Metabolic defence against oxidative stress: the road less travelled so far.

Bacteria have survived, and many have thrived, since antiquity in the presence of the highly-reactive chalcogen-oxygen (O2 ). They are known to evoke intricate strategies to defend themselves from the reactive by-products of oxygen-reactive oxygen species (ROS). Many of these detoxifying mechanisms have been extensively characterized; superoxide dismutase, catalases, alkyl hydroperoxide reductase and the glutathione (GSH)-cycling system are responsible for neutralizing specific ROS. Meanwhile, a pool of NADPH-the reductive engine of many ROS-combating enzymes-is maintained by metabolic enzymes including, but not exclusively, glucose-6 phosphate dehydrogenase (G6PDH) and NADP-dependent isocitrate dehydrogenase (ICDH-NADP). So, it is not surprising that evidence continues to emerge demonstrating the pivotal role metabolism plays in mitigating ROS toxicity. Stemming from its ability to concurrently decrease the production of the pro-oxidative metabolite, NADH, while augmenting the antioxidative metabolite, NADPH, metabolism is the fulcrum of cellular redox potential. In this review, we will discuss the mounting evidence positioning metabolism and metabolic shifts observed during oxidative stress, as critical strategies microbes utilize to thrive in environments that are rife with ROS. The contribution of ketoacids-moieties capable of non-enzymatic decarboxylation in the presence of oxidants-as ROS scavengers will be elaborated alongside the metabolic pathways responsible for their homeostases. Further, the signalling role of the carboxylic acids generated following the ketoacid-mediated detoxification of the ROS will be commented on within the context of oxidative stress.

Evaluation of tolerability and ability to increase immunosuppression in renal transplant patients converted from mycophenolate mofetil to enteric-coated mycophenolate sodium.

BACKGROUND: Dose reductions or discontinuations of mycophenolate mofetil (MMF) result in higher incidences of acute rejection and graft loss. Converting renal transplant patients experiencing MMF-related gastrointestinal (GI) side effects to equimolar enteric-coated mycophenolate sodium (EC-MPS) may relieve GI symptoms. METHODS: In this prospective 12-month study, renal transplant patients maintained on suboptimal MMF doses (<1500 mg/d) due to GI intolerance were converted to equimolar EC-MPS followed by incremental EC-MPS dose increases (180 mg/d) every 7 weeks to an established maximum, if well tolerated. Changes in GI symptoms were assessed by physician judgment and Gastrointestinal Symptom Rating Scale (GSRS). RESULTS: Twenty-five patients (mean age: 52.0 +/- 13.6 years) were converted from MMF (930.0 +/- 153.4 mg/d) to equimolar EC-MPS (669.6 +/- 110.5 mg/d) at day 0. Twenty-three of 25 patients tolerated equimolar dose conversion and one or more EC-MPS dose increments at week 28. Compared to baseline, patients received significantly more EC-MPS at week 28 and week 49 (mean dose: 1033.0 +/- 164.8 mg/d, P < .0001 and 1001.7 +/- 209.0 mg/d, P < .0001, respectively). Two patients dropped out by week 7 for reasons unrelated to EC-MPS. The mean serum creatinine remained stable and no clinical acute rejection episodes occurred over 12 months. Mean GSRS total score remained stable through month 12 when compared to day 0 despite increases in EC-MPS dose. CONCLUSION: In renal transplant patients receiving suboptimal MMF doses due to GI symptoms, conversion to EC-MPS enabled equimolar prescription and subsequent dose increase without increased GI intolerance.

Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells.

Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disorders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytoskeletal dynamics. Whereas the control cells had well-defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular morphology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as alpha-ketoglutarate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases.

Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients.

Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti-proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single-dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half-life was similar. Single-dose everolimus co-administration did not affect the steady-state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice-daily dosing schedule used in adults.

Transjugular intrahepatic portosystemic shunt prior to renal transplantation in a child with autosomal-recessive polycystic kidney disease and portal hypertension: A case report.

Autosomal-recessive polycystic kidney disease (ARPKD) can cause renal failure and portal hypertension in children. Portal hypertension may complicate the course of renal transplantation (Tx). We report the successful outcome of a patient with end-stage renal disease (ESRD) and portal hypertension treated with transjugular intrahepatic portosystemic shunt (TIPS), a minimally invasive endovascular technique of portosystemic shunt, prior to renal Tx.

Neoral pharmacokinetics in Latino and Caucasian pediatric renal transplant recipients.

Interpopulation variability of drug pharmacokinetics (PK) has been described. For example, the systemic clearance of nifedipine is higher in Mexicans than Caucasians. African-Americans have a lower cyclosporine bioavailability than Caucasians. Limited data are available in the Latino population. Under identical conditions, we compared the PK profile of Neoral (cyclosporine for microemulsion) obtained in stable pediatric renal transplant recipients of Latino and Caucasian origin. A slightly lower area under the curve (AUC) when corrected for dose per body surface area or per kilogram of body weight was observed in Caucasians compared with Latinos. This difference was more pronounced in the younger age group (< 12 years) with a higher peak-to-trough ratio. However, the Caucasians required a higher dosage of Neoral than the Latinos to achieve that same AUC. There was no difference between the groups in the time (tmax) to reach maximal concentration (Cmax) of Neoral. A higher apparent clearance of the drug was observed in the Caucasians compared with the Latinos, especially in the younger age group. No differences in pre- and post-dose levels were observed between the two groups. These differences might affect dose adjustment between the two subpopulations.

Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4.

Mature human aorta contains a 70-kDa versican fragment, which reacts with a neoepitope antiserum to the C-terminal peptide sequence DPEAAE. This protein therefore appears to represent the G1 domain of versican V1 (G1-DPEAAE(441)), which has been generated in vivo by proteolytic cleavage at the Glu(441)-Ala(442) bond, within the sequence DPEAAE(441)-A(442)RRGQ. Because the equivalent aggrecan product (G1-NITEGE(341)) and brevican product (G1-EAVESE(395)) are generated by ADAMTS-mediated cleavage of the respective proteoglycans, we tested the capacity of recombinant ADAMTS-1 and ADAMTS-4 to cleave versican at Glu(441)-Ala(442). Both enzymes cleaved a recombinant versican substrate and native human versican at the Glu(441)-Ala(442) bond and the mature form of ADAMTS-4 was detected by Western analysis of extracts of aortic intima. We conclude that versican V1 proteolysis in vivo can be catalyzed by one or more members of the ADAMTS family of metalloproteinases.

Hais cuaj txub kaum txub--to speak of all things: a Hmong cross-cultural case study.

Cross-cultural medicine is a field that describes how disparate value and belief systems concerning health and disease affect the delivery of health care. This report describes the conflict between a Hmong immigrant family and the Western medical establishment over the care of their child with end stage renal disease [ESRD]. The health care providers, social service agencies and medical center failed to adequately respond to the needs of the family. The medical staff [nephrologist, nurse coordinator, dietician, social worker, and CPS worker] worked with a transcultural nurse, Hmong community health worker and the family, to design and negotiate a treatment plan that would be acceptable to the family and the health care team. Trust was reestablished between the family and the healthcare providers and the medical outcome for the child improved.

The use of community surveys for health planning: the experience of 56 northwest rural communities.

A rural health services development program of the University of Washington School of Medicine has worked for 15 years with communities throughout the five-state region of Alaska, Idaho, Montana, Washington and Wyoming to strengthen their health systems. In the course of that work, 56 communities were surveyed about their utilization and opinions of local health systems. This database allows the following generalizations to be made about rural Northwest communities: (1) People think highly of their local hospitals, physicians and other key components of the acute medical care system and want their hospitals to remain open. Older respondents are more satisfied than younger respondents; (2) the typical hospital market share is 36 percent, the typical physician market share is 50 percent (3) satisfaction with discrete, well-funded services such as pharmacy, ambulance and dentistry is quite high, whereas satisfaction with mental health and substance abuse treatment is significantly lower; (4) the most commonly cited serious problems in surveyed communities were "too few physicians or- services" and "care is too expensive"; and (5) there is great variation between communities in both satisfaction and utilization.

Redesigning financial management education for the nursing administration graduate student.

The changes and expansion in the nurse administrator role indicate a need for a specialized body of financial knowledge and skills for making system focused decisions that integrate the clinical and business aspects of healthcare. A survey of nurse administrators and chief executive officers showed high agreement on the important financial management concepts to the nurse administrator role. A graduate level financial management course that includes concepts for course content and practice applications is proposed.

1,25-Dihydroxyvitamin D3--a hormone with immunomodulatory properties.

The active vitamin D metabolite, 1,25-dihydroxyvitamin D3[1,25-(OH)2D3], exerts immunosuppressive activity. At a cellular and molecular level, the hormone preferentially targets helper T cell activity (Th1) by inhibiting the secretion of both IL-2 and IFN-gamma by Th1 and by suppressing the secretion pro-Th1 cytokine IL-12 by antigen-presenting cells. The active metabolite further inhibits class II antigen expression and enhances suppressor cell activity. In animal models of autoimmunity, 1,25-(OH)2D3 prevents the development of experimental autoimmune encephalomyelitis, reduces the incidence of diabetes, and attenuates murine lupus. The hormone also prolongs graft survival in animal models of transplantation. In humans, non-classical use of 1,25-(OH)2D3 has led to an anti-proliferative effect in psoriasis, antineoplastic effect in prostate cancer, and immunomodulatory effect in scleroderma. The development of less hypercalcemic analogs might open a new therapeutic area for vitamin D3.

A systematic analysis of 40 random genes in cultured vascular smooth muscle subtypes reveals a heterogeneity of gene expression and identifies the tight junction gene zonula occludens 2 as a marker of epithelioid "pup" smooth muscle cells and a participant in carotid neointimal formation.

An accumulation of evidence suggests that vascular smooth muscle is composed of cell subpopulations with distinct patterns of gene expression. Much of this evidence has come from serendipitous discoveries of genes marking phenotypically distinct aortic cultures derived from 12-day-old and 3-month-old rats. To identify more systematic differences, we isolated 40 genes at random from libraries of these 2 cultures and examined message expression patterns. To determine consistency of differential expression, we measured mRNA levels in 4 sets of cultures in 6 phenotypically distinct aortic cell clones and in balloon injured rat carotid arteries to determine the relevance of these differences in vitro to in vivo biology. The following 5 consistently differentially expressed genes were identified in vitro: zonula occludens 2 (ZO-2); peroxisome proliferator-activated receptor delta (PPARdelta); secreted protein, acidic and rich in cysteine (SPARC); alpha1(I)collagen; and A2, an uncharacterized gene. We examined these 5 clones during carotid artery injury and an inconsistently differentially expressed clone Krox-24 because, as an early response transcription factor, it could be involved in the injury response. PPARdelta, A2, and Krox-24 mRNAs were upregulated during the day after injury. ZO-2 and alpha1(I)collagen messages were modulated for up to a month, whereas SPARC message showed no consistent change. An analysis of ZO-2 and other tight junction genes indicates that tight junctions may play a role in smooth muscle biology. These data suggest that a systematic analysis of these libraries is likely to identify a very large number of differentially expressed genes. ZO-2 is particularly intriguing both because of this tight junction gene's pattern of prolonged over-expression after injury and because of its potential role in determining the distinctive epithelioid phenotype of smooth muscle cells identified in rat and other species.

Versican/PG-M isoforms in vascular smooth muscle cells.

The expression of increased amounts of proteoglycans in the extracellular matrix may play a role in vascular stenosis and lipid retention. The large chondroitin sulfate proteoglycan versican is synthesized by vascular smooth muscle cells (SMCs), accumulates during human atherosclerosis and restenosis, and has been shown to bind LDLs. We recently demonstrated that adult rat aortic SMCs express several versican mRNAs. Four versican splice variants, V0, V1, V2, and V3, have recently been described, which differ dramatically in length. These variants differ in the extent of modification by glycosaminoglycan chains, and V3 may lack glycosaminoglycan chains. In this study, we characterized versican RNAs from rat SMCs by cloning, sequencing, and hybridization with domain-specific probes. DNA sequence was obtained for the V3 isoform, and for a truncated V0 isoform. By hybridization of polyadenylated RNA with domain-specific probes, we determined that the V0, V1, and V3 isoforms are present in vascular SMCs. We confirmed the presence of the V3 isoform in polyadenylated RNA and in RT-PCR products by hybridization with an oligonucleotide that spans the splice junction between the hyaluronan-binding domain and the epidermal growth factor-like domain. In addition, a novel splice variant was cloned by PCR amplification from both rat and human SMC RNA. This appears to be an incompletely spliced variant, retaining the final intron. PCR analysis shows that this intron can be retained in both V1 and V3 isoforms. The predicted translation product of this variant would have a different carboxy-terminus than previously described versican isoforms.

Nonsteroidal anti-inflammatory drug use in adolescence.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been recently released as over-the-counter drugs making them more widely available to the general public. We present five cases of adolescents with complications, including acute and chronic renal failure, related to the use of NSAIDs. Risk factors for NSAID nephrotoxicity include chronic illness, dehydration, ethanol and use of other medications. Adolescents should be educated about the risks and prevention of NSAID toxicity.

Intraocular pressure change measured by Goldmann tonometry after laser in situ keratomileusis.

PURPOSE: To assess the accuracy of Goldmann tonometry after laser in situ keratomileusis (LASIK). SETTING: University-based refractive surgery group (Clinique du Laser Visuel). METHOD: The database of patients who had LASIK was retrospectively reviewed. Preoperative and postoperative intraocular pressure (IOP) was measured in 145 patients. The correlation between decrease in IOP and various preoperative and intraoperative parameters was evaluated by regression analysis. Only one eye in patients having bilateral surgery was used for statistical analysis. RESULTS: Laser in situ keratomileusis was associated with a mean decrease in IOP of 1.9 mm Hg +/- 2.9 (SD). There was no significant correlation between the decrease and any parameter evaluated. CONCLUSION: Intraocular pressure after LASIK decreased by a mean of 1.9 +/- 2.9 mm Hg. The cause of the decrease remains unknown.

The syndrome of autoimmune interstitial nephritis and membranous nephropathy.

A 2-year-old male patient was evaluated for Fanconi syndrome with hypertension and failure to thrive. Renal biopsy revealed autoimmune interstitial nephritis with membranous nephropathy. The patient developed autoimmune hemolytic anemia and intractable diarrhea with villous atrophy of the jejunum. He progressed to end-stage renal disease and was transplanted without recurrent disease. Immune work-up done prior to immunosuppressive therapy showed marked elevation of IgE. Studies of T lymphocyte cytokine production showed normal production of interleukin-4 but depressed levels of interferon-gamma. The simultaneous occurrence of autoimmune interstitial nephritis and membranous nephropathy in a young male represents a unique syndrome. Abnormalities of T lymphocyte subpopulations and their cytokines may be involved in the pathogenesis of this disorder.