A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a genetically heterogenous disorder with 41 genes so far identified. Among these genes, ESRRB whose mutations are responsible for DFNB35 hearing loss in Pakistani and Turkish families. This gene encodes the estrogen-related receptor beta. In this study, we report a novel mutation (p.Y305H) in the ESRRB gene in a Tunisian family with ARNSHL. This mutation was not detected in 100 healthy individuals. Molecular modeling showed that the p.Y305H mutation is likely to alter the conformation of the ligand binding-site by destabilizing the coactivator binding pocket. Interestingly, this ligand-binding domain of the ESRRB protein has been affected in 5 out of 6 mutations causing DFNB35 hearing loss. Using linkage and DHPLC analysis, no more mutations were detected in the ESRRB gene in other 127 Tunisian families with ARNSHL indicating that DFNB35 is most likely to be a rare type of ARNSHL in the Tunisian population.     

Validation of inertial measurement units with an optoelectronic system for whole-body motion analysis

The potential of inertial measurement units (IMUs) for ergonomics applications appears promising. However, previous IMUs validation studies have been incomplete regarding aspects of joints analysed, complexity of movements and duration of trials. The objective was to determine the technological error and biomechanical model differences between IMUs and an optoelectronic system and evaluate the effect of task complexity and duration. Whole-body kinematics from 12 participants was recorded simultaneously with a full-body Xsens system where an Optotrak cluster was fixed on every IMU. Short functional movements and long manual material handling tasks were performed and joint angles were compared between the two systems. The differences attributed to the biomechanical model showed significantly greater (P ≤ .001) RMSE than the technological error. RMSE was systematically higher (P ≤ .001) for the long complex task with a mean on all joints of 2.8° compared to 1.2° during short functional movements. Definition of local coordinate systems based on anatomical landmarks or single posture was the most influent difference between the two systems. Additionally, IMUs accuracy was affected by the complexity and duration of the tasks. Nevertheless, technological error remained under 5° RMSE during handling tasks, which shows potential to track workers during their daily labour.     

P40phox associates with the neutrophil Triton X-100-insoluble cytoskeletal fraction and PMA-activated membrane skeleton: a comparative study with P67phox and P47phox

NADPH oxidase is an O2*- -generating enzyme found in phagocytes such as neutrophils. It is composed of a membrane-bound cytochrome b, the cytosolic proteins p67phox, p47phox, p40phox, and the G-protein p21rac. The system is dormant in resting cells but acquires catalytic activity on exposure to appropriate stimuli. Cytochrome b, p67phox, p47phox, and rac2 associate with the cytoskeleton and membrane skeleton of activated neutrophils. It is not known whether p40phox associates with the cytoskeleton. The purpose of this study was to analyze the subcellular distribution of p40phox. When resting neutrophils were lysed in Triton X-100 or octyl glucoside buffer and separated into detergent-soluble and detergent-insoluble fractions, p40phox and p67phox were mainly associated with the detergent-insoluble fraction (defined as the cytoskeleton), whereas p47phox was mainly found in the soluble fraction. Neutrophil activation by phorbol myristate acetate (PMA) induced p47phox translocation to the cytoskeleton but did not affect the distribution of p40phox or p67phox. Using immunofluorescence confocal microscopy, we found that p40phox colocalized with filamentous actin. In neutrophils from a p67phox-deficient patient with detectable p40phox, p40phox associated with the cytoskeleton only after activation by PMA. A complex containing the three proteins was isolated from the cytoskeleton of activated neutrophils. When activated membranes were treated with Triton X-100 buffer, p40phox, p47phox, and p67phox were found in the membrane skeleton enriched in NADPH-oxidase activity; some p40phox and p47phox was found in the soluble membrane fraction, but no p67phox was detected. These findings show that p40phox, like p67phox and p47phox, binds to the cytoskeleton and membrane skeleton. In addition, p40phox can dissociate from p67phox in activated membranes.     

Elevated cord serum IgE increases the risk of aeroallergen sensitization without increasing respiratory allergic symptoms in early childhood

BACKGROUND: Increasing prevalence of allergic disorders has focused attention on primary prevention. There is a need to improve the accuracy of early-life predictors of atopy so that the at-risk population can be accurately defined and preventive measures instituted. OBJECTIVE: The predictive capacity of elevated cord IgE, with or without family history of atopy, to allergic symptoms and skin prick test (SPT) sensitization is evaluated in a birth cohort followed up prospectively for 4 years. METHODS: A birth cohort of 1456 consecutively born children was recruited in 1989. Data were collected on family history of atopy and cord serum total IgE (cord IgE) was measured. Of these, 1218 children were seen in the clinic at 4 years to determine the development of symptoms and signs of allergic disease and 981 were skin tested to a range of common food and aeroallergens. RESULTS: Of 1218 children reviewed at age 4 years, 218 (17.8%) had symptoms of respiratory allergy and, of those skin tested (n = 981), 192 (19.6%) reacted positively. Twice as many children with elevated cord IgE (>/= 0.5 kU/L) at birth became sensitized to aeroallergens by age 4 years (34.8% vs 17.3%, P < 0. 001). Positive predictive value (PPV) of elevated cord IgE for the development of aeroallergen sensitization was better than that of family history of atopy (34.8 vs 22.6%). Combining paternal atopy with elevated cord IgE substantially increased the predictive capacity (PPV 77.8%). Cord IgE levels did not correlate with clinical asthma or rhinitis at age 4 years and PPV for allergic respiratory symptoms remained poor at all cutoffs. CONCLUSION: Cord IgE is better than family history for predicting atopy as defined by allergen sensitization and this predictive value can be further increased by combining cord IgE with paternal atopy.     

Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study

Objective  This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients.
Methods  Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled.
Results  Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant ( P =  0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71% vs. 27%), hepatobiliary (41% vs. 8%) and respiratory (5% vs. 28%).
Conclusion  This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.     

Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia

The purpose of the present study is to investigate the frequency of HLA-B27 and its alleles in reactive arthritis (ReA) and in ankylosing spondylitis (AS) in Tunisia. HLA-B27 alleles were typed by PCR amplification with sequence-specific primers. We studied 17 patients with ReA associated with urethritis or with gastrointestinal infection; 42 HLA-B27-positive patients with AS and 100 healthy controls. Eleven ReA patients (67.7%) were HLA-B27 positive. There was an increased frequencies of HLA-B27 (P = 7.76 × 10⁻¹², OR = 59.30) and a moderate increase of HLA-B51 (P = 0.015; OR = 4.91) alleles in ReA patients when compared with healthy controls. Four B27 subtypes were identified: B*2702, 05, 09 and B*2712. The distribution of these alleles in the ReA patients was 37.5% for B*2702 and B*2705. Only these two subtypes were detected in 18 (42.8%) and 24 (57.1%), respectively, of the AS patients. B*2709 and B*2712 were relatively rare in ReA patients and were identified in one case each. Our results showed a restricted number of HLA-B27 subtypes associated with ReA and AS. B*2702 and 2705 were common in ReA and AS patients.     

Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size

OBJECTIVES: We tested the hypothesis that the reperfusion syndrome (RS), defined as an additional elevation of the ST segment upon reperfusion, may be a marker of microcirculatory reperfusion injury during acute myocardial infarction (AMI). BACKGROUND: The pathophysiology of the RS is unknown, and its prognostic implications are controversial. METHODS: Twenty-one patients with an anterior AMI treated < or =12 h after onset by primary coronary angioplasty (PTCA) were studied. Coronary velocity reserve (CVR), an index of microcirculatory function, was measured using a Doppler guidewire. Left ventricular (LV) ejection fraction, infarct size (percent defect) and LV end-systolic volume index (LVESVi) were evaluated by radionuclide ventriculography, 201T1 single-photon emission computed tomography and contrast ventriculography, respectively. RESULTS: Baseline ST elevation and pain-to-TIMI 3 time were similar in patients with and without RS. Patients with RS (10/21) had a lower post-PTCA CVR than patients without RS (median [95% confidence interval]: 1.2 [1-1.3] vs. 1.6 [1.5-1.7], p < 0.005). Even though predischarge CVR was similar in the two groups, infarct size at six weeks (26 [21 to 37] vs. 14 [10-17]% 201T1 defect, p = 0.001) and predischarge LVESVi (45% [40 to 52] vs. 30% [29 to 38] mL/m2, p = 0.001) were larger, and LV ejection fraction at six weeks (40% [37 to 46] vs. 55% [50 to 60], p = 0.004) was lower in patients with RS than in patients without RS. CONCLUSIONS: Patients with RS during primary PTCA for an anterior AMI have a transiently lower CVR than patients without RS, but sustained LV dysfunction and larger infarct size, suggesting that RS is a marker of microcirculatory reperfusion injury.     

Relevant factors in mitral valve reconstructive surgery. Report of 150 cases

150 patients had mitral valve repair for mitral valve incompetence. There were 57 males and 93 females with a mean age of 22 years, 39% were less than 15 years of age. 60% of the patients were in Class II NYHA and 40% in Class III and IV. According to Carpentier's classification, isolated type I was present in 18 patients (12%), type II in 98 patients (64%) and type III in 34 cases (24%). Mitral repair included correction of valve prolapse, valvular enlargement with pericardial patch and annuloplasty with semi-rigid ring in 128 cases and PTFE patch along the posterior leaflet in 12 cases. The perioperative mortality rate was 2.6% (4 patients). All patients had early post-operative echocardiography. According to this, mitral regurgitation was absent or tiny in 135 patients (92%), grade II in 10 cases and grade III in 2 cases. It was moderate or important in twelve patients (8%). In the late post-operative period, three patients were lost to follow-up. All the others patients were reoperated upon for mitral dysfunction in a mean time of 37 months. The reason for reoperation was in the majority of the cases the recurrence of mitral regurgitation related to increase of valvular and sub valvular disease. The late mortality rate is 7% (10 patients). Out of 126 reviewed survivors on the long run, 71 patients (56%) are asymptomatic in class I, 53 patients (42%) in class II and 2 patients in class III NYHA. Mitral valvuloplasty is the preferred procedure in mitral insufficiency surgical management. It is associated to a low early mortality and morbidity rate. Despite the need for reoperation in about 10% of the cases in the long follow-up, mitral repair offers a good quality of life without anticoagulant treatment.     

Approaches to the reversal of malnutrition,inflammation, and atherosclerosis in end-stage renal disease

Uremic malnutrition and chronic inflammation are important comorbid conditions that predict poor clinical outcome in end-stage renal disease (ESRD) patients. These conditions are also closely associated with cardiovascular disease, the major cause of death in ESRD patients. A pathophysiologic link between malnutrition, inflammation, and atherosclerosis has been proposed in this patient population. Indeed, multiple lines of evidence suggest that chronic inflammation can predispose ESRD patients to a catabolic and atherogenic state. Malnutrition can also result from chronic inflammation and can accelerate the progression of cardiovascular disease. Whereas a single common etiology has not been identified in this complex process, nutritional and anti-inflammatory interventions provide potential treatment options to counter the high mortality and morbidity in ESRD patients.