Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras

OBJECTIVE: To analyse the epidemiological evolution of cryptococcosis in France after the introduction of highly active antiretroviral therapy (HAART). DESIGN: Retrospective study of cryptococcosis cases recorded at the National Reference Center for Mycoses in France since 1985. METHODS: Using the national surveillance data, we reviewed 1644 cases of HIV-associated cryptococcosis diagnosed in France (population, 59 million) between 1985 and 2001 and compared them to 335 cases recorded in HIV-negative patients. RESULTS: The total number of cryptococcosis cases evolved in parallel to that recorded for HIV-infected patients. Changes occurring after HAART introduction were analysed. A negative binomial regression model established a 46% decrease of the incidence of cryptococcosis during the post-HAART era (1997-2001, n = 292) compared to the pre-HAART era (1985-1996, n = 1352). According to multivariate analysis, African origin, older age, heterosexual HIV contamination, no previous AIDS-defining illness, and no previous HIV infection diagnosis were variables independently associated with an increased risk of cryptococcosis during the post-HAART era. During the same period, the characteristics of the HIV-negative population did not change. CONCLUSIONS: Our analysis of the national surveillance identified demographic factors associated with an increased risk of cryptococcosis in the post-HAART era suggesting that failure to consult and considering oneself not at risk were determinant in the current epidemiology of HIV-related cryptococcosis in France.     

Analysis of the membrane glycoproteins of platelets in the Wiskott-Aldrich syndrome

We have examined the plasma membrane glycoproteins of platelets from three unrelated patients with the Wiskott-Aldrich syndrome. Single- or two-dimensional SDS-polyacrylamide gel electrophoresis was performed. Glycoproteins were located by staining for carbohydrate, or by autoradiography when the platelets had been surface-labelled with 125I prior to solubilization. In one patient a slight decrease in the 125I-labelling intensity of GP Ib, GP Ia and a 125I-labelled polypeptide of Mr 168,000 were noted. For the two other patients the glycoprotein profiles were indistinguishable from those of normal subjects. These results clearly indicate that abnormalities in platelet membrane glycoproteins are not a common trait among Wiskott-Aldrich patients, and thus cannot be regarded as primary defects in this disease.     

Retrospective Outcome Analysis of 39 Patients Who Underwent Lip Surgery for Cutaneous Carcinoma

Purpose

The treatment of lip carcinomas needs tumor surgical resection with safety margins respect. The aim of this study was to report the oncologic and aesthetic/functional outcomes of a retrospective monocentric case series of 39 patients treated for cutaneous lip cancer.

Methods

This retrospective study assessed 56 patients who were treated for a lip carcinoma between 2008 and 2012 and included 39 patients with cutaneous lip basal cell carcinoma or squamous cell carcinoma. Clinical, surgical and pathological data were reviewed, and patients were interviewed for follow-up data. A comparison was made between the marked surgical margins and the margins observed under microscopy after histologic process.

Results

The most frequent tumor type was basal cell carcinoma in 69.2 %. The measured surgical margins were superior to the histological margins in 24 cases (61.5 %) and were inferior in 13 cases (33.3 %). Overall survival and recurrence-free survival rates at 1 year were 97.5 and 95 % respectively.

Conclusion

Differences between the surgical margins and the final histologic margins were the main finding of this retrospective study. These differences were attributed to surgical practices and modification during the histological process. Nevertheless, we did not observe a higher rate of recurrence or death in our study than in literature.

     

Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis

OBJECTIVES: Osteopenia increases the morbidity of primary biliary cirrhosis (PBC). In this study, we have compared two bisphosphonates, alendronate and cyclical etidronate, that inhibit osteoclast-mediated bone resorption and have examined their effects on bone mass in patients with this disease. METHODS: A total of 32 women with PBC were randomly assigned to receive alendronate (10 mg/day) or etidronate (400 mg/day) for 14 days every 3 months. Bone mineral density of the lumbar spine and proximal femur were measured initially and every 6 months. Bone fractures and markers of bone mineral metabolism were also evaluated. RESULTS: Sixteen patients were allocated to each group, which were comparable with respect to the severity of PBC and osteopenia. Thirteen patients in each group completed the 2-yr trial. Both treatments increased bone mineral density after 2 yr, although the increase at the lumbar spine and at the proximal femur was significantly higher in patients receiving alendronate than in patients on etidronate. This higher effect of alendronate paralleled with changes in the biochemical markers of bone turnover. No patient developed new vertebral fractures, but new peripheral fractures were detected in two patients on alendronate and in one on etidronate. There were no serious adverse effects. Neither treatment impaired liver function or cholestasis. CONCLUSIONS: Alendronate effectively increases bone mass and has greater antiresorptive power than etidronate in patients with primary biliary cirrhosis, and is associated with minor or no side effects.     

Comparative genomic hybridization is a powerful tool, complementary to cytogenetics, to identify chromosomal abnormalities in childhood acute lymphoblastic leukaemia

Cytogenetics has a strong prognostic value in childhood acute lymphoblastic leukaemia (ALL), but results are often incomplete because of the poor chromosome morphology. To improve this analysis, we tested comparative genomic hybridization (CGH) for the detection of chromosomal imbalances. 72 children were retrospectively analysed using CGH. Only 53% of the patients had been fully banded by standard methods. With CGH, 36 patients retained a normal chromosomal profile and 36 had unbalanced abnormalities. No amplification was detected. Fluorescence in situ hybridization (FISH) with centromeric and unique sequence probes was used in those cases with discrepancies or unsuccessful karyotype to validate CGH results. CGH enabled clear identification of unbalanced chromosomal abnormalities, even in some cases which had a normal karyotype. In view of the strong prognostic value of hyperdiploidy in childhood ALL, CGH appears to be a powerful technique, complementary to conventional cytogenetics.     

Phenylphenols,biphenols, bisphenol-A and 4-tert-octylphenol exhibit alpha and beta estrogen activities and antiandrogen activity in reporter cell lines

We previously demonstrated the interactions of different chemical compounds with estrogen receptors ERalpha and ERbeta and the androgen receptor (AR) using different reporter cell lines. In this study, we characterize the ERalpha, ERbeta and AR activity of different biphenyls using the same tools. We provide evidence that several phenyl derivatives present both estrogenic and antiandrogenic activity. The extent of hydroxylation and the position of the hydroxyl function were important in determining their estrogenicity and antiandrogenicity. Of the tested compounds, bisphenol-A and 4,4' biphenol had very high estrogenic activity, although it was lower than that of the strong estrogenic alkylphenol, 4-tert-octylphenol. Bisphenol-A and 4,4' biphenol were able to activate ERs at concentrations lower than 1 microM, whereas the other compounds only activated at concentrations above 1 microM. Interestingly, 4,4' biphenol was a better agonist for ERbeta than for ERalpha. No androgenic activity was detected for any of these compounds. Bisphenol-A, 3-OH phenylphenol, 4-OH phenylphenol and 4,4' biphenol exhibited antiandrogenic activity close to that of 4-tert-octylphenol (IC(50) approximately 5 microM). In whole cell binding assays, these compounds displaced [3H] R1881 with Ki = 10 microM. Although these Ki values seem high in comparison with that of hydroxyflutamide (0.4 microM), one must keep in mind that environmental chemicals can accumulate in adipose tissues for several years. In conclusion, these environmental chemicals may have a negative impact on androgen action during fetal and post-natal life.     

Increased neuronal nitric oxide synthase-derived NO production in the failing human heart

Experimental data suggest that nitric oxide (NO) generated from neuronal NO synthase (nNOS) modulates the myocardial inotropic state. To assess the contribution of NO, derived from endothelial and neuronal isoforms, to the pathophysiology of congestive heart failure in human beings, we compared expression, localisation, and specific activity of NOS isoforms in myocardium from patients with dilated cardiomyopathy with those in controls who had died from head trauma or intracranial bleeds. Diseased hearts had a significant increase in nNOS mRNA and protein expression, and activity associated with the translocation of nNOS to the sarcolemma through interactions with caveolin 3. Enhanced nNOS activity counteracted a decrease in eNOS expression and activity. Our results provide evidence of increased nNOS-derived NO in the failing human heart. Such altered regulation may be important in the pathophysiology of cardiac dysfunction in human congestive heart failure.     

Direct Control of Brown Adipose Tissue Thermogenesis by Central Nervous System Glucagon-Like Peptide-1 Receptor Signaling

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)–deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r^−/− mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.The increasing incidence of type 2 diabetes (T2D) and obesity worldwide has prompted the need for new therapies. Agonism of the receptor for glucagon-like peptide-1 (GLP-1) is currently one of the most successfully and widely used therapies for T2D. GLP-1 is a product of proglucagon that also gives rise to glucagon (GCG) and oxyntomodulin (OXM) (1). Both GLP-1 and its receptor (GLP-1R) are expressed in peripheral tissues and in areas of the central nervous system (CNS) involved in the control of energy balance. Treatment with GLP-1R agonists improves glycemic control and reduces body weight in diabetic humans (2). Studies in animals have demonstrated that CNS–GLP-1R signaling contributes to the body weight–reducing effect of these agonists (3).GCG is produced in the α cells of the pancreatic islets and is involved in the maintenance of euglycemia. Although its exogenous administration induces body weight loss associated with anorexia and increased energy expenditure (4), GCG has been traditionally dismissed as a potential drug target because of its diabetogenic effects. However, recent preclinical data have shown that simultaneous activation of both GLP-1R and GCG receptor (GCGR) leads to greater efficacy in both glycemic control and weight loss than the activation of GLP-1R alone (5,6).OXM can bind to and activate both GLP-1R and GCGR (7), and studies with rodents (8,9) and humans (10) suggest that it may be efficacious in treating obesity and diabetes. OXM regulates feeding, at least in part, through GLP-1R (7,11). There is evidence that OXM action in the CNS reduces body weight by increasing energy expenditure (12). This may involve activation of brown adipose tissue (BAT) metabolism, since intracerebroventricular (ICV) administration of OXM reduces the weight of interscapular BAT (iBAT) pads and increases body temperature in rats (12). The relative contribution of GLP-1R and GCGR to this process has never been investigated; however, it is known that GCG regulates iBAT activity, and this may be, at least in part, centrally mediated (13). The contribution of GLP-1R to the control of energy expenditure, and more specifically to BAT metabolism, remains largely unknown.The sympathetic nervous system (SNS) is essential for control of BAT metabolism by the CNS (14) and is involved in the CNS–GLP-1R control of lipid metabolism in white adipose tissue (WAT) (15). This, in addition to the evidence that GCG may increase BAT thermogenesis through actions in the CNS (13), led us to hypothesize that the action(s) of GCGR and GLP-1R in the brain controls BAT thermogenesis through the SNS. Here, we show that central administration of both GCGR and GLP-1R agonists increased SNS activity to iBAT and induced thermogenesis. Thus, we propose that CNS–GLP-1R may contribute to the control of energy balance by regulating BAT thermogenesis. The existence of functional BAT in adult humans has now been determined (16–18), and effort needs to be directed toward a better understanding of the regulation of this tissue as a target for antiobesity therapeutics. The increase in BAT metabolism described here may contribute to the weight loss induced by GCGR and GLP-1R agonists in both animal models and humans.