Apolipoprotein E epsilon4 allele frequency in elderly depressed patients with and without cerebrovascular disease

Late-onset depression (LOD) could be a very early manifestation of Alzheimer's disease (AD), although contradictory results have been reported. Cerebrovascular disease (CVD) may favor the development of LOD, and that the particular forms of vascular depression should be individualized. The Apolipoprotein E (ApoE) epsilon4 allele was shown to be a risk factor for AD. Its role in LOD is controversial, while it is still unknown in vascular depression. Our objective was to clarify the relationship between ApoE epsilon4 allele and LOD in patients with and without CVD. We examined the ApoE phenotypes in a sample of 311 subjects: 50 with vascular LOD, 24 with LOD without CVD, 115 with AD and 122 normal controls (NC). The study of the ApoE epsilon4 allele frequency showed significant differences between: AD group and the vascular LOD and NC groups; LOD group without CVD compared with NC group (p<0.05 to 0.001). The frequency of the epsilon4 allele in the LOD group without CVD did not differ significantly from the AD group, similarly the frequency of the epsilon4 allele in the vascular LOD group was not different from that in NC. The study suggests an association between the ApoE epsilon4 allele and the LOD without CVD. These patients could be at risk of developing AD by an epsilon4-dependent pathway. In contrast, the results show no association between the presence of ApoE epsilon4 allele and vascular depression and provide further evidence in support of the concept that ApoE epsilon4 allele is not associated with clinical CVD.     

Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome

We analyzed the factors and outcome of patients with disseminated adenovirus infection (dAdV) after allogeneic hematopoeitic stem cell transplantation (HSCT). Thirty patients with dAdV were identified among 620 allogeneic HSCT recipients. Primary diseases were leukemia (n=17), Fanconi anemia (n=12) or others (n=1). Source of stem cells was unrelated in 28 and related in 2 patients. The graft consisted of peripheral blood (n=3), bone marrow (n=12) and unrelated cord-blood (UCB, n=15). Risk factors for dAdV in unrelated HSCT recipients were previous Fanconi disease (p=0.03) and GVHD (p=0.02) in children, and cord blood source of stem cells (p=0.029) and GVHD (0.024) in adults.     

Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: Array CGH study of 47 unrelated cases

Investigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, revealed a proportion of unsuspected imbalances. It was estimated recently that 40% of apparently balanced de novo translocations with abnormal phenotype were associated with cryptic deletion.We explored 47 unrelated mental retardation patients carrying an apparently balanced chromosomal rearrangement with high-resolution oligonucleotides arrays. We included 33 de novo cases (21 translocations, 7 inversions and 5 complex chromosomal rearrangements (CCR)) and 14 inherited cases (7 translocations, 5 inversions and 2 CCR).Twenty of the 47 cases (42.6%) carried a cryptic deletion ranging from 60 kb to 15.37 Mb. It concerned 16/33 de novo rearrangements (8/21 translocations, 4/7 inversions and 4/5 CCR) and 4/14 inherited rearrangements (1/7 translocations, 2/5 inversions and 1/2 CCR). The proportion of imbalances was not statistically different between de novo and inherited cases.Our results support that about 40% apparently balanced chromosomal rearrangements with abnormal phenotype are in fact imbalanced and that these rearrangements should be systematically investigated by array CGH independently of their de novo or inherited character.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

Chronic active gastritis in X-linked lymphoproliferative disease

Gastric lesions in primary constitutive immune deficiencies include multifocal atrophic gastritis, erosive pangastritis, and a pattern of gastric lesions reminiscent of graft-versus-host disease. We describe the genetic anomalies in 2 monozygotic twins with an X-linked lymphoproliferative disease (XLP; MIM 308240), a rare familial setting of high susceptibility to Epstein-Barr virus (EBV). Since early childhood, both twin brothers exhibited a severe chronic active atrophic pangastritis. A germline screening of the SH2D1A (MIM 300490) and BIRC4 (MIM 300079) genes was performed, and also a high-resolution whole-genome SNP profiling (Infinium Sentrix Human-1 Genotyping BeadChip, Illumina). A 3 Megabase deletion in the Xq25 region, encompassing the SH2D1A gene, was defined by SNP array genotyping. Histologic analysis of yearly or twice yearly gastric biopsies in both children showed a Helicobacter pylori-negative, Epstein-Barr virus-negative chronic active atrophic pangastritis, with superficial ulcer formation, foveolar hyperplasia, glandular dilatation and ultimately pseudopyloric and intestinal metaplasia. No such chronic active inflammatory gastric lesions have been reported to date in XLP. The similarities between XLP and common variable immunodeficiency (MIM 240500) underscore the need for early recognition and close monitoring of these gastric lesions, with special regard to their neoplastic potential. No infectious cause was determined. We favor a dysimmune mechanism in the development of this chronic atrophic gastritis, presenting a striking similarity to the recently described atrophic autoimmune pangastritis.     

A novel mutation in the dynamin 2 gene in a Charcot-Marie-Tooth type 2 patient: clinical and pathological findings

Mutations in dynamin 2 (DNM2) have been associated with autosomal dominant centronuclear myopathy, dominant intermediate Charcot-Marie-Tooth (CMT) type B and CMT2. Here, we report a novel DNM2 mutation in the Pleckstrin homology domain of DNM2 (p.K559del) in a patient with an axonal length-dependent sensorimotor polyneuropathy predominantly affecting the lower limbs. Neuropathy is associated with congenital cataracts, ophthalmoparesis, ptosis and neutropenia. There was no evidence of a skeletal myopathy on EMG or muscle biopsy. We suggest that this constellation of clinical features can help the diagnosis and selection of patients for direct DNM2 genetic analysis.