Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes

Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and Sao Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7-408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log(10) copies/mL; 95% CI, .90-3.25 log(10) copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.

Acute hyperglycemia rapidly stimulates VEGF mRNA translation in the kidney. Role of angiotensin type 2 receptor (AT2)

Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. Acute hyperglycemia increased synthesis of intrarenal Ang I and Ang II and resulted in activation of both Ang II receptors, AT1 and AT2, in the kidney. Losartan (specific AT1 antagonist) or PD123319 (specific AT2 antagonist) did not affect hyperglycemia but prevented activation of renal AT1 and AT2, respectively. In murine renal cortex, acute hyperglycemia increased VEGF protein but not mRNA content after 24 h, which suggested translational regulation. Blockade of AT2, but not AT1, prevented increase in VEGF synthesis by inhibiting translation of VEGF mRNA in renal cortex. Acute hyperglycemia increased VEGF expression in wild type but not in AT2 knockout mice. Binding of heterogeneous nuclear ribonucleoprotein K to VEGF mRNA, which stimulates its translation, was prevented by blockade of AT2, but not AT1. The Akt-mTOR-p70(S6K) signaling pathway, involved in the activation of mRNA translation, was activated in hyperglycemic kidneys and was blocked by the AT2 antagonist. Elongation phase is an important step of mRNA translation that is controlled by elongation factor 1A (eEF1A) and 2 (eEF2). Expression of eEF1A and activity of eEF2 was higher in kidney cortex from hyperglycemic mice and only the AT2 antagonist prevented these changes. To assess selectivity of translational control of VEGF expression, we measured expression of fibronectin (FN) and laminin beta 1 (lam beta 1): acute hyperglycemia increased FN expression at both protein and mRNA levels, indicating transcriptional control, and did not affect the expression of lam beta 1. To confirm results obtained with PD123319, we induced hyperglycemia in AT2 knockout mice and found that in the absence of AT2, translational control of VEGF expression by hyperglycemia was abolished. Our data show that acute hyperglycemia stimulates Ang II synthesis in murine kidney cortex, this leads to AT2 activation and stimulation of VEGF mRNA translation, via the Akt-mTOR-p70(S6K) signaling pathway. Our data show that exclusive translational control of protein expression in the kidney by acute hyperglycemia is not a general phenomenon, but do not prove that it is restricted to VEGF. (C) 2010 Elsevier Inc. All rights reserved.

Role of p21 and oxidative stress on renal tubular resistance after acute ischaemic injury

Background. Subsequent ischaemic episodes may induce renal resistance. P21 is a cell cycle inhibitor that may be induced by oxygen-free radicals and may have a protective effect in ischaemic acute kidney injury (AKI). This study aimed at evaluating the role of oxidative stress and p21 on tubular resistance in a model of acquired resistance after renal ischaemia and in isolated renal tubules. Methods. Wistar rats were divided into: Group 1-sham; Group 2-sham operated and after 2 days submitted to 45-min ischaemia; and Group 3-45-min ischaemia followed after 2 days by a second 45-min ischaemia. Plasma urea was evaluated on Days 0, 2 and 4. Serum creatinine, creatinine clearance and oxidants (thiobarbituric acid-reactive substances) were determined 48 h after the second procedure (Day 4). Histology, immunohistochemistry for lymphocytes (CD3), macrophages (ED1), proliferation (PCNA) and apoptosis (TUNEL) were also evaluated. Rat proximal tubules (PTs) were isolated by collagenase digestion and Percoll gradient from control rats and rats previously subjected to 35 min of ischaemia. PTs were submitted to 15-min hypoxia followed by 45-min reoxygenation. Cell injury was assessed by lactate dehydrogenase release and hydroperoxide production (xylenol orange). Results. Ischaemia induced AKI in Group 2 and 3 rats. Subsequent ischaemia did not aggravate renal injury, demonstrating renal resistance (Group 3). Renal function recovery was similar in Group 2 and 3. Plasma and urine oxidants were similar among in Group 2 and 3. Histology disclosed acute tubular necrosis in Group 2 and 3. Lymphocyte infiltrates were similar among all groups whereas macrophages infiltrate was greater in Group 3. Cell proliferation was greater in Group 2 compared with Group 3. Apoptosis was similar in groups 2 and 3. The p21 expression was increased only in Group 3 whereas it was similar in groups 1 and 2. PTs from the ischaemia group were sensitive to hypoxia but resistant to reoxygenation injury which was followed by lower hydroperoxide production compared to control PT. Conclusion. Renal resistance induced by ischaemia was associated with cell mechanism mediators involving oxidative stress and increased p21 expression.

Differential monocyte STAT6 activation and CD4(+)CD25(+)Foxp3(+) T cells in kidney operational tolerance transplanted individuals

In organ transplantation, the immunosuppression withdrawal leads, in most cases, to rejection. Nonetheless, a special group of patients maintain stable graft function after complete withdrawal of immunosuppression, achieving a state called ""operational tolerance."" The study of such patients may be important to understand the mechanisms involved in human transplantation tolerance. We compared the profile of CD4(+)CD25(+)Foxp3(+) T cells and the signaling pathways IL-6/STAT3 (signal transducers and activators of transcription) and IL-4/STAT6 in peripheral blood mononuclear cells of four kidney transplant groups: (i) operational tolerance (OT), (ii) chronic allograft nephropathy (CR), (iii) stable graft function under standard immunosuppression (Sta), (iv) stable graft function under low immunosuppression, and (v) healthy individuals. Both CR and Sta displayed lower numbers and percentages of CD4(+)CD25(+)Foxp3(+) T cells compared with all other groups (p < 0.05). The OT patients displayed a reduced activation of the IL-4/STAT6 pathway in monocytes, compared with all other groups (p < 0.05). The lower numbers of CD4(+)CD25(+)Foxp3(+) T cells observed in CR individuals may be a feature of chronic allograft nephropathy. The differential OT signaling profile, with reduced phosphorylation of STAT6, in monocytes` region, suggests that some altered function of STAT6 signaling may be important for the operational tolerance state. Crown copyright (C) 2010 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. All rights reserved.

Forefoot Deformity in Diabetic Neuropathic Individuals and its Role in Pressure Distribution and Gait

Background. Foot deformities have been related to diabetic neuropathy progression but their influence on plantar distribution during dynamic tasks is not completely understood. The purpose of the present study was to investigate the influence of metatarsal head prominence and claw toes on regional plantar pressures during gait in patients with diabetic neuropathy Methods Seventy-one adults participated in this study categorized into three groups: a control group (CG, n = 32), patients with diabetic neuropathy without any foot deformities (DG, n = 20), and patients with diabetic neuropathy with metatarsal head prominence and/or claw toes (DMHG, n = 19). Plantar pressure variables (contact area, peak pressure, and maximum mean pressure) were evaluated during gait on rearfoot, midfoot, and forefoot using capacitive insoles (Pedar-X System, Novel Inc., Munich, Germany). A general linear model was applied to repeatedly measure and analyze variance relationships between groups and areas. Results. DMHG. presented larger contact areas at the forefoot and midfoot along with higher peak pressure at the rearfoot compared to the other two groups The DG showed higher mean pressure at the midfoot compared to:the other two groups. Conclusion. The coexistence of diabetic neuropathy and metatarsal head prominence in addition to claw toes, resulted in overloading the rearfoot and enhancing the contact area of forefoot and midfoot while walking. This plantar pressure distribution is a result of a different coordination pattern adopted in order to reduce plantar loads at the anterior parts of the foot that were structurally altered. Patients with diabetic neuropathy without any forefoot deformities presented a different plantar pressure distribution than patients with deformities suggesting that both neuropathy and structural foot alterations can influence foot rollover mechanisms.

Dobutamine Stress Echocardiography in Heart Transplant Recipients` Evaluation: The Role of Reinnervation

Introduction. Orthotopic heart transplantation renders the recipient denervated. This remodeling of the intrinsic cardiac nervous system should be taken in account during functional evaluation for allograft coronary artery disease. Dobutamine stress echocardiography (DSE) has been used to detect patients at greater risk. The aim of this study was to determine whether patients with various autonomic response levels, and supposed reinnervation patterns, show the same response to DSE. Methods. We studied 20 patients who had survived more than 5 years after orthotopic heart transplantation. All patients underwent a Holter evaluation. We considered patients with low variability to be those with less than a 40-bpm variation from the lowest to highest heart rate, so-called ""noninnenervated"" (group NI). Patients who had 40-bpm or more variation were considered to show high variability and called ""reinnervated"" (group RI). After that, all patients performed an ergometric test and DSE. Results. Groups were defined as NI (n = 9) and RI (n = 11). Ergometric tests confirmed this response with NI patients showing less variability when compared to RI patients (P = .0401). During DSE, patients showed similar median heart rate responses according to the dobutamine dose. Spearmen correlation showed r = 1.0 (P = .016). Conclusions: DES was effective to reach higher heart rates, probably related to catecholamine infusion. These findings may justify a better response when evaluating cardiac allograft vasculopathy in heart transplant patients.

Differential display and suppression subtractive hybridization analysis of the pulp of ripening banana

The fruit of banana undergoes several important physico-chemical changes during ripening. Analysis of gene expression would permit identification of important genes and regulatory elements involved in this process. Therefore, transcript profiling of preclimacteric and climacteric fruit was performed using differential display and Suppression subtractive hybridization. Our analyses resulted in the isolation of 12 differentially expressed cDNAs, which were confirmed by dot-blots and northern blots. Among the sequences identified were sequences homologous to plant aquaporins, adenine nucleotide translocator, immunophilin, legumin-like proteins, deoxyguanosine kinase and omega-3 fatty acid desaturase. Some of these cDNAs correspond to newly isolated genes involved in changes related to the respiratory climacteric, or stress-defense responses. Functional characterization of ripening-associated genes could provide information useful in controlling biochemical pathways that would have an impact on banana quality and shelf life. (C) 2009 Elsevier B.V. All rights reserved.

The incremental role of obstructive sleep apnoea on markers of atherosclerosis in patients with metabolic syndrome

Objective: Metabolic syndrome (MS) is associated with subclinical atherosclerosis, but the relative role of obstructive sleep apnoea (OSA) is largely unknown. The main objective of this study is to determine the impact of OSA on markers of atherosclerosis in patients with MS. Methods: Eighty-one consecutive patients with MS according to the Adult Treatment Panel III underwent a clinical evaluation, polysomnography, laboratory and vascular measurements of carotid intima media thickness (IMT), carotid-femoral pulse wave velocity (PWV) and carotid diameter (CD) in a blind fashion. OSA was defined as an apnoea-hypopnoea index (AHI) >= 15 events/hour. Multiple linear regression was performed to determine the variables that were independently associated with the vascular parameters. Results: Fifty-one patients (63%) had OSA. No significant differences existed in age, sex, MS criteria, and cholesterol levels between patients with (MS+OSA) and without OSA (MS-OSA). Compared with MS-OSA patients, MS+OSA patients had higher levels of IMT (661 +/- 117 vs. 767 +/- 140 mu m), PWV (9.6 +/- 1.0 vs. 10.6 +/- 1.6 m/s), and CD (6705 +/- 744 vs. 7811 +/- 862 mu m) (P < 0.001 for each comparison). Among patients with MS+OSA, all vascular parameters were similar in patients with and without daytime sleepiness. The independent parameters associated with IMT, PWV, and CD were AHI, abdominal circumference, and systolic blood pressure (R(2) = 0.42); AHI and systolic blood pressure (R(2) = 0.38); and AHI, age, abdominal circumference and systolic blood pressure (R(2) = 0.45), respectively. The R(2) of AHI for IMT, PWV and CD was 0.12, 0.10 and 0.20, respectively. Conclusions: OSA is very common and has an incremental role in atherosclerotic burden in consecutive patients with MS. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Pathogenic role of anti-endothelial cell antibodies in autoimmune rheumatic diseases

Anti-endothelial cells antibodies have been detected in numerous autoimmune and inflammatory diseases, including systemic lupus erythematous, rheumatoid arthritis, vasculitis and sarcoidosis. Anti-endothelial cells antibodies bind to endothelial cell antigens and induce endothelial damage. Their effects on the endothelial cell have been considered responsible, at least in part, by the vascular injury which occurs in these pathological conditions. Lupus (2009) 18, 1233-1238.