New evidence for,and challenges in,linking small CGG repeat expansion FMR1 alleles with Parkinson's disease

We recently reported a significant increase in the frequency of carriers of grey zone (GZ) alleles of FMR1 gene in Australian males with Parkinson's disease (PD) from Victoria and Tasmania. Here, we report data comparing an independent sample of 817 PD patients from Queensland to 1078 consecutive Australian male newborns from Victoria. We confirmed the earlier finding by observing a significant excess of GZ alleles in PD (4.8%) compared to controls (1.5%). Although both studies provided evidence in support of an association between GZ‐carrier status and increased risk for parkinsonism, the existing evidence in the literature from screening studies remains equivocal and we discuss the need for alternative approaches to resolve the issue.     

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.     

Fc gamma receptor II (CD32) on malignant B cells influences modulation induced by anti-CD19 monoclonal antibody

Antigenic modulation is one of many factors determining the effectiveness of monoclonal antibody (MoAb)-mediated therapy. To select the isotype of a CD19 MoAb most suitable for radioimmunotherapy of patients with B-cell malignancies, we studied the influence of MoAb isotype on modulation, after binding of the MoAb to different cell-line cells. The CD19-IgG1 MoAb was found to induce modulation of CD19 antigens on Daudi cell line cells more rapidly than did its IgG2a switch variant. We provide evidence that this difference in modulation rate is caused by the expression of Fc gamma receptor II (Fc gamma RII) on these cells. Experiments aimed at elucidating the mechanism of Fc gamma RII involvement in modulation induction by CD19-IgG1 showed that Fc gamma RII did not comodulate with CD19 MoAbs. However, cocrosslinking of CD19 and Fc gamma RII with CD19-IgG1 MoAb resulted in enhanced calcium mobilization in Daudi cells. This increased signal induction accompanies the enhanced capping and subsequent modulation of CD19 antigens. Because Fc gamma RII is expressed in varying densities on malignant B cells in all differentiation stages, our results have implications for the MoAb isotype most suitable for use in MoAb-based therapy of patients with B-cell malignancies.     

Impact of nationwide measles vaccination campaign among children aged 9 months to 14 years,Zimbabwe, 1998-2001

Zimbabwe (population 11,365,000) introduced nationwide one-dose measles vaccination in 1981. This strategy reached 70%-80% of infants <1 year of age over the next two decades; in 1998, a nationwide supplemental immunization activity (SIA) targeting all children aged 9 months to 14 years achieved 93% coverage. Surveillance data were examined to determine the impact of these strategies. During 1985-1997, there were 8529-49,812 measles cases annually. After the SIA, laboratory confirmation of the first 5 outbreak cases and all sporadic cases was required. In 1999 and 2000, 1343 (88%) of 1534 suspected cases had adequate specimens submitted and 28 (2%) were measles IgM positive. In 2001, of 529 suspected cases, 513 (97%) had adequate specimens and only 7 (1%) were measles IgM positive. These data suggest that indigenous measles transmission in Zimbabwe has been interrupted and that high prevalence of human immunodeficiency virus seropositivity does not hinder vaccination-induced measles control. High vaccination coverage obtained through the routine health care system supplemented by periodic follow-up SIAs will be required to maintain low transmission levels.     

A radioreceptor assay for quantitating plasma factor VIII/von Willebrand's protein

A sensitive and precise radioreceptor assay for determining plasma levels of human factor VIII/von Willebrand's factor (FVIII/vWF) has been developed by taking advantage of the FVIII/vWF receptor sites on human platelets. Paraformaldehyde-fixed platelets, which were processed and then stored, retained FVIII/vWF binding activity and therefore could be used as a convenient source of receptors. The human plasma samples to be tested were initially filtered on 4% agarose columns to concentrate the FVIII/vWF protein in the void volume and to remove the factor(s) that interferes with the assay. The percent recovery of FVIII/vWF in the pooled eluent was measured by the recovery of added trace 125I-FVIII/vWF. The coefficients of intra- and interassay variation were 6% and 10%, respectively. The plasma FVIII/vWF concentrations determined by the assay for pooled normal plasma, hemophilia A plasma, and plasmas from two patients with von Willebrand's disease were 16.3 +/- 0.5, 52.6 +/- 1.5, 6.8 +/- 0.8, and 3.2 +/- 0.2 microgram/ml, respectively. The range of plasma FVIII/vWF concentrations varied between 8.3 microgram/ml and 24.9 microgram/ml for 10 normal adults. The plasma FVIII/vWF concentrations determined by the radioreceptor assay correlated well with levels measured by the ristocetin-induced platelet aggregation method, thus demonstrating the functional relevancy of the radioreceptor assay for plasma FVIII/vWF.