Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity.

MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor-linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W).

Oral epithelial reactive atypia/dysplasia: An underestimated true atypia/dysplasia?

Several clinical and histological features, usually associated with chronic inflammation could complexify the diagnosis of oral epithelial dysplasia (OED). These changes in response to inflammatory stimuli, or re-epithelialization events, are described as reactive epithelial atypia or dysplasia (REA/D). Within a REA/D scenario (for example in the edges of chronic traumatic ulcers), the diagnosis of OED could be challenging for oral pathologists due to an unfeasibility to accurate the true nature of that changes.

Back to the Future: Penicillin-Susceptible Staphylococcus aureus.

Background: Widespread penicillin usage rapidly resulted in the emergence of penicillin resistance in Staphylococcus aureus. However, new data suggest that penicillin susceptibility may be in a period of renaissance. The objective of our study was to quantify penicillin resistance in methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia.

Bioinactive ACTH causing glucocorticoid deficiency.

Context: A 4-year-old girl and a 4-month-old boy presented with hypoglycemia, normal electrolytes, low cortisol, and high ACTH. A diagnosis of primary adrenal insufficiency was made and initial treatment was with glucocorticoids and mineralocorticoids. The genes known to cause ACTH resistance were normal.

Comparison of eight commercial enzyme immunoassays for the detection of Clostridium difficile from stool samples and effect of strain type.

We compared the performance of 8 Clostridium difficile enzyme immunoassays to cell cytotoxicity neutralization assay and toxigenic culture. The effect of strain type on assay performance was also examined. There were a total of 71 (14.

Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity.

Heterozygous null mutations in the melanocortin-4 receptor (MC4R) cause early-onset obesity in humans, indicating that metabolic homeostasis is sensitive to quantitative variation in MC4R function. Most of the obesity-causing MC4R mutations functionally characterized so far lead to intracellular retention of receptors by the cell's quality control system. Thus, recovering cell surface expression of mutant MC4Rs could have a beneficial therapeutic value.

Epidemiology and antifungal susceptibility of bloodstream Candida isolates in Quebec: Report on 453 cases between 2003 and 2005.

Background: Between May 2003 and April 2005, a population-based surveillance of Candida bloodstream infections was conducted in Quebec. A total of 453 episodes of candidemia (464 yeast isolates) from 54 participating hospitals were studied.

Results: The annual incidence rate was three per 100,000 population.

Mycobacterium haemophilum epididymal abscess in a renal transplant patient.

Mycobacterium haemophilum is an established cause of cutaneous lesions in immunocompromised hosts. We report the first known case of epididymal abscess, which highlights the need to work up all specimens that are acid-fast bacillus-positive for M. haemophilum from immunocompromised hosts, regardless of body site.

A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.

Background: In March 2003, several hospitals in Quebec, Canada, noted a marked increase in the incidence of Clostridium difficile-associated diarrhea.

Methods: In 2004 we conducted a prospective study at 12 Quebec hospitals to determine the incidence of nosocomial C. difficile-associated diarrhea and its complications and a case-control study to identify risk factors for the disease.

Influence of RANTES, SDF-1 and TGF-beta levels on the value of interleukin-7 as a predictor of virological response in HIV-1-infected patients receiving double boosted protease inhibitor-based therapy.

Objectives: Interleukin-7 (IL-7), RANTES (regulated on activation, normal T cell expressed and secreted), stromal cell-derived factor-1 (SDF-1) and transforming growth factor-beta (TGF-beta) appear to share certain biological properties in vitro and all are involved in HIV-1 disease progression. Our earlier observations indicated that IL-7 levels decrease upon CD4 T-cell recovery and represent a new, independent predictor of virological response. Here, we examine associations among circulating levels of IL-7, RANTES, SDF-1 and TGF-beta in hopes of gaining insight into their contribution to the predictive value of IL-7.

Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients.

Purpose: To assess the virologic and immunologic response to a boosted double-protease inhibitor (PI) regimen of highly pretreated patients infected with HIV-1 and to examine the role of PI resistance and concentration of serum saquinavir.

Method: In an open-label prospective study, lopinavir/ritonavir, saquinavir-sgc, lamivudine, and other nucleoside analogues were offered to highly pretreated patients who had advanced HIV-1 infection and who had failed at least 2 previous highly active antiretroviral therapy regimens including at least 1 nonnucleoside reverse transcriptase inhibitor. The relationship between baseline drug resistance and steady-state saquinavir serum levels and early (week 4) and sustained (week 48) virologic response was documented.

Characterization of a novel binding partner of the melanocortin-4 receptor: attractin-like protein.

The gene dosage effect of the MC4-R (melanocortin 4 receptor) on obesity suggests that regulation of MC4-R expression and function is critically important to the central control of energy homoeostasis. In order to identify putative MC4-R regulatory proteins, we performed a yeast two-hybrid screen of a mouse brain cDNA library using the mouse MC4-R intracellular tail (residues 303-332) as bait. We report here on one positive clone that shares 63% amino acid identity with the C-terminal part of the mouse attractin gene product, a single-transmembrane-domain protein characterized as being required for agouti signalling through the melanocortin 1 receptor.

Interleukin-7 levels may predict virological response in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy.

Objectives: To examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy.

Methods: Thirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy.

Overexpression of the V3 vasopressin receptor in transgenic mice corticotropes leads to increased basal corticosterone.

The vasopressin V3 receptor (V3) is specifically expressed in pituitary corticotropes and mediates the stimulatory effect of vasopressin on adrenocorticotropic hormone (ACTH) release. The V3 gene is overexpressed in corticotrope pituitary tumours compared to normal pituitaries. We hypothesized that V3 overexpression might induce changes in corticotrope function and alter the regulation of the hypothalamic-pituitary-adrenal axis.

Yield of smear, culture and amplification tests from repeated sputum induction for the diagnosis of pulmonary tuberculosis.

Objectives: To assess the yield of repeated sputum induction for the diagnosis of active tuberculosis in patients who do not produce spontaneous sputum, or with smear-negative spontaneous samples.

Methods: Induced sputum was examined with fluorescent microscopy, two amplification methods (PCR Amplicor MTB, and MTD2), and cultured for mycobacteria using liquid (Bactec 12B) and Lowenstein-Jensen media. Bronchoscopy and collection of other specimens were performed at the discretion of the treating physician.

Multicenter comparison of Roche COBAS AMPLICOR MONITOR version 1.5, Organon Teknika NucliSens QT with Extractor, and Bayer Quantiplex version 3.0 for quantification of human immunodeficiency virus type 1 RNA in plasma.

The performance and characteristics of Roche COBAS AMPLICOR HIV-1 MONITOR version 1.5 (CA MONITOR 1.5) UltraSensitive (usCA MONITOR 1.

Accuracy and utility of commercially available amplification and serologic tests for the diagnosis of minimal pulmonary tuberculosis.

Diagnosis of patients with minimal active tuberculosis (TB) is difficult, as there is no single test with high sensitivity and specificity. The yield and clinical utility of a combination of diagnostic tests were prospectively studied among 500 consecutive patients referred for sputum induction for diagnosis of possible active TB. Patients underwent sputum induction, chest X-ray, tuberculin testing, and had blood drawn for serologic testing (Detect-TB test; Biochem ImmunoSystems).

Nucleotide sequence and structural organization of the human vasopressin pituitary receptor (V3) gene.

In the pituitary, vasopressin triggers ACTH release through a specific receptor subtype, termed V3 or V1b. We cloned the V3 cDNA and showed that its expression was almost exclusive to pituitary corticotrophs and some corticotroph tumors. To study the determinants of this tissue specificity, we have now cloned the gene for the human (h) V3 receptor and characterized its structure.

Gene and cDNA cloning and characterization of the mouse V3/V1b pituitary vasopressin receptor.

The gene of the mouse V3/V1b receptor was identified by homology cloning. One of the genomic clones contained the entire coding sequence. The cDNA presented high identity with rat (92%) and human (84%) sequences.

Simple strategy for direct identification of medically important yeast species from positive blood culture vials.

We compared direct inoculation of the Auxacolor yeast identification system from positive blood culture vials to standard identification with the API 20C AUX (API 20C), using 44 prospectively collected clinical specimens and 25 seeded blood culture vials. Direct inoculation of the Auxacolor system was accurate and more rapid than standard identification with the API 20C.

Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours.

Objective: The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA.

Evaluation of the auxacolor system for biochemical identification of medically important yeasts.

We compared the Auxacolor yeast identification system (Sanofi Diagnostics Pasteur) with the API 20C Aux (bioMerieux-Vitek) using 105 isolates of medically important yeasts. The Auxacolor system provided more rapid, accurate results and displayed less interobserver variability than the API 20C Aux.

Detection of renal artery stenosis with Doppler sonography before and after administration of captopril: value of early systolic rise.

Objective: The goal of this study was to assess the value of quantitative and qualitative analysis of the early systolic rise on Doppler waveforms obtained before and after administration of captopril in patients suspected of having renal artery stenosis.

Subjects And Methods: Seventy-one hypertensive patients (135 kidneys) were studied with transrenal Doppler sonography. Ninety-six kidneys were studied again after administration of captopril.