Current topics in HIV-1 pathogenesis: The emergence of deregulated immuno-metabolism in HIV-infected subjects

International audienceHIV-1 infection results in long-lasting activation of the immune system including elevated production of pro-inflammatory cytokine/chemokines, and bacterial product release from gut into blood and tissue compartments, which are not fully restored by antiretroviral therapies. HIV-1 has also developed numerous strategies via viral regulatory proteins to hijack cell molecular mechanisms to enhance its own replication and dissemination. Here, we reviewed the relationship between viral proteins, immune activation/inflammation, and deregulated metabolism occurring in HIV-1-infected patients that ultimately dampens the protective innate and adaptive arms of immunity. Defining precisely the molecular mechanisms related to deregulated immuno-metabolism during HIV-1 infection could ultimately help in the development of novel clinical approaches to restore proper immune functions in these patients

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.

We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed 'familial benign hematuria.' Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension

Prévention du carcinome rénal : l’approche nutrigénétique

La fréquence du cancer du rein (RCC), 3 % des cancers humains, augmente dans les pays industrialisés, laissant supposer l’intervention de facteurs toxiques (xénobiotiques et/ou alimentation, trichloréthylène, tabagisme et obésité). Le RCC survient le plus souvent sous forme sporadique mais est également retrouvé dans un contexte familial : la maladie de von Hippel-Lindau (VHL). L’existence, d’une part, d’une grande hétérogénéité intra- et inter-familiale dans le contexte du VHL et, d’autre part, la susceptibilité variable à des carcinogènes chimiques dans les formes sporadiques, laisse supposer, en outre, la participation de gènes modificateurs conditionnels. Afin d’identifier des sous-groupes d’individus particulièrement exposés ou, au contraire, protégés du fait de certains génotypes, nous avons collecté une série de 460 tumeurs et de patients appartenant à 79 familles VHL et développé un outil informatique, l’« universal mutation database » (UMD) pour les mutations du gène VHL, permettant de rechercher des corrélations. Les mutations du gène VHL à l’origine à la fois des RCC sporadiques et de la maladie de VHL sont de nature différente : 1) dans les tumeurs sporadiques, 83 % des mutations du gène VHL sont des mutations aboutissant à un décalage du cadre de lecture (délétion, insertion, non-sens = « frameshift »). Les 17 % restant comprennent des transversions (3/4) et des transitions (1/4). Cette proportion élevée de transversions suggère fortement l’implication de substances carcinogènes (fumée de tabac) dont l’impact est largement conditionné par la variabilité génétique de l’activité des enzymes de biotransformation ; 2) pour les formes familiales, les mutations de type faux sens prédominent dans 65 % des cas. Cette différence permet de définir un facteur pronostique de développer un RCC pour les patients VHL en fonction de la nature de la mutation germinale dont ils sont porteurs. Afin de repérer les génotypes conférant un risque élevé en présence de substances potentiellement carcinogènes, nous avons établi le génotype des patients pour 8 gènes (une cinquantaine de génotypes) impliqués dans le métabolisme des xénobiotiques. Cette étude fait apparaître une relation significative entre le développement d’un RCC et des combinaisons d’allèles comprenant : CYPIA1 ("variant"), NAT2 et NAT1 (acétyleurs lents) et GSTM1 (allèle nul). D’éventuelles associations entre les génotypes "à risque" et le profil des mutations somatiques observées chez les patients, mais aussi à différents stades tumoraux, pourraient aider à 1) préciser la nature de certains profils de mutagenèse en relation avec l’activité ou la déficience de telle ou telle enzyme du métabolisme des xénobiotiques et sous l’effet de tel ou tel carcinogène ; 2) montrer que, dans le contexte du VHL, certaines combinaisons d’allèles de ces différents gènes confèrent un risque particulier de développer certains types de tumeur. Ainsi, suivre "à la trace" des substances potentiellement carcinogènes, à la fois par l’empreinte laissée au niveau de l’ADN, ainsi qu’à travers les allèles conditionnellement délétères de gènes participant à leur détoxication, devrait permettre une meilleur prévention grâce à une alimentation personnalisée pour les individus présentant ces génotypes

The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy:The RENAAL Study

The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL Study.BackgroundDiabetic nephropathy has become the single most important cause of end-stage renal disease (ESRD) worldwide. Strategies to slow the rate of loss of renal function in these patients have been developed. We examined the risk factors that predict loss of kidney function (doubling of serum creatinine) or ESRD (dialysis or transplantation) in patients with type 2 diabetes in whom blood pressure was controlled.MethodsWe evaluated risk factors for doubling of serum creatinine or the development of ESRD in the Reduction of End Points in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study, which included 1513 patients with type 2 diabetes and nephropathy.ResultsUnivariate analyses demonstrated a group of 23 risk factors that significantly predicted doubling of serum creatinine or ESRD. From these univariate analyses, a multivariate model was developed that demonstrated four independent risk factors: proteinuria, serum creatinine, serum albumin, and hemoglobin level. Proteinuria was the strongest and most consistent risk factor. The multivariate risk model was derived from only the placebo group and was similar to that derived for the total population, suggesting that the risk predictors for progression of kidney disease were independent of therapy.ConclusionAfter control of blood pressure in type 2 diabetic patients with nephropathy, proteinuria, degree of renal failure, serum albumin, and hemoglobin level are independent risk factors that predict renal outcomes. The level of proteinuria proved to be the most important risk for progressive kidney injury in these diabetic patients

Insight on variables leading to burnout in cancer physicians

Although communication skills training programs have been recommended to reduce physicians' burnout, few studies have investigated their efficacy. This study assessed the impact of two training programs on cancer physicians' burnout. Especially, it identified some variables leading to burnout in order to develop effective interventions. Burnout was assessed with the Maslach Burnout Inventory. No statistically significant impact of training programs on burnout was observed. The amount of clinical workload and the overuse of some facilitative communication skills were associated with cancer physicians' burnout. The content of such programs must be redefined to reduce burnout

Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis

The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif–containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2–IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients