Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia

Reported here are studies of Fanconi anemia fetal cells that led to the first use of umbilical cord blood for hematopoietic reconstitution in a clinical trial. Prenatal diagnosis and HLA typing were performed in fetuses at risk for Fanconi anemia (FA) to identify, prior to birth, those that were unaffected with the syndrome and were HLA-identical to affected siblings. Umbilical cord blood was harvested at the delivery of these infants; assays of progenitor cells indicated the presence of colony-forming units-granulocyte-macrophage (CFU-GM) in numbers similar to those of bone marrow CFU-GM that are associated with successful engraftment in HLA-matched allogeneic bone marrow transplantation. The possibility that umbilical cord blood from a single individual can be used as an alternative to bone marrow for hematopoietic reconstitution has now been demonstrated by the successful engraftment of two patients with FA. Progenitor cell assays of umbilical cord blood collected at the birth of a child affected with FA, who had been misdiagnosed on the basis of chorionic villus sampling (CVS) studies, indicated a profound deficiency in colony formation, consistent with previously reported abnormalities in the growth of FA cells in vitro. These results suggest that the hematopoietic disorder in FA is related to an underlying problem with cell proliferation.     

Generation and Characterization of Mice with Myh9 Deficiency

Mutant alleles of MYH9 encoding a class II non-muscle myosin heavy chain-A (NMMHC-IIA) have been linked to hereditary megathrombocytopenia with or without additional clinical features that include sensorineural deafness, cataracts, and nephritis. To assess its biological role in the affected targets, particularly the inner ear, we have generated and characterized mice with Myh9 deficiency. These mice were generated using the XA136 ES cell line (BayGenomics, http://baygenomics.ucsf.edu/) carrying gene trap insertion in Myh9, within the intron flanking exons 4 and 5. Mice heterozygous for the Myh9 null allele, Myh9 +/- were expanded on C57BL/6J background. Intercross of the Myh9 +/- mice did not yield Myh9 -/- pups, indicating embryonic lethality, subsequently determined to occur at or before E7.5, thus precluding a post-natal analysis of the effects of complete Myh9 deficiency. The heterozygous mice were normal for their hearing, parameters of platelet integrity and renal function despite their Myh9 haplo-insufficiency. In addition, the age-dependent auditory threshold of the Myh9 +/- mice and their wild type littermates, spanning from 3 to 12 months of age, were similar indicating that Myh9 haplo-insufficiency does not contribute towards accelerated age-related hearing loss (AHL). The embryonic lethality associated with the complete Myh9 deficiency establishes a critical role for this non-muscle myosin in fetal development. The results of these studies do not support the Myh9 haploinsufficiency as a pathogenic factor in the etiology of auditory dysfunction.     

Antioxidants in central nervous system diseases: preclinical promise and translational challenges

Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (alpha-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson's disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate's mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.     

Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial

BACKGROUND: Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. METHODS: 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. FINDINGS: Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI -0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4.4, 95% CI 1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. INTERPRETATION: Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.     

A study on the association with hepatitis B and hepatitis C in 1557 patients with lichen planus

Background Previous reports have demonstrated contradicting results on the association between lichen planus and hepatitis. Objectives The aim of this study was to investigate the association between lichen planus and viral hepatitis. Methods Patients with lichen planus were compared with controls regarding the prevalence of viral hepatitis in a case‐control study using logistic multivariate regression models. The study was performed utilizing the medical database of Clalit Health Services. Results The study included 1557 lichen planus patients over the age of 20 years and 3115 age‐ and gender‐matched controls. The prevalence of hepatitis C in patients with lichen planus was higher than that in the control group (1.9%, 0.4% respectively, P < 0.001). In a multivariate analysis, lichen planus was associated with hepatitis C (OR 4.19, 95% CI 2.21; 7.93). The prevalence of hepatitis B in patients with lichen planus was similar to that in the control group (0.9%, 0.5% respectively, P = 0.12). A multivariate analysis revealed that lichen planus was not associated with hepatitis B (OR 1.69, 95% CI 0.82; 3.47). Conclusion Lichen planus is associated with hepatitis C but not with hepatitis B. Physicians who care for patients with lichen planus should consider screening patients with lichen planus for hepatitis C.     

Two year cumulative incidence of trunk abnormalities in a schoolpopulation in Rotterdam, The Netherlands

We conducted a study of the 2 year cumulative incidence of trunkabnormalities in a cohort of 3,071 11 year old children (1,621boys, 1,450 girls). The following data were recorded: height,weight, signs of puberty and menarche. Trunk abnormality wasassessed in the erect child (asymmetry of shoulders and waistline,imbalance of the trunk, scoliosis, lordosis, kyphosis, swaybackand flexibility) and by the forward bending test (FBT) (ribhump or lumbar prominence, persisting scoliosis, kyphosis anddeviant lateral aspect). A normal FBT both at baseline and atfollow-up was found in 84% of the boys and in 79% of the girls.The 2 year cumulative incidence of an abnormal FBT was 10% inboys and 13% in girls.