Sudden death associated with danon disease in women

Danon disease is an X-linked systemic disorder characterized by left ventricular hypertrophy, mental retardation, and skeletal myopathy affecting young men. Electrocardiogram usually displays a Wolff-Parkinson-White preexcitation pattern. Less has been reported about the phenotype in women, although later-onset cardiac symptoms have been described. The aim of this study was to expand the knowledge of the phenotype of Danon disease in women. We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype. Affected family members carried a nucleotide substitution at position 294 in exon 3 (c.294 G → A) that changed a tryptophan residue to a stop codon at position W98X in the lysosome-associated membrane protein 2 (LAMP2) gene. Four women died suddenly (1 aborted) at 37 to 54 years of age. Wolff-Parkinson-White pattern with atrioventricular block was detected in 2 of 6 women. Four had successful pregnancies without symptoms of heart failure. cMRI showed late gadolinium enhancement areas in a clinically healthy woman who was a mutation carrier. Two patients underwent heart transplantation; histology of explanted hearts demonstrated severe interstitial fibrosis, hypertrophic cardiomyocytes with cytoplasmic vacuoles, and myofibrillar disarray. In conclusion, LAMP2 mutation can cause a severe arrhythmogenic phenotype in women that includes a high risk of sudden death. cMRI may be useful in women harboring LAMP2 mutations to permit early detection of cardiac involvement and guide timely considerations of implantable cardioverter-defibrillator therapy. Heart transplantation should be considered at onset of heart failure symptoms owing to rapid progression of the disease.     

Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans

Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. (HEPATOLOGY 2012;56:1108-1116).     

Alexithymia in the medically ill. Analysis of 1190 patients in gastroenterology,cardiology, oncology and dermatology

Objective

To use the Diagnostic Criteria for Psychosomatic Research (DCPR) for characterizing alexithymia in a large and heterogeneous medical population, in conjunction with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and other DCPR criteria.

Method

Of 1305 patients recruited from 4 medical centers in the Italian Health System, 1190 agreed to participate. They all underwent an assessment with DSM-IV and DCPR structured interviews. A total of 188 patients (15.8%) were defined as alexithymic by using the DCPR criteria. Data were submitted to cluster analysis.

Results

Five clusters of patients with alexithymia were identified: (1) alexithymia with no psychiatric comorbidity (29.3% of cases); (2) depressed somatization with alexithymic features (23.4%); (3) alexithymic illness behavior (17.6%); (4) alexithymic somatization (17%) and (5) alexithymic anxiety (12.8%).

Conclusions

The results indicate that DCPR alexithymia is associated with a comorbid mood or anxiety disorder in about one third of cases; it is related to various forms of somatization and abnormal illness behavior in another third and may occur without psychiatric comorbidity in another subgroup. Identification of alexithymic features may entail major prognostic and therapeutic differences among medical patients who otherwise seem to be deceptively similar since they share the same psychiatric and/or medical diagnosis.     

Measurement of the Aortic Annulus Diameter Using Transesophageal Echocardiography and Multislice Computed Tomography—Are They Truly Comparable?

Background

For transcatheter aortic valve implantation (TAVI), transesophageal echocardiography (TEE) and multislice computed tomography (MSCT) measurements of the aortic annulus diameter (AAD) are often regarded as competitive. We evaluated if 1 MSCT method could be interchangeable with TEE measurements.

Methods

We compared AAD measurements performed using TEE, MSCT, and transthoracic echocardiography (TTE) in 129 consecutive patients with severe aortic stenosis (AS) who were referred for TAVI. Using MSCT, AAD was measured in the 3-chamber (3C) view and at the level of the virtual basal ring (mean diameter [MD] of the long-axis [LA] and short-axis [SA] diameters, and AAD derived from the cross-sectional area [CSA] and the circumference). Correlations with echocardiographic measurements and agreement regarding the TAVI strategy (decision to implant and choice of prosthesis size based on manufacturer cutoff recommendations) were assessed.

Results

AAD measured in 3C (intraclass correlation [ICC], 0.79) and MD emphasizing the weight of the SA (MD4 [3 SA + LA/4]; ICC, 0.76) and MD5 [4 SA + LA/5; ICC, 0.75]) provided the highest correlation and the best agreement with TEE (kappa = 0.47, 0.27, and 0.31 respectively). However, TTE provided a better a correlation and agreement with TEE than all MSCT methods (ICC, 0.87; kappa = 0.66). The agreement between MSCT and TEE varied with AAD eccentricity and degree of aortic valve calcification (AVC), but in all subsets, values observed with MSCT never reached those observed with TTE.

Conclusions

MSCT and TEE are measuring different landmarks and consequently MSCT and TEE measurements are not interchangeable. Prospective randomized studies aimed at defining which method provides the best clinical results are clearly needed.     

Rac1-dependent cell cycle exit of MGE precursors and GABAergic interneuron migration to the cortex

Cortical γ-aminobutyric acid (GABA)ergic interneurons are characterized by extraordinary neurochemical and functional diversity. Although recent studies have uncovered some of the molecular components underlying interneuron development, including the cellular and molecular mechanisms guiding their migration to the cortex, the intracellular components involved are still unknown. Rac1, a member of the Rac subfamily of Rho-GTPases, has been implicated in various cellular processes such as cell cycle dynamics, axonogenesis, and migration. In this study, we have addressed the specific role of Rac1 in interneuron progenitors originating in the medial ganglionic eminence, via Cre/loxP technology. We show that ablation of Rac1 from Nkx2.1-positive progenitors, results in a migratory impairment. As a consequence, only half of GABAergic interneurons are found in the postnatal cortex. The rest remain aggregated in the ventral telencephalon and show morphological defects in their growing processes in vitro. Ablation of Rac1 from postmitotic progenitors does not result in similar defects, thus underlying a novel cell autonomous and stage-specific requirement for Rac1 activity, within proliferating progenitors of cortical interneurons. Rac1 is necessary for their transition from G1 to S phase, at least in part by regulating cyclin D levels and retinoblastoma protein phosphorylation.     

A fast and effective method to assess myocardial hyperemia in acute myocarditis by magnetic resonance

Current cardiac magnetic resonance (CMR) quantitative signs for the diagnosis of myocarditis include myocardial edema, fibrosis and myocardial hyperemia (Hyp). Methods for the assessment of Hyp are actually complex and time-consuming. To test a simple and fast method to assess Hyp, using contrast enhancement steady state free precession (ceSSFP) technique. CMR imaging at 1.5T was performed on 39 patients with diagnosis of acute myocarditis and in 20 healthy controls. Hyp was evaluated in systolic and diastolic frames (Hyp-SYS and Hyp-DIA) as areas of myocardial hyperintensity in ceSSFP images early after gadolinium injection. Myocardial edema was evaluated using T2-STIR images. Myocardial fibrosis was assessed in conventional late gadolinium enhancement (LGE) images. A value of ≤12.1 g of Hyp-DIA was obtained as cut-off of normality in healthy controls. Using this threshold, Hyp was detected in 30 patients (77 %) with myocarditis. LGE was detected in 36 patients (92 %), and myocardial edema in 38 (97 %) patients with myocarditis A linear relation was found between Hyp-DIA and the extent of myocardial edema (R² 0.48, 95 % CI 0.47–0.85, p < 0.001) and the extent of LGE (R² 0.41, 95 % CI 0.31–0.61, p < 0.001). Patients with hyperemia had higher levels of C-reactive protein (p < 0.001), a higher extent of LGE (p < 0.05) and a larger left atrial area (p < 0.05). ceSSFP sequence at CMR is a novel and fast method to assess myocardial hyperemia in patient with acute myocarditis. Compared with non-Hyp subjects, patients with Hyp had more signs of inflammation and myocardial damage.