The paradoxes of Mycobacterium tuberculosis molecular evolution and consequences for the inference of tuberculosis emergence date.

The date of Mycobacterium tuberculosis complex emergence has been the subject of long debates. New studies joining archaeological efforts with sequencing methods raise high hopes for solving whether this emergence is closer to 70,000 or to 6000 years before present. Inferring the date of emergence of this pathogen based on sequence data requires a molecular clock. Several clocks inferred from different types of loci and/or different samples, using both sound reasoning and reliable data, are actually very different, which we refer to as the paradoxes of M. tuberculosis molecular evolution. After having presented these paradoxes, we will remind the limits of the molecular clocks used in the different studies such as the assumption of homogeneous substitution rate. We will then review recent results that shed new light on the characteristics of M. tuberculosis molecular evolution: traces of diverse selection pressures, the impact of host dynamics, etc. We provide some ideas on what to do next to get nearer to a reliable dating of Mycobacterium tuberculosis complex emergence. Among them, the collection of additional remains from ancient tuberculosis seems still essential.

Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.

BACKGROUND AND PURPOSE: Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter-2 (GlyT2), there are also some reports of toxicity and their development was discontinued. EXPERIMENTAL APPROACH: In order to clarify the possibility of targeting GlyT2 for the treatment of pain, we have used an integrated approach comprising in vitro pharmacology, selectivity, bioavailability, in vivo efficacy and safety assessment to analyse the properties and efficacy of ALX-1393 and Org-25543, the two published GlyT2 inhibitors from which in vivo data are available. KEY RESULTS: We report that these compounds have a different set of undesirable properties that limit their usefulness as pharmacological tools. Importantly, we discover that inhibitors of GlyT2 can exert an apparent reversible or irreversible inhibition of the transporter and describe a new class of reversible GlyT2 inhibitors that preserves efficacy while avoiding acute toxicity. CONCLUSIONS AND IMPLICATIONS: Our pharmacological comparison of two closely related GlyT2 inhibitors with different modes of inhibition provides important insights into their safety and efficacy profiles, uncovering that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. These findings shed light into the drawbacks associated with the early GlyT2 inhibitors and describe a new mechanism that might serve as the starting point for new drug development.

Clinical presentation of leptospirosis: a retrospective study of 34 patients admitted to a single institution in metropolitan France.

Leptospirosis has a highly variable clinical presentation, which may be related to different infecting serovars, host factors, or a combination of these. This study investigated retrospectively 34 consecutive patients with serologically confirmed leptospirosis admitted during the period 1992-2002. On admission, the most frequent symptoms were fever (100%), headache (75%), myalgia (55%), arthralgia (45%) and vomiting (39%). Pertinent laboratory findings included lymphopenia (85%), thrombocytopenia (75%), elevated liver enzymes (87%) and renal abnormalities (proteinuria, 77%; haematuria, 58%; elevated serum creatinine, 53%). The study confirmed the variable clinical and biological symptoms of leptospirosis, and indicated that lymphopenia is a common feature of leptospirosis cases.

[Antibody avidity: use for the diagnosis of HIV early infection]. / Avidité des anticorps: application au diagnostic d'infection récente à VIH1.

Determination of IgG avidity is useful to distinguish primary infection from reactivation or reinfection in viral, parasitic or bacterial infections. For diagnosis of HIV type 1 primary infection, the detection of IgM antibodies is often useless since they are also found in chronic infection. The usual serology (Elisa, western-blot, p24 antigen) may present no interest if done too late (more than 2 or 3 months after infection). Therefore, we have developed a test to determine the avidity of anti-HIV1 antibodies, using 1 M guanidine as denaturing agent. We have adapted the measurement of avidity to the Axsym automatic system for a routine use. Indeed, since requests for avidity determinations are sporadic, the use of microplates is not convenient. Using this assay, we found a low avidity (less than 50%) in immunocompetent and recent infected patients (less than 6 months), compared to old infected patients (more than 12 months) who had high avidity (80 to 100%). However, early treated patients (in the 6 months after contamination) had also low avidities but with a slower development of antibody maturation (8 to 27 months versus 2 to 8 months in non treated patients). To conclude, the determination of the anti-HIV1 avidity, according to the proper procedures explained here (notion of treatment and/or serious immunodepression), may help the physician to date the infection in each new infected patient who might benefit from an early treatment.

[Hepatobiliary actinomycosis. Apropos of 3 cases with pseudocancerous aspects]. / Actinomycose hépato-biliaire. A propos de 3 cas d'allure pseudo-cancéreuse.

Three cases of hepatobiliary actinomycosis are reported. In all cases, carcinoma was initially suspected. One patient underwent cytoaspiration under sonographic guidance. Diagnosis was obtained by autopsy in one case, laparotomy and biopsy in the other cases. Confusion with cancer is frequent in actinomycosis, especially in hepatic lesions.