass spectrometry (LC-MS/MS) is advantageous in in-vivo receptor occupancy assays at pre-clinical drug developmental stages. Relatively, its application is effective in terms of high throughput, data reproducibility, sensitivity, and sample processing. In this perspective, we have evaluated the use of FTC-146 as a non-radiolabelled tracer to determine the sigma-1 receptor occupancy of test drugs in mice brain. Further, the brain and plasma exposures of test drug were determined at their corresponding occupancies. In this occupancy method, the optimized tracer treatment (sacrification) time after intravenous administration was 30?min. The tracer dose was 3?µg/kg and specific brain regions of interest were frontal cortex, pons and midbrain. Mice were pretreated orally with SA4503, fluspidine, haloperidol, and donepezil followed by tracer treatment. Among the test drugs, SA4503 was used as positive control group at its highest test dose (7?mg/kg, intraperitoneal). There was a dose-dependent decrease in brain regional FTC-146 binding in pretreated mice. From the occupancy curves of SA4503, fluspidine, haloperidol, and donepezil the effective dose (ED50) value ranges are 0.74–1.45, 0.09–0.11, 0.11–0.12, and 0.07–0.09?mg/kg, respectively. Their corresponding brain effective concentration (EC50) values are 74.3–132.5, 3.4–3.7, 122.5–139.5, and 8.8–11.0?ng/g and plasma EC50 values are 34.3–53.7, 0.08–0.10, 7.8–9.5, and 0.6–0.7?ng/mL. Brain regional distribution and binding inhibition upon pretreatment were comparable with data reported with labeled [18F]FTC-146. Drug exposures were simultaneously determined and correlated with sigma-1 occupancy from the same experiment. Wide category drugs can be assayed for sigma-1 receptor engagement and their correlation with exposures aid in clinical development.  相似文献   
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