Quality of Life and Outcomes in African Americans with CKD

Low health-related quality of life (HRQOL) has been associated with increased risk for hospitalization and death in ESRD. However, the relationship of HRQOL with outcomes in predialysis CKD is not well understood. We evaluated the association between HRQOL and renal and cardiovascular (CV) outcomes in 1091 African Americans with hypertensive CKD enrolled in the African American Study of Kidney Disease and Hypertension (AASK) trial and cohort studies. Outcomes included CKD progression (doubling of serum creatinine/ESRD), CV events/CV death, and a composite of CKD progression or death from any cause (CKD progression/death). We assessed HRQOL, including mental health composite (MHC) and physical health composite (PHC), using the Short Form-36 survey. Cox regression analyses were used to assess the relationship between outcomes and five-point decrements in MHC and PHC scores using measurements at baseline, at the most recent annual visit (time-varying), or averaged from baseline to the most recent visit (cumulative). During approximately 10 years of follow-up, lower mean PHC score was associated with increased risk of CV events/CV death and CKD progression/death across all analytic approaches, but only time-varying and cumulative decrements were associated with CKD progression. Similarly, lower mean MHC score was associated with increased risk of CV events/CV death regardless of analytic approach, while only time-varying and cumulative decrements in mean MHC score was associated with CKD progression and CKD progression or death. In conclusion, lower HRQOL is associated with a range of adverse outcomes in African Americans with hypertensive CKD.     

Frequency of behavioural problems at one year following traumatic brain injury: Correspondence between patient and caregiver reports

A group of 62 adults with significant (i.e., ventilation required for > 24 hours) traumatic brain injury (TBI) were assessed approximately one year following their injury. The people with TBI and their primary caregivers completed the patient and relative/friend versions respectively, of the 20-item Head Injury Behaviour Rating Scale (HIBS). Responses by the patient and caregiver groups were compared for the total number of problems reported and the frequency of specific problem behaviours. The caregiver group reported a greater total number of problem behaviours and a higher frequency for 19 of the 20 specific behaviours. These differences between the patients' and caregivers' reports were statistically significant for seven of the 19 problem behaviours. The majority (86%) of these significant differences were on items from the Behavioural Regulation, rather than the Emotional Regulation, subscale of the HIBS. The implications of these findings for the practice of neuropsychological rehabilitation are presented.     

Residual effects of a traumatic brain injury on locomotor capacity: a first study of spatiotemporal patterns during unobstructed and obstructed walking

OBJECTIVES: To understand the residual locomotor effects of a traumatic brain injury (TBI) on unobstructed and obstructed walking. PARTICIPANTS: Eight young, high-functioning adults with TBI and 4 healthy subjects. MAIN OUTCOME MEASURES: Spatiotemporal gait parameters and their relation to specific clinical measures of severity and locomotor and balance abilities. RESULTS: Subjects with TBI walked slower and showed a tendency for greater foot clearances in all conditions. Slower walking was due to decreased stride lengths and not cadence, while higher foot clearances were due to placing the trailing foot farther from the obstacle and increasing hip flexion angles during avoidance. CONCLUSIONS: The results suggest that this highly functional TBI population used increased caution. Measures of injury severity did not provide simple predictions of locomotor ability, but the one-legged stance test with eyes closed correlated to walking capacity.     

The glutathione-related detoxification pathway in the human breast: a highly coordinated system disrupted in the tumour tissues

Glutathione and the associated enzymes, glutathione S-transferases, peroxidases, and reductase, have been implicated in cancer chemoresistance. This pathway was investigated in paired cancerous and peritumoral breast samples from 41 women. The tumours exhibited a higher redox status as deduced from increased transferase, peroxidase, and reductase activities and from higher total and reduced glutathione contents. Several components were strongly correlated in peritumoral tissues, suggesting a highly co-ordinated glutathione pathway that appeared disrupted in breast tumours with only a few correlations left. Therefore, resistance could spontaneously result from deregulated variations in the glutathione pathway, which might be relevant to the malignant disease progression.     

Expression and regulation of drug metabolizing enzymes in an immortalized rat hepatocyte cell line.

A hepatic cell line has been immortalized after simian vacuolating virus 40 infection of adult rat hepatocytes maintained in defined culture conditions. This cell line, designated SVHep B4, expressed nuclear large T antigen, exhibited an extended lifespan (50 subcultures) and had a hepatocyte-like morphology. Expression and regulation of drug metabolizing enzymes were studied in long-term cultures of SVHep B4 cells. Significant activities of phase I and phase II enzymes were detected. gamma-Glutamyltransferase, a marker often increased in neoplastic and dedifferentiated hepatocytes, showed a low activity whereas the hepatospecific enzyme tyrosine aminotransferase was expressed at levels similar to those in liver. Responsiveness of drug metabolizing enzymes to inducers was investigated with phenobarbital, dexamethasone and methylcholanthrene. IIB and IA subfamilies of cytochrome P450 were increased, respectively, by phenobarbital (170%) and methylcholanthrene (500%). Glucuronidation of 1-naphthol was increased by phenobarbital (140%) and 3-methylcholanthrene (160%). Phenobarbital, methylcholanthrene and dexamethasone were found to increase significantly gamma-glutamyltransferase while tyrosine aminotransferase activity was enhanced by dexamethasone. Stable expression and inducibility of drug metabolizing enzymes in long-term cultures of the SVHep B4 cell line demonstrate that immortalization of adult hepatocytes represents a promising tool for drug biotransformation studies in vitro.     

Changes of plasma and tissue gamma-glutamyltransferase under the influence of drugs

Measurement of gamma-glutamyltransferase (GGT) activity in plasma is widely used in clinical biology (in order to detect hepatic diseases or to monitor treatment for alcoholism), and also in pharmacology (since this test is the only plasmatic marker for hepatic induction in human). However, the correct interpretation of a high plasmatic activity should take into account the various analytical factors which can affect results, as well as the physiological parameters known to modify this activity. It also requires its comparison to defined reference values. Several mechanisms may be involved in the increase of plasmatic activity as an index of hepatic induction, such as an increase in the protein synthesis, a release of the enzyme from the membrane or a modification in the biliary flux.     

Control of oxidative posttranslational cysteine modifications: from intricate chemistry to widespread biological and medical applications

Cysteine residues in proteins and enzymes often fulfill rather important roles, particularly in the context of cellular signaling, protein-protein interactions, substrate and metal binding, and catalysis. At the same time, some of the most active cysteine residues are also quite sensitive toward (oxidative) modification. S-Thiolation, S-nitrosation, and disulfide bond and sulfenic acid formation are processes which occur frequently inside the cell and regulate the function and activity of many proteins and enzymes. During oxidative stress, such modifications trigger, among others, antioxidant responses and cell death. The unique combination of nonredox function on the one hand and participation in redox signaling and control on the other has placed many cysteine proteins at the center of drug design and pesticide development. Research during the past decade has identified a range of chemically rather interesting, biologically very active substances that are able to modify cysteine residues in such proteins with huge efficiency, yet also considerable selectivity. These agents are often based on natural products and range from simple disulfides to complex polysulfanes, tetrahydrothienopyridines, α,β -unsaturated disulfides, thiuramdisulfides, and 1,2-dithiole-3-thiones. At the same time, inhibition of enzymes responsible for posttranslational cysteine modifications (and their removal) has become an important area of innovative drug research. Such investigations into the control of the cellular thiolstat by thiol-selective agents cross many disciplines and are often far from trivial.     

A Three-Dose Intramuscular Injection Schedule of Anthrax Vaccine Adsorbed Generates Sustained Humoral and Cellular Immune Responses to Protective Antigen and Provides Long-Term Protection against Inhalation Anthrax in Rhesus Macaques

A 3-dose (0, 1, and 6 months) intramuscular (3-IM) priming series of a human dose (HuAVA) and dilutions of up to 1:10 of anthrax vaccine adsorbed (AVA) provided statistically significant levels of protection (60 to 100%) against inhalation anthrax for up to 4 years in rhesus macaques. Serum anti-protective antigen (anti-PA) IgG and lethal toxin neutralization activity (TNA) were detectable following a single injection of HuAVA or 1:5 AVA or following two injections of diluted vaccine (1:10, 1:20, or 1:40 AVA). Anti-PA and TNA were highly correlated (overall r² = 0.89 for log₁₀-transformed data). Peak responses were seen at 6.5 months. In general, with the exception of animals receiving 1:40 AVA, serum anti-PA and TNA responses remained significantly above control levels at 28.5 months (the last time point measured for 1:20 AVA), and through 50.5 months for the HuAVA and 1:5 and 1:10 AVA groups (P < 0.05). PA-specific gamma interferon (IFN-γ) and interleukin-4 (IL-4) CD4⁺ cell frequencies and T cell stimulation indices were sustained through 50.5 months (the last time point measured). PA-specific memory B cell frequencies were highly variable but, in general, were detectable in peripheral blood mononuclear cells (PBMC) by 2 months, were significantly above control levels by 7 months, and remained detectable in the HuAVA and 1:5 and 1:20 AVA groups through 42 months (the last time point measured). HuAVA and diluted AVA elicited a combined Th1/Th2 response and robust immunological priming, with sustained production of high-avidity PA-specific functional antibody, long-term immune cell competence, and immunological memory (30 months for 1:20 AVA and 52 months for 1:10 AVA). Vaccinated animals surviving inhalation anthrax developed high-magnitude anamnestic anti-PA IgG and TNA responses.