[Andropause and testosterone deficiency: how to treat in 2012?]. / Andropause et carence en testostérone: le point en 2012.

Age-related hypogonadism is a clinical syndrome defined as a low serum testosterone level (< 11 nmol/l) with precise clinical symptoms: diminished libido, erectile dysfunction, and loss of morning erection. Testosterone supplementation has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life. In spite of an inverse relationship between testosterone levels and various cardiovascular risk factors (obesity, insulin resistance and type 2 diabetes mellitus), there is no evidence of a positive effect of testosterone replacement therapy towards these risk factors. So far, the long-term safety of testosterone replacement therapy has not been established. Evidence has been found that testosterone replacement therapy has a causative and worsening role in prostate cancer urging not to treat patients with a history of prostate cancer. Finally, patients with high cardiovascular risk, including those with congestive heart failure, should not be treated.

[Management of type 2 diabetes in 2010. Insulins and injectable drugs: role of the general practitioner]. / Prise en charge du diabète de type 2 en 2010. Insulines et injectables: le médecin généraliste a sa place.

Type 2 diabetes mellitus is a complex metabolic disease inducing an important rise of the cardiometabolic risk. Medical care must therefore be targeted to multiple risk factor reduction and address all modifiable risk factors (high LDL-cholesterol, low HDL, hypertension, hyperglycaemia, tobacco), as well as sedentarity and obesity. Glycaemic control aimed to achieve HbA1C < 7% is associated with a reduction in microvascular and macrovascular complications. Unfortunately, many patients do not reach these therapeutic targets. This progressive disease correlates with an inexorable destruction of the beta cells, therefore the therapeutic options must regularly be upgraded. The use of injectable drugs (GLP-1 agonists and insulins) are part of the general practitioner's therapeutic arsenal.

Hyperglycemia induces attention and gait deficits in diabetic mellitus patients.

AIMS: Patients with diabetes mellitus experience a large number of falls and bone fractures that are not related solely to complications of the disease. The purpose of our study was to determine whether transient hyperglycemia affects attentional functions and gait. METHODS: This was a case-control study. We asked 17 patients with type 1 or type 2 diabetes mellitus to perform three visual tests and one visual and auditory attention test (Phasic Alert A1-4 and A2-3, Go/No Go, Intermodal Comparison). Mean response time (ms) and total number of errors were assessed. Ten of the patients also performed a tandem gait test consisting of three steps. The total distance travelled (TDT, in mm) by the center of pressure was measured with a pressure-sensitive calibrated platform. Transient hyperglycemia was defined as blood glucose level greater than 13, 8 mmol/L at the time of the test. These same patients were retested 1-3 days later at a blood glucose level at least 5, 5 mmol/L lower than the initial values (T24-72h). Nineteen patients with diabetes mellitus were matched with the original participants and performed the same test under normoglycemic conditions. RESULTS: During transient hyperglycemia, the mean response time (ms) and the TDT were significantly longer. The mean response time for the four tests increased by 53, 5 ms (P < 0.001). There was no increase in the number of errors. The TDT of the center of pressure increased significantly by 102 mm (P < 0.001). CONCLUSIONS: Transient hyperglycemia alters attention and gait in patients with diabetes mellitus.

Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.

Prevalence, aetiologies and significance of clubbing in a department of general internal medicine.

BACKGROUND: Clubbing remains an amazing clinical sign. Its strong association with serious disease is still a clinical enigma. Moreover, the significance of diagnosing clubbing is not well established. The aim of our study was to evaluate prevalence, aetiology and clinical significance of clubbing in a department of general internal medicine. PATIENTS AND METHODS: During one year (1511 admissions), all patients with digital clubbing assessed by determining ratio of the distal phalangeal depth (DPD) to the interphalangeal depth (IPD) and with the presence of Swamroth sign were included. Fifteen patients were diagnosed with clubbing (10 males and 5 females). They underwent complete physical examination, pulmonary CT-scan, bone scintigraphy, blood gas analysis and were compared with 86 matched controls. RESULTS: Aetiology were renal cell carcinoma, pulmonary arteriovenous malformation, AIDS, inflammatory pseudo-tumour of the lung, adenocarcinoma of unknown origin in one case and in one case, Pet-scan suspected neoplasia but histology was not obtained. In 9 cases, no aetiology was found. Bone scan was normal in 14 cases and revealed periostitis in one case (idiopathic clubbing). Compared to control group, there was no difference in blood gas analysis but emphysema was more often present in patients with clubbing (p<0.01). No patient without aetiology developed cancer in the one year follow-up. CONCLUSION: Clubbing is present in 1% of admission in a department of general internal medicine and is associated in nearly 40% with serious disease. In 60% of cases, aetiology is not identified but follow-up do not disclosed cancer.

Spontaneous remission in a patient with therapy-related myelodysplastic syndrome (t-MDS) with monosomy 7.

We describe a case of spontaneously reversible refractory anaemia, a subtype of myelodysplastic syndrome (MDS), with monosomy 7 secondary to chronic treatment with azathioprine (AZA) in a young renal transplant recipient. AZA was stopped after that conventional cytogenetics and fluorescence in situ hybridization (FISH) had demonstrated the existence of a monosomy 7 clone, 4 months later, haematological values had considerably improved and the karyotypic examination as well as the FISH analysis were normal. The spontaneous remission of this MDS with monosomy 7, which is usually associated with a particularly poor prognosis, could be due to the recovery of a better immunosurveillance following the withdrawal of AZA.

HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway.

It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)

Palmitoylation of CCR5 is critical for receptor trafficking and efficient activation of intracellular signaling pathways.

CCR5 is a CC chemokine receptor expressed on memory lymphocytes, macrophages, and dendritic cells and also constitutes the main coreceptor for macrophage-tropic (or R5) strains of human immunodeficiency viruses. In the present study, we investigated whether CCR5 was palmitoylated in its carboxyl-terminal domain by generating alanine substitution mutants for the three cysteine residues present in this region, individually or in combination. We found that wild-type CCR5 was palmitoylated, but a mutant lacking all three Cys residues was not. Through the use of green fluorescent fusion proteins and immunofluorescence studies, we found that the absence of receptor palmitoylation resulted in sequestration of CCR5 in intracellular biosynthetic compartments. By using the fluorescence recovery after photobleaching technique, we showed that the non-palmitoylated mutant had impaired diffusion properties within the endoplasmic reticulum. We next studied the ability of the mutants to bind and signal in response to chemokines. Chemokines binding and activation of G(i)-mediated signaling pathways, such as calcium mobilization and inhibition of adenylate cyclase, were not affected. However, the duration of the functional response, as measured by a microphysiometer, and the ability to increase [(35)S]guanosine 5'-3-O-(thio)triphosphate binding to membranes were severely affected for the non-palmitoylated mutant. The ability of RANTES (regulated on activation normal T cell expressed and secreted) and aminooxypentane-RANTES to promote CCR5 endocytosis was not altered by cysteine replacements. Finally, we found that the absence of receptor palmitoylation reduced the human immunodeficiency viruses coreceptor function of CCR5, but this effect was secondary to the reduction in surface expression. In conclusion, we found that palmitoylated cysteines play an important role in the intracellular trafficking of CCR5 and are likely necessary for efficient coupling of the receptor to part of its repertoire of signaling cascades.