Cerebral sinus venous thrombosis in Swiss children

Aim To describe the characteristics of paediatric cerebral sinus venous thrombosis (CSVT) in Switzerland. Method Data on clinical features, neuroimaging, risk factors, and treatment were collected for all children in Switzerland younger than 16 years of age who had CSVT between January 2000 and December 2008. A follow‐up examination and a cognitive assessment were performed (mean follow‐up period 26mo). Differences between neonates and children (patients older than 28d) were assessed and predictors of outcome were determined. Results Twenty‐one neonates (14 males, seven females; mean age 9d, SD 8d) and 44 children (30 males, 14 females; mean age 8y 7mo, SD 4y 5mo) were reported. The incidence of paediatric CSVT in Switzerland was 0.558 per 100 000 per year. In neonates, the deep venous system was more often involved and parenchymal injuries were more common. The strongest predictor of poor outcome was neonatal age (odds ratio 17.8, 95% confidence interval 0.847–372.353). Most children showed global cognitive abilities within the normal range, but impairments in single cognitive subdomains were frequent. Interpretation Paediatric CSVT is rare. Its outcome is poor in neonates. Most children have good neurological outcomes, but some patients have individual neuropsychological impairments.     

Cardiac resynchronization improves heart failure in one patient with Myotonic Dystrophy type 1. A case report

We report an improvement in symptoms of heart failure, a reduced left ventricular dysfunction and induced reverse remodelling in one patient with Myotonic Dystrophy type 1, showing an early onset ventricular dysfunction secondary to a complete left bundle branch block (LBBB) who underwent cardioverter defibrillator CRT (ICD- CRT) implantation.Key words: myotonic dystrophy, cardiac resynchronization therapy, sudden death     

Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A

Summary. One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFα, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.     

Role of Thromboxane A2 Receptor on the Effects of Oxidized LDL on Microvascular Endothelium Nitric Oxide,Endothelin‐1, and IL‐6 Production

Objective: The aim of this study was to determine to what extent thromboxane A₂ (TP) receptor mediates the effect of oxidated low‐density lipoprotein (LDL) on nitric oxide (NO), interleukin (IL)‐6, and endothelin‐1 (ET‐1) release by microvascular endothelial cells. Methods: Endothelial nitric oxide synthase (eNOS), nitrites and nitrates (NO₂/NO₃), ET‐1, and IL‐6 production were measured following human microvascular endothelial cell 1 exposure to isoprostane‐8‐epi‐PGF_2α (F₂IP), a natural agonist of the TP receptor present in oxidized LDL, or native, low‐, or medium‐oxidized LDL either with the TP‐receptor blocker, SQ29.548, or its vehicle. Results: F₂IP and both native and oxidized LDL enhanced NO₂/NO₃. F₂IP through the TP receptor stimulated eNOS (eight‐fold), while the oxidized LDL effect (two‐to five‐fold) was only partially prevented by SQ29.548. While LDL concentration and degree of oxidation synergistically and independent of SQ29.548 stimulated IL‐6, F₂IP had no effect. F₂IP induced a modest (+50%) increase in ET‐1. LDL, independent of concentration or degree of oxidation, stimulated (+120%) ET‐1 production, and this effect was only partially attenuated by SQ29.548. Conclusions: In microvascular endothelial cells, LDL concentration and degree of oxidation synergistically stimulate NO and IL‐6 production, but only NO release is largely mediated by the TP receptor. LDL facilitates ET‐1 release independent of concentration and degree of oxidation; TP‐receptor stimulation is only partially responsible for this effect.     

SYNTHESIS,PHARMACOLOGICAL, CONFORMATIONAL,AND DYNAMIC STUDIES OF THE POTENT HORMONE ANTAGONISTS [1-PENICILLAMINE, 4-THREONINE]-OXYTOCIN AND [1-PENICILLAMINE, 2-PHENYLALANINE, 4-THREONINE] -OXYTOCIN

The solid phase synthesis of [1-penicillamine, 4-threonine]-oxytocin and [1-penicillamine 2-phenylalanine, 4-threonine]-oxytocin is reported. The two compounds have no in vitro milk ejecting activity and no in vivo or in vitro oxytocic activity, but both are potent antagonists in these three assay systems. In the in vitro oxytocic assay, [1-penicillamine, 4-threonine]-and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin have pA₂ values of 7.55 ± 0.04 and 7.67 ± 0.02, respectively, and both inhibit the uterine contractile response to oxytocin in nonpregnant and pregnant rats. [1-Penicillamine, 2-phenylalanine, 4-threonine]-oxytocin has a weak antipressor activity and at high doses, consistently caused a weak and transient fall in blood pressure in the rat. Carbon-13 nuclear magnetic resonance chemical shift parameters and spin-lattice relaxation times (T₁) indicate that these two new oxytocin antagonists have very similar conformation and dynamic properties to oxytocin inhibitors which have previously been examined. These results are discussed in terms of conformational and dynamic models of oxytocin antagonism at the uterus. It is suggested that conformational restrictions at the 2- and 4-positions of penicillamine-1 analogues of oxytocin are important to antagonist activity and potency.     

Conformation and dynamics of the chemotactic peptide formyl-L-methionyl-L-leucyl-L-phenylalanine in solution

Several conformational and dynamic features of the chemotactic peptide formyl-L-methionyl-L-leucyl-L-phenylalanine in solution have been delineated by investigations of NMR and IR spectroscopic parameters. Both 1D and 2D NMR experiments have been performed for detection of scalar and dipolar proton-proton connectivities, whereas ¹³C and ¹H relaxation parameters have been interpreted in terms of molecular dynamics. The main conformation appeared to be unfolded with the three hydrophobic side chains extending in divergent directions with respect to the backbone. The existence of relatively weak inter-molecular hydrogen bonds was demonstrated, involving the formamide end group, with increase in the hydrophobicity of the external surface.     

Contemporary Surgical Treatment for Atrial Fibrillation

Traditional surgical treatment of AF is the Cox-Maze III procedure. The Cox-Maze III procedure cures AF in >90% of patients and virtually eliminates the risk of stroke. Recent understanding of the importance of the pulmonary veins and left atrium in the pathogenesis of AF has resulted in the development of new surgical approaches. New operations to ablate AF use alternate energy sources (radiofrequency, microwave, cryothermy) and simplified left atrial lesion sets. These operations cure AF in 70–80% of patients. This article describes contemporary and emerging surgical approaches to AF, synthesizes results of these operations, and proposes a strategy for choice of operation based on patient presentation. (PACE 2003; 26[Pt. II]:1641–1644)     

The Effect of Dietary Exposure to a Mirex Plus Chlordecone Combination on CCl4 Hepatotoxicity

The Effect of Dietary Exposure to a Mirex Plus Chlordecone Combinationon CCl₄ Hepatotoxicity. BELL, A. N., AND MEHENDALE, H. M. (1985).Fundam. Appl. Toxicol. 5, 679–687. The purpose of thesestudies was to investigate the effect of a mirex plus chlordeconecombination on CCl₄-induced hepatotoxicity. Male Sprague-Dawleyrats were maintained on control diet or on diets containing10 ppm chlordecone (CD), 10 ppm mirex (M), or M plus CD (10ppm each; MCD) for 15 days. On Day 15 the rats received a singleip injection of CCl₄ (100 µl/kg) and hepatotoxicity wasassessed 24 hr later. Animals in the control group receivingCCU alone were unaffected. Significant increases in liver-to-bodyweight ratios were observed in all three pretreatment groupsfollowing CCl₄ challenge. Increases in serum enzymes (SGPT,SGOT, and ICD) occurred in all three pretreatment groups withCD = MCD > M > control. While MCD and CD pretreatmentled to significant cholestasis and decreases in PG excretion,no such effect was observed with M. Light microscopic examinationof tissues revealed swollen hepatocytes (balloon cells), hepatocellularnecrosis, and lipid accumulation in the MCD, CD, and M groupsfollowing CCl₄ challenge. In summary, as assessed by serum enzymeelevation, biliary flow and hepatic excretory function, M pretreatmentled to only a slight increase in CCl₄ hepatotoxicity. The MCDcombination pretreatment did not potentiate hepatotoxicity abovethat seen with CD alone. These results provide additional evidencethat CD pretreatment results in a rather specific sensitizationof animals to CCl₄ toxicity in ways independent Of the actionsOf M