Progressive polyepiphyseal dysplasia with arthropathy: a distinct disorder from idiopathic juvenile arthritis and pseudorheumatoid dysplasia?

Juvenile idiopathic arthritis is an inflammatory disease with various onset-forms which can sometimes be difficult to distinguish from genetic inflammatory/rheumatoid-like osteoarthropathies. In this report, we describe two boys with severe chronic arthralgia, stiffness and swelling of joints, motor weakness and joints contractures evolving despite immunosuppressive treatments and for whom all biological and molecular exams failed to identify a prompt diagnosis. Some findings also overlap with pseudorheumatoid dysplasia but WISP3 gene molecular analysis failed to identify any mutation for both patients. Therefore, we propose that these boys show a clinical entity distinct from the actually known genetic inflammatory/rheumatoid-like osteoarthropathies.     

The evolution of human immunodeficiency virus type-1 (HIV-1) envelope molecular properties and coreceptor use at all stages of infection in an HIV-1 donor-recipient pair

To trace the evolutionary patterns underlying evolution of coreceptor use within a host, we studied an HIV-1 transmission pair involving a donor who exclusively harbored CCR5-using (R5) variants throughout his entire disease course and a recipient who developed CXCR4-using variants. Over time, R5 variants in the donor optimized coreceptor use, which was associated with an increased number of potential N-linked glycosylation sites (PNGS) and elevated V3 charge in the viral envelope. Interestingly, R5 variants that were transmitted to the recipient preserved the viral characteristics of this late stage genotype and phenotype. Following a selective sweep, CXCR4-using variants subsequently emerged in the recipient coinciding with a further increase in the number of PNGS and V3 charge in the envelope of R5 viruses.Although described in a single transmission pair, the transmission and subsequent persistence of R5 variants with late stage characteristics demonstrate the potential for coreceptor use adaptation at the population level.     

Adaptation of methotrexate determination in serum with Unicel DxC600(®)

High-dose methotrexate treatment requires pharmacological monitoring in order to tailor administration of folinic acid to reduce side effects. The aim of the study was to validate the adaptation of the EMIT reagent on the l'Unicel DxC 600? Beckman Coulter. The establishment of two assays was necessary to obtain a quantification limit as low as possible (0.05 μmol/L). The linearity of the adapted methods extends from 0.05 to 0.25 μmol/L on the one hand, and from 0.25 to 1 μmol/L on the other hand. For each method, fidelity and accuracy were studied and the limits of detection and quantification were quantified. The correlation with the FPIA method was performed on the Abbott TDX(?). The results of all tests are satisfactory with coefficients of variation (CV) of repeatability and reproducibility of less than 6%. However the daily assays are heavy as 66% of blood samples require at least two dosages and 30% a manual dilution.     

Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-?, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.     

Combination of single nucleotide polymorphism and variable-number tandem repeats for genotyping a homogenous population of Mycobacterium tuberculosis Beijing strains in China

The standard 15- and 24-locus variable-number tandem repeat (VNTR) genotyping methods have demonstrated adequate discriminatory power and a small homoplasy effect for tracing tuberculosis (TB) transmission and predicting Mycobacterium tuberculosis lineages in European and North American countries. However, its validity for the definition of transmission in homogenous M. tuberculosis populations in settings with high TB burdens has been questioned. Here, we genotyped a population-based collection of 191 Beijing strains based on standard 15-locus VNTR (VNTR-15) and 8 single nucleotide polymorphisms (SNPs) in Shanghai, China. Limited discriminatory power and high rates of VNTR homoplasy were observed in the homogenous population of evolutionarily "modern" Beijing strains. Additional typing of three hypervariable loci (VNTR3820, VNTR4120, and VNTR3232) was performed for VNTR-15-based clusters. High variations of hypervariable alleles were observed in clusters with inconsistent SNP sublineages. We concluded that SNPs and hypervariable VNTR loci are helpful to enhance the discriminatory power and decrease the VNTR homoplasy effect for defining clusters. We recommend the combination of standard VNTR-15 and SNPs as first-line typing methods and the hypervariable loci for second-line typing of clustered strains for molecular epidemiology studies of homogenous M. tuberculosis populations.     

MicroRNAs in multiple sclerosis and experimental autoimmune encephalomyelitis

MicroRNA (miRNA) are small non-coding RNA molecules about 21-25 nucleotides long. They control gene regulation by translational repression and cleavage. Several studies have shown that many miRNA are associated with the etiology of different diseases. Recent developments in diverse miRNA profiling platforms like microarray and quantitative real-time PCR may enable the identification of specific miRNA as novel diagnostic and predictive markers for various diseases. MiRNAs could even be used as therapeutic drug targets. Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system. Dysregulated immune system processes result in demyelination of neurons and consequently, electrical impulses that travel along the nerves are disrupted resulting in the impairment of organs. In the past three years, there has been an increased interest in establishing miRNA-based biomarkers for MS. So far, there are six studies on miRNA expression in MS patients in which first miRNAs were discovered as potential disease markers. For instance, one study showed that blood levels of miR-145 can discriminate MS patients from healthy controls, and another showed that active lesions in the brain are characterized by a strong up-regulation of miR-155. Studies on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, further support the significance of miRNA as e.g. mice with miR-155 deletion are highly resistant to EAE. Such investigations help to understand the molecular processes involved in the disease. The identification of miRNA markers that are associated with type of MS, individual disease activity or clinical progression under treatment may open new avenues for early diagnosis and optimized therapy of MS.     

Activity-related dyspnea is not modified by psychological status in people with COPD, interstitial lung disease or obesity

Sensory (physiological) and affective (psychological) dimensions of dyspnea have been described but the usefulness of measuring psychological status in addition to ventilatory capacity (spirometry, lung volumes) in the assessment of exertional dyspnea remains controversial. We hypothesized that activity-related dyspnea would not be modified by psychological status. Principal component analysis (PCA) was used to reduce the number of parameters (psychological or functional) to fewer independent dimensions in 328 patients with altered ventilatory capacity: severe obesity (BMI ≥ 35, n = 122), COPD (n = 128) or interstitial lung disease (n = 78). PCA demonstrated that psychological status (Hospital Anxiety-Depression, Fatigue Impact scales) and dyspnea (Medical Research Council [MRC] scale) were independent dimensions. Ventilatory capacity was described by three main dimensions by PCA related to airways, volumes, and their combination (specific airway resistance, FEV(1)/FVC), which were weakly correlated with dyspnea. In conclusion, in patients with COPD, interstitial lung disease or severe obesity, psychological status does not modify activity-related dyspnea rating as evaluated by the MRC scale.     

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.