David F. Andrews

Intramuscular desferrioxamine in patients with Alzheimer's disease

Although epidemiological and biochemical evidence suggests that aluminium may be associated with Alzheimers disease (AD), there is no convincing proof of a causal link for aluminium in disease progression. We have completed a two year, single-blind study to investigate whether the progression of dementia could be slowed by the trivalent ion chelator, desferrioxamine. 48 patients with probable AD were randomly assigned to receive desferrioxamine (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. No significant differences in baseline measures of intelligence, memory, or speech ability existed between groups. Activities of daily living were assessed and videorecorded at 6, 12, 18, and 24 month intervals. There were no differences in the rate of deterioration of patients receiving either placebo or no treatment. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03) and variances (p less than 0.04). The mean rate of decline was twice as rapid for the no-treatment group. Appetite (n = 4) and weight (n = 1) loss were the only reported side-effects. We conclude that sustained administration of desferrioxamine may slow the clinical progression of the dementia associated with AD.

A Robust Method for Multiple Linear Regression

Techniques of fitting are said to be resistant when the result is not greatly altered in the case a small fraction of the data is altered: techniques of fitting are said to be robust of efficiency when their statistical efficiency remains high for conditions more realistic than the utopian cases of Gaussian distributions with errors of equal variance. These properties are particularly important in the formative stages of model building when the form of the response is not known exactly. Techniques with these properties are proposed and discussed.

A one-hit model of cell death in inherited neuronal degenerations

In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often assumed to reflect the occurrence of age-dependent cumulative damage. For example, it has been suggested that oxidative stress disrupts metabolism in neurological degenerative disorders by the cumulative damage of essential macromolecules. A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show in contrast that the kinetics of neuronal death in 12 models of photoreceptor degeneration, hippocampal neurons undergoing excitotoxic cell death, a mouse model of cerebellar degeneration and Parkinsons and Huntingtons diseases are all exponential and better explained by mathematical models in which the risk of cell death remains constant or decreases exponentially with age. These kinetics argue against the cumulative damage hypothesis; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a ‘one-hit’ biochemical model in which mutation imposes a mutant steady state on the neuron and a single event randomly initiates cell death. This model appears to be common to many forms of neurodegeneration and has implications for therapeutic strategies.

Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn's disease☆☆☆

BACKGROUND & AIMS Recurrence of Crohns disease frequently occurs after surgery. A randomized controlled trial was performed to determine if mesalamine is effective in decreasing the risk of recurrent Crohns disease after surgical resection is performed. METHODS One hundred sixty-three patients who underwent a surgical resection and had no evidence of residual disease were randomized to a treatment group (1.5 g mesalamine twice a day) or a placebo control group within 8 weeks of surgery. The follow-up period was a maximum of 72 months. RESULTS The symptomatic recurrence rate (symptoms plus endoscopic and/or radiological confirmation of disease) in the treatment group was 31% (27 of 87) compared with 41% (31 of 76) in the control group (P = 0.031). The relative risk of developing recurrent disease was 0.628 (90% confidence interval, 0.40-0.97) for those in the treatment group (P = 0.039; one-tail test) using an intention-to-treat analysis and 0.532 (90% confidence interval, 0.32-0.87) using an efficacy analysis. The endoscopic and radiological rate of recurrence was also significantly decreased with relative risks of 0.654 (90% confidence interval, 0.47-0.91) in the effectiveness analysis and 0.635 (90% confidence interval, 0.44-0.91) in the efficacy analysis. There was only one serious side effect (pancreatitis) in subjects in the treatment group. CONCLUSIONS Mesalamine (3.0 g/day) is effective in decreasing the risk of recurrence of Crohns disease after surgical resection is performed.

TRANSFORMATIONS OF MULTIVARIATE DATA

SUMMARY Methods, which are extensions of the techniques of Box and Cox [19641, are proposed for obtaining data-based transformations of multivariate observations to enhance the normality of their distribution and also possibly to simplify the model (e.g. improve additivity, homoscedasticity, etc.). Specifically, power transformations of the original variables are estimated to effect both marginal and joint normality. A method for improving directional normality is also described. Examples are included to illustrate some properties of the methods.

Are hereditary hemochromatosis mutations involved in Alzheimer disease

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.

Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease

BACKGROUND & AIMS The aim of this study was to determine the risk of endoscopic/radiological recurrence of Crohns disease postoperatively and the long-term outcome. METHODS A randomized placebo-controlled trial was performed to determine the effectiveness of mesalamine in preventing recurrent Crohns disease postoperatively. Patients in the control group were examined endoscopically/radiologically before entry into and annually during the trial. Findings were classified as minimal or severe. RESULTS There were 76 patients (49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal ileal resections. Overall, 55 endoscopic/radiological recurrences were observed in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1 year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%-71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic (mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9 +/- 17.4 months). Patients with severe endoscopic/radiological disease were significantly more likely to be or become symptomatic than those with minimal disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS This study suggests that postoperative endoscopic/radiological recurrences occur later than previously reported. Furthermore, many of these patients, especially with minimal disease, will remain asymptomatic.

Methods for Assessing Multivariate Normality

Publisher Summary This chapter presents some techniques for assessing the normality of multivariate data and illustrates their performance by some examples. The chapter presents methods under the following headings: (1) univariate techniques for evaluating marginal normality, (2) multivariate techniques for evaluating joint normality, and (3) other procedures based on unidimensional views of the multi-response data. Performing an initial transformation on the data and then using standard methods of analysis is a prevalent and often useful approach in analyzing data. Therefore, as a general approach under each of the three categories of the aforementioned methods, the assessment of normality may be made by inquiring about the need for a transformation. However, an approach that is not explicitly dependent on data-based transformations is also possible.

The robustness and optimality of response surface designs

Abstract Recent work on extended optimality criteria for robust designs is applied to response surface problems. Methods of calculation are described and the criteria illustrated with several examples. The extended criteria discriminate among designs equivalent by other criteria.

Involvement of ApoE E4 and H63D in Sporadic Alzheimer's Disease in a Folate-Supplemented Ontario Population

Dysregulation of iron homeostasis is implicated in Alzheimers disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.