Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

AIMS: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM. METHODS AND RESULTS: A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04). CONCLUSION: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.     

Regional citrate anticoagulation during hemodialysis: a simplified procedure using Duocart biofiltration

BACKGROUND: Regional citrate anticoagulation during hemodialysis is promising, but its clinical implementation is routinely cumbersome because a continuous adjustment of calcium infusion at the dialyzer outlet is needed. Duocart biofiltration (DCB) is a new hemodialysis method using a calcium and magnesium-free dialysate containing only sodium chloride and bicarbonate combined with the infusion into the venous line of a solution containing the ionic complement (K, Ca, Mg) and glucose. Since the dialysate is calcium- and magnesium-free and infusion rate of the solution containing calcium is automatically determined by the dialysis delivery system according to the on-line measured value of ionic dialysance, DCB seems a technique especially suitable for citrate anticoagulation procedure. METHODS: Thirty DCB sessions were performed in 10 patients with increased risk of bleeding. A commercially available mixture of trisodium citrate, citric acid and glucose was infused into the arterial line at a rate equal to 3% of dialyzer blood flow. The ionic complement (K: 48 mM, Ca: 42 mM, Mg: 14 mM, glucose: 110 mM) was infused at a rate equal to 1/24 ionic dialysance value automatically determined each 15 min by the dialysis monitor. DCB sessions were compared to 21 conventional bicarbonate hemodialysis (BHD) sessions with low-molecular-weight heparin anticoagulation. RESULTS: Whole blood activated clotting time (WBACT) measured in the venous line (before infusion of ionic complement) was 200% of the WBACT value in the arterial line. Clotting and citrate-related adverse events were not observed. Postdialysis compression time of the arteriovenous access is significantly (p<0.001) shorter after DCB sessions (3.9+/-1.1 min) compared with BHD sessions (8.7+/-4.6 min). CONCLUSION: Citrate anticoagulation during Duocart biofiltration is effective, safe and suitable for routine use because calcium infusion rate is automatically adjusted without the need of monitoring degree of anticoagulation and level of ionized calcium.     

Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes

The progression of immune responses is generally associated with an increase in the overall avidity of antigen-specific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8 T cell population that targets residues 206-214 of the beta cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206-214)) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP(206-214)-specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP(206-214)-specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate- or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill beta cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery.     

A farnesyltransferase inhibitor attenuates cardiac myocyte hypertrophy and gene expression

The overexpression of either oncogenic ras or calmodulin in cardiac myocytes can elicit a hypertrophic response, albeit their recruitment by physiologically relevant stimuli remains unresolved. The present study utilized a pharmacological approach to examine the role of ras and calmodulin in norepinephrine- and endothelin-1-stimulated hypertrophy of neonatal rat cardiac myocytes. The pretreatment of cardiac myocytes with the farnesyltransferase inhibitor BMS-191563 (25 microM) increased the level of unfarnesylated ras in the cytosolic fraction, and caused a concomitant 42 +/- 2% decrease in immunodetectable farnesylated ras in the particulate fraction. In parallel, BMS-191563 pretreatment inhibited norepinephrine-mediated 3H-leucine uptake (80 +/- 10% decrease: n = 6; P<0.01), whereas a significant but less pronounced effect on the endothelin-1 response (46 +/- 6% decrease: n = 6; P<0.05) was observed. The calmodulin inhibitor W7 caused a 50 +/- 10% decrease (n = 8; P<0.05) of norepinephrine stimulated protein synthesis, whereas the endothelin-1 response was unaffected. Consistent with the recruitment of ras, BMS-191563 pretreatment attenuated norepinephrine and endothelin-1-stimulated extracellular signal-regulated kinase (ERK) activity. However, PD098059-mediated inhibition of MEK-dependent stimulation of ERK did not alter the hypertrophic response of either agonist. At the molecular level, the pretreatment with either BMS-191563 or W7 attenuated the norepinephrine-mediated increase of prepro-ANP and -BNP mRNA. Likewise, BMS-191563 caused a significant decrease of endothelin-1-mediated expression of the natriuretic peptide mRNAs, but to a lesser extent, as compared to norepinephrine. Thus, the present study has shown the treatment of neonatal rat cardiac myocytes with a farnesyltransferase inhibitor can attenuate the hypertrophic phenotype in response to physiologically relevant stimuli, thereby supporting a role of the small GTP-binding protein ras. Moreover, these data further suggest alternative ras-independent signaling pathways are also implicated in the hypertrophic response, albeit, there appears to exist a stimulus-specific heterogeneity in their recruitment.     

Recurrent supraventricular tachycardias prevalence and pathophysiology after RF ablation: A 5-year registry

Background

The introduction of technique of radiofrequency (RF) catheter ablation in 1990, has revolutionized management of different types of paroxysmal supraventricular tachycardia (PSVT). In spite of higher success rate, there were reported recurrences among different types of SVT. The aim of this study was to report the efficacy of RF ablation, its complications, recurrence rate and its predictors.

Methods

The material of this study (our 3rd registry) included patients who underwent electrophysiological study (EPS) and radiofrequency ablation of their supraventricular tachycardia in the past 5 years, starting from January 2002 to January 2007 at The Critical Care Medicine Department, Cairo University.

Results

Out of 400 pts studied, 381 (95%) had been subjected to radiofrequency ablation (RF) ablation while the remaining 19 pts (4.7%) refused ablation for fear of possible complications. Out of the 381 pts, 366 (96%) had their target tachycardia successfully terminated, from them 26 pts (7%) experienced recurrence after having successful RF ablation. Nine pts (34.6%) of total recurrence was reported in pts with AVNRT, 7 pts (26.9%) of total recurrence was reported in pts with AVRT utilizing septal accessory pathway (Rt AS and /or Rt PS AP), 4 pts (15.4%) was reported in pts with double AP, 2 pts (7.7%) of total recurrence was reported in pts with AFl, one pt (3.8%) of total recurrence was reported in cases of AT. Redo ablation have been carried out successfully in 25 pts (96.2%), and one pt (3.8%) refused ablation for fear of possible complications.

Conclusions

Although electrophysiological study and RF ablation eliminated different types of SVT. However, there may be increased incidence of recurrence among pts with AVNRT and AVRT utilizing concealed septal AP and multiple APs secondary to the complexity of AVN physiology, the critical location of septal AP, the clinical expertise, and poor electrophysiological criteria for good procedural success.     

Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for spontaneous bacterial peritonitis in cirrhotic ascites: a prospective randomized open-label comparative multicenter study

Background and aim

Primary prevention of spontaneous bacterial peritonitis (SBP) is an important strategy to reduce morbidity and mortality in cirrhotic patients with ascites. Efficacy and safety of alternating rifaximin and norfloxacin as primary prophylaxis is questionable.

Methods

Three hundred thirty-four cirrhotic patients with high SAAG (≥1.1) ascites, protein level in ascitic fluid less than 1.5 g/dL with advanced liver disease (Child-Pugh score >9 points with serum bilirubin level >3 mg/dL) or renal impairment (serum creatinine level >1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or serum sodium level <130 mEq/L) were included in an open-label, randomized study aimed at comparing alternating use of norfloxacin and rifaximin vs. norfloxacin or rifaximin alone as primary prophylaxis for SBP. Both intention-to-treat and per-protocol efficacy analyses were done after 6 months of treatment by assessment of ascitic fluid neutrophil count. Safety analysis was done for all intention-to-treat populations.

Results

Alternating norfloxacin and rifaximin showed superior prophylaxis by intention-to-treat (74.7 vs. 56.4 % vs. 68.3 %, p < 0.048). Pairwise analysis showed that alternating regimen had lower probability to develop SBP when compared to a norfloxacin-based regimen in intention-to-treat (p = 0.016) and per protocol analysis (p = 0.039). There was no difference among the studied groups regarding the incidence and severity of adverse events reported.

Conclusions

Alternating norfloxacin- and rifaximin-based primary prophylaxis for SBP showed higher efficacy with the same safety profile when compared with monotherapy of norfloxacin.

     

Antibiotic resistance determinants of multidrug-resistant Acinetobacter baumannii clinical isolates in Algeria

Antibiotic susceptibility testing was performed on 71 Acinetobacter baumannii clinical isolates, and presence of antibiotic resistance genes was screened for by PCR amplification and sequencing. Resistance rates were very high for aminoglycosides (22–80%), fluoroquinolones (>90%), and cephalosporins (>90%) but remained low for rifampin (2.8%) or null for colistin. Antibiotic resistance encoding genes detected were as follows: bla_TEM-128 gene (74.6%), aph(3′)-VI (50.7 %), aadA (63.4%), ant(2″)-I (14.1%), aac(3)-Ia (91.1%), aac(6′)-Ib (4.2%), mutation Ser83Leu in gyrA (94.4%), double mutations Ser83Leu and Ser80Leu (or Ser84Leu) in gyrA and parC (69.0%), and mutation I581N in RRDR of the rpoB gene.     

Maxillary expansion and molar rotation using the Nitanium Molar Rotator

In a presentation illustrated by clinical cases, the author describes the Nitanium Molar Rotator (NMR), its indications and its use, its advantages and its disadvantages. He also shows how to incorporate this super flexible arch wire with excellent memory and tight fitting bracket insertion in lateral sectors in order to maximize expansion of the maxilla. With this device orthodontists can create or modify the tipping of molars as they are being distalized.     

Plasmid-mediated TEM-3 extended-spectrum beta-lactamase production in Salmonella typhimurium in Casablanca.

Isolates of extended-spectrum beta-lactamase (ESBL)-producing Salmonella typhimurium were recovered from children admitted to the IbnRochd University Hospital of Casablanca in 1994. These isolates produced TEM-3 as shown by PCR, isoelectric focusing and sequencing. Production of TEM-3 and resistance to gentamicin were encoded by a 10 kb plasmid that could be transferred by conjugation and transformation. This report extends the list of ESBLs produced by S. typhimurium and stresses the need for continuous surveillance of non-typhoidal Salmonella to adapt antibiotic treatment and preventive measures.     

Endovascular management of early hepatic artery thrombosis after living donor liver transplantation

To study the feasibility of endovascular management of early hepatic artery thrombosis (HAT) after living‐donor liver transplantation (LDLT) and to clarify its role as a less invasive alternative to open surgery. A retrospective review of 360 recipients who underwent LDLT. Early HAT developed in 13 cases (3.6%). Diagnosis was performed using Doppler, CT angiography, and digital subtraction angiography. Intra‐arterial thrombolysis (IAT) was performed using streptokinase or tPA. In case of underlying stricture, PTA was attempted. If the artery did not recanalize, continuous infusion was performed and monitored using Doppler US. Initial surgical revascularization was successful in 2/13 cases. IAT was performed in 11/13 cases. The initial success rate was 81.8% (9/11), the failure rate was 18.2% (2/11). Rebound thrombosis developed in 33.3% (3/9). Hemorrhage developed after IAT in 2/11 cases (18.2%). Definite endovascular treatment of HAT was achieved in 6/11 cases (54.5%) and definite treatment (surgical, endovascular or combined) in 9/13 cases (69%). (Follow‐up 4 months–4 years). Endovascular management of early HAT after LDLT is a feasible and reliable alternative to open surgery. It plays a role as a less invasive approach with definite endovascular treatment rate of 54.5%.