Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation

Human leucocyte antigen (HLA)-C molecules regulate the function of natural killer cells and may be subdivided into two groups, C(1) and C(2), based on their specificity for inhibitory killer immunoglobulin-like receptors. We analysed the impact of the HLA-C genotype on outcome of HLA-C-matched unrelated donor haematopoietic stem cell transplantation (URD-HSCT) recipients. HLA-C(2) homozygous patients (n = 18) had lower probability of overall survival (P = 0.01) and disease-free survival (P = 0.02), resulting from increased relapse rate (P = 0.02) when compared with both HLA-C(1) homozygous (n = 43) and HLA-C(1),C(2) heterozygous (n = 50) subgroups. Patients lacking HLA-C(1) should, therefore, be considered at increased risk of relapse following HLA-C-matched URD-HSCT.     

Global and regional left ventricular function in patients undergoing transcatheter closure of secundum atrial septal defect

This study sought to evaluate global and regional left ventricular (LV) function before and early after device closure of atrial septal defects (ASDs) in patients with normal pulmonary pressure. Global LV diastolic function was unaffected by ASD closure. An improvement in global LV systolic function at rest resulted in an increase in stroke volume at rest. Nevertheless, total cardiac output did not change after the procedure, because of a decrease in heart rate at rest counterbalancing the increase in stroke volume. Thus, lateral and inferior LV regional systolic function were preserved after device implantation. Moreover, no changes in regional LV diastolic function were highlighted during the study.     

Functional involvement of Annexin-2 in cAMP induced AQP2 trafficking

Annexin-2 is required for the apical transport in epithelial cells. In this study, we investigated the involvement of annexin-2 in cAMP-induced aquaporin-2 (AQP2) translocation to the apical membrane in renal cells. We found that the cAMP-elevating agent forskolin increased annexin-2 abundance in the plasma membrane enriched fraction with a parallel decrease in the soluble fraction. Interestingly, forskolin stimulation resulted in annexin-2 enrichment in lipid rafts, suggesting that hormonal stimulation might be responsible for a new configuration of membrane interacting proteins involved in the fusion of AQP2 vesicles to the apical plasma membrane. To investigate the functional involvement of annexin-2 in AQP2 exocytosis, the fusion process between purified AQP2 membrane vesicles and plasma membranes was reconstructed in vitro and monitored by a fluorescence assay. An N-terminal peptide that comprises 14 residues of annexin-2 and that includes the binding site for the calcium binding protein p11 strongly inhibited the fusion process. Preincubation of cells with this annexin-2 peptide also failed to increase the osmotic water permeability in the presence of forskolin in intact cells. Altogether, these data demonstrate that annexin-2 is required for cAMP-induced AQP2 exocytosis in renal cells.     

Ischemic etiology of heart failure identifies patients with more severely impaired exercise capacity

BACKGROUND: Peak oxygen uptake (peak VO2) and the regression slope of ventilation against CO2 production during exercise (VE/VCO2 slope) are powerful prognostic indicators in patients with chronic heart failure (CHF). Our purpose was to evaluate the influence of CHF etiology on peak VO2 and VE/VCO2 slope, independently of demographic, clinical, Doppler-echocardiographic and neurohormonal factors. METHODS: Data were collected from 239 CHF patients referred for a cardiopulmonary exercise test as part of their clinical evaluation. Patients were stratified according to their CHF etiology (ischemic versus non-ischemic). RESULTS: The etiology of heart failure was ischemic in 143 patients (60%) and non-ischemic in 96 (40%). Patients with ischemic etiology, compared with those with non-ischemic etiology, showed a lower peak VO2 (15.4+/-4.2 versus 17.8+/-4.8 ml/kg/min, p<0.0001) and a steeper VE/VCO2 slope (38.1+/-6.8 versus 34+/-5.3, p<0.0001). In the univariate model, age (r=-0.36, p<0.0001), female sex (r=-0.21, p=0.001), ischemic CHF etiology (r=-0.26, p<0.0001) and NYHA class (r=-0.52, p<0.0001) correlated with peak VO2. At multivariate analysis, ischemic CHF etiology (beta=-0.23, p=0.001) was a predictor of peak VO2 (R(2)=0.49) independently of age (beta=-0.23, p=0.001), female sex (beta=-0.25, p=0.0006) and NYHA class (beta=-0.31, p<0.0001). Similarly, ischemic etiology (beta=0.29, p=0.001) predicted the VE/VCO2 slope (R(2)=0.38) independently of E/A ratio (beta=0.27, p=0.01) and resting heart rate (beta=0.22, p=0.01). CONCLUSIONS: Etiology of heart failure may influence the functional capacity and the ventilatory response to exercise.     

Patau syndrome with long survival in a case of unusual mosaic trisomy 13

We report a 12-year-old patient with Patau syndrome, in whom two cell lines were present from birth, one with total trisomy 13 due to isochromosome (13q), and one with partial trisomy 13. A cytogenetic re-evaluation at 9 years of age brought to light in skin fibroblasts a third cell line, partially monosomic for chromosome 13. The derivatives (13) present in the three cell lines were characterized through fluorescence in situ hybridization (FISH) experiments with suitable probes; the results suggested a sequence of rearrangements which beginning from an isochromosome (13q) could have led to the other two derivatives. We report the clinical data at birth and at the age of 12; at this age pigmentary lesions with phylloid pattern were noted. Cytogenetic findings of the chromosomal analyses on different tissues, including skin fibroblasts from differently pigmented areas, are also reported.     

Coenzyme Q10 and exercise training in chronic heart failure.

AIMS: There is evidence that plasma coenzyme Q(10) (CoQ(10)) levels decrease in patients with advanced chronic heart failure (CHF). However, it is not known whether oral CoQ(10) supplementation may improve cardiocirculatory efficiency and endothelial function in patients with CHF. METHODS AND RESULTS: We studied 23 patients in NYHA class II and III (20 men, three women, mean age 59+/-9 years) with stable CHF secondary to ischaemic heart disease [ejection fraction 37+/-7%], using a double-blind, placebo-controlled cross-over design. Patients were assigned to each of the following treatments: oral CoQ(10) (100 mg tid), CoQ(10) plus supervised exercise training (ET) (60% of peak VO(2), five times a week), placebo, and placebo plus ET. Each phase lasted 4 weeks. Both peak VO(2) and endothelium-dependent dilation of the brachial artery (EDDBA) improved significantly after CoQ(10) and after ET as compared with placebo. CoQ(10) main effect was: peak VO(2)+9%, EDDBA +38%, systolic wall thickening score index (SWTI) -12%; ET produced comparable effects. CoQ(10) supplementation resulted in a four-fold increase in plasma CoQ(10) level, whereas the combination with ET further increased it. No side effects were reported with CoQ(10). CONCLUSIONS: Oral CoQ(10) improves functional capacity, endothelial function, and LV contractility in CHF without any side effects. The combination of CoQ(10) and ET resulted in higher plasma CoQ(10) levels and more pronounced effects on all the abovementioned parameters. However, significant synergistic effect of CoQ(10) with ET was observed only for peak SWTI suggesting that ET amplifies the already described effect of CoQ(10) on contractility of dysfunctional myocardium.     

C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population

It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.     

Traumatic arteriovenous pial fistula masquerading as a carotid-cavernous fistula: an uncommon disorder with an unusual presentation

Traumatic intracranial pial arteriovenous fistulae are infrequent lesions. Their cardinal signs have been related to mass effect and hemorrhage, but their clinical manifestations due to venous retrograde flow into ophthalmic veins has never been described. This phenomenon is usually seen in dural arteriovenous fistula draining to the cavernous sinus or carotid-cavernous sinus fistula.A traumatic intracranial pial arteriovenous fistula arising from the supraclinoid internal carotid artery in a young patient was revealed by aggressive behavior and ophthalmologic manifestations. The endovascular management included the use of coils, stent, and ethylene-vinyl alcohol with transient balloon occlusion of the parent vessel.     

Transient reactivation of occult hepatitis B virus infection despite lamivudine prophylaxis in a patient treated for non-Hodgkin lymphoma

A female patient with non-Hodgkin lymphoma who tested positive for surface antigen of the hepatitis B virus and negative for hepatitis B core antibody experienced a reactivation of occult HBV infection 20 months after rituximab discontinuation despite lamivudine prophylaxis covering the 4 months of rituximab administration and the subsequent 12 months.