“CADASIL coma” in an Italian homozygous CADASIL patient: comparison with clinical and MRI findings in age-matched heterozygous patients with the same G528C NOTCH3 mutation

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by mutations in the NOTCH3 gene, with a striking variability in phenotypic expression. To date, only two homozygous patients have been reported, with divergent phenotypic features. We describe an Italian CADASIL patient, homozygous for G528C mutation, in whom early manifestation of the disease was migraine, but whose clinical evolution was characterized by a reversible acute encephalopathy followed by full recovery (“CADASIL coma”). Clinical evaluation, MR scan, neuropsychological and neurophysiological investigation did not reveal substantial differences between our homozygous patient and her heterozygous relatives sharing the same mutation, or between our patient and a group of heterozygous individuals with the same mutation but from different families. Skin biopsy identified peculiar features in the homozygous patient, with cytoplasmic pseudoinclusions likely containing granular osmiophilic material (GOM) in the vascular smooth muscle cells, but further studies are necessary to substantiate their possible relationships with CADASIL homozygosis. “CADASIL coma” did not seem to be specific of patient’s homozygosis, since it was observed in one of her heterozygous relatives, whereas its pathogenesis seems to be related to peculiar constellations of unknown predisposing factors. The present study demonstrated that CADASIL conforms to the classical definition of dominant diseases, according to which homozygotes and heterozygotes for a defect are phenotypically indistinguishable.     

Effect of water contamination on the shear bond strength of self-ligating brackets

PurposeThe aim of the present study is to evaluate the effect of water contamination on the shear bond strength (SBS) and adhesive remnant index (ARI) score of self-ligating brackets.Materials and methodsOne conventional bracket and three different self-ligating brackets were bonded onto 160 bovine permanent mandibular incisors, divided randomly into 8 groups. For each type of bracket, 20 samples were bonded on dry enamel and 20 after water contamination. After 24 h, all specimens were tested for SBS using an Instron Universal Testing Machine, and ARI scores were evaluated.ResultsAll groups showed clinically adequate SBSs. Quick brackets bonded onto dry enamel showed significantly higher SBSs than all other groups tested, whereas the lowest shear strength values were recorded for Step, Quick, and Damon 3MX brackets bonded onto contaminated enamel and for Damon 3MX onto dry enamel. Frequency distribution of ARI Scores showed a prevalence of ARI “2” and “3” for all the groups tested.ConclusionsWater contamination reduces the SBS of self-ligating brackets, but significant differences have been found only for Quick brackets. All groups showed a significant higher frequency of ARI Score of “2” and “3”.     

Daily dialysis reduces pulse wave velocity in chronic hemodialysis patients

Pulse wave velocity (PWV) is a predictor of morbidity and mortality in patients with end-stage renal disease (ESRD). Dialysis patients show cyclic changes in PWV related to their hydration status and blood pressure. Our aim is to assess the impact of daily dialysis on PWV. We performed a randomized crossover study of 60 patients who underwent standard hemodialysis (HD) three times per week for at least 6 months. Patients were classified into three groups according to their PWV values before (pre-) and after (post-) HD, with a cutoff value of 12 m s(-1), as follows: the low-low (LL) group had normal pre-HD and post-HD PWV; the high-low (HL) group had high pre-HD PWV and normal post-HD PWV; and the high-high (HH) group had high pre- and post-HD PWV. All patients continued standard HD for 2 weeks. A total of 10 patients from each group were randomly assigned to continue standard HD for 1 week and then underwent daily dialysis for 1 week. The remaining 10 patients underwent daily dialysis for 1 week and then underwent standard HD for 1 week. PWV values were measured before and 1 h after each dialysis session. With daily dialysis treatment, 2 of 20 patients (10%) moved from the PWV-HH group to the PWV-HL group, whereas 18 of 20 patients (90%) moved from the PWV-HL group to the PWV-LL group (P = 0.030). Daily dialysis reduces PWV in the ESRD patients. As PWV is a strong predictor of mortality in ESRD and has cyclic variations in patients who are on standard HD, we believe that daily dialysis may be used in patients with high PWV levels to reduce their mortality risk.     

Analysis of mutational status, SNP rs16754, and expression levels of Wilms tumor 1 (WT1) gene in acute promyelocytic leukemia

Overexpression, polymorphisms, and mutations of the WT1 gene have been reported in several human tumors including acute myeloid leukemia (AML) and variably correlated with prognosis. Acute promyelocytic leukemia (APL) represents the AML subset disclosing higher WT1 expression levels; however, no WT1 studies specifically focused on APL have been conducted. We screened for the presence of mutations, SNP rs16754, and expression levels of WT1 gene in 103 adult patients with newly diagnosed APL. Fms-like tyrosine kinase (FLT3) mutations were analyzed as well. WT1 mutations were identified in four (4?%) patients. At least one copy of the minor SNP rs16754 allele (WT1 ^AG or WT1 ^GG) was detected in 30 (29?%) patients. Six patients (6?%) were homozygous for the minor allele (WT1 ^GG ) and this genotype was associated with higher WT1 mRNA copies (p?=?0.018). FLT3 mutations were found in 37?% of patients and correlated with high WT1 mRNA expression (p?=?0.004). Patients heterozygous or homozygous for the minor allele and patients homozygous for major (WT1 ^AA) allele did not differ in terms of presenting features. In adult APL, WT1 gene mutational and polymorphic profile shows similarities with pediatric AML rather than with adult AML.     

Echocardiographic Evaluation of Right Ventricular Stroke Work Index in Advanced Heart Failure: A New Index?

BackgroundRight ventricular (RV) function plays a pivotal role in advanced heart failure patients, especially for screening those who may benefit from left ventricular assist device (LVAD) implantation. We introduce RV contraction pressure index (RVCPI) as a new echo-Doppler parameter of RV function. The accuracy of RVCPI in detecting RV failure was compared with the criterion standard, the RV stroke work index (RVSWI) obtained through right heart catheterization in advanced heart failure patients referred for heart transplantation or LVAD implantation.Methods and ResultsRight heart catheterization and echo-Doppler were simultaneously performed in 94 consecutive patients referred to our center for advanced heart failure (ejection fraction (EF) 24 ± 8.8%, 40% NYHA functional class IV). RV stroke volume and invasive pulmonary pressures were used to obtain RVSWI. Simplified RVCPI (sRVCPI) was derived as TAPSE × (RV ? right atrial pressure gradient). Close positive correlation between sRVCPI and RVSWI was found (r = 0.68; P < .001). With logistic regression, we found that increased sRVCPI showed an independent reduced risk (odds ratio 0.98, 95% confidence interval [CI] 0.97–0.99; P = .016) for patients to present a depressed RVSWI (<0.25 mm Hg/L·m²). Simplified RVCPI showed high diagnostic accuracy (area under the receiver operating characteristic curve 0.94, 95% CI 0.89–0.99) and good sensitivity and specificity (92% and 85%, respectively) to predict depressed RVSWI with the use of a cutoff value of <400 mm·mm Hg.ConclusionsIn patients with advanced heart failure, the new simple bedside sRVCPI closely correlated with RVSWI, providing an independent, noninvasive, and easy tool for the evaluation of RV function.     

Genetic structure of Ascaris roundworm in Japan and patterns of its geographical variation

Ascaris roundworm isolates from Japan and central Europe were examined by sequencing analyses to better understand geographically induced nucleotide variation and genotype distribution according to host. Three well-supported clusters (denoted as A, B, C) were identified by generating cox1 sequences of mtDNA from these regions. Among 5 pig isolates collected in eastern Honshu, Japan, in 2010, 3 carried DNA characteristics for cluster A and 2 corresponded with the characteristics of cluster B. The sequence of the human isolate JH1 from north-central Honshu, fixed in formalin since 1972, conformed to the characteristics of cluster A. Differential analysis of ribosomal ITS1 region revealed the JH1 isolate sequence profile of Ascaris lumbricoides. Cluster C, which was the most distinguish cluster, was formed by reference Slovak isolates and has been so far found almost exclusively in European pigs. A fluctuating prevailing distribution of A and B lineages in human and pig hosts in different territories of the world and the global distribution of several haplotypes indicate their establishment before secondary differentiation in a given region due to host affiliation. The protocol established for DNA isolation from formalin-fixed specimens using the modified procedure with the Qiagen extraction set can be used as a tool for retrospective studies in ascarid helminths when only archival specimens are available.     

Autoimmune hepatitis after liver transplantation

Liver transplantation is an effective treatment for patients with end-stage acute and chronic autoimmune hepatitis. However, despite the good outcomes reported, disease recurrence is relatively common in the allograft. In addition, autoimmunity and autoimmune liver disease can arise de novo after transplantation for non-autoimmune liver disorders. Little is known about the mechanisms by which autoimmune diseases develop after liver transplantation, but genetic factors, molecular mimicry, impaired regulatory T-cell responses, and exposures to new alloantigens might be involved. Regardless of the pathogenic mechanisms, it is important to remain aware of the existence of recurrent and de novo autoimmune hepatitis after liver transplantation; these disorders are similar to classic autoimmune hepatitis and are therefore not treated with standard antirejection strategies.