Ian Abramson

The power law arises commonly in modeling the number of vertices of a given degree in large graphs. In estimating the degree of the power law, the typical approach is to truncate by eye the log-log plot, then fit a linear equation to the remaining log-transformed data. Here we formulate a hard-coded truncation rule to replace the visual truncation, justify

Annualized rates of cognitive change in Alzheimer's disease (AD), an important index of disease progression, show marked variability. To determine factors leading to such variability, we computed rates of change in a cohort of patients with AD tested annually with the Mini Mental State Examination (MMSE) and the more detailed Dementia Rating Scale (DRS). Estimates of rates of change (slopes) and intercepts were calculated using least squares and best linear unbiased predictors (BLUPs). Potential predictors of rates of change were examined using multivariate linear regression analysis. We found that the MMSE had more noise than the DRS. For the MMSE, slopes showed a moderate floor effect and a slight ceiling, depending on initial MMSE scores. These effects were less prominent for the DRS, for which slopes increased as intercepts decreased. In analyses of predictors of change, the MMSE was less useful than the DRS. In multiple linear regression models using DRS data, predictors showed statistically stronger effects and explained a greater extent of variation of slopes than did similar models using MMSE data. For example, among patients who died and underwent brain examination at autopsy, neuropathology of Lewy bodies plus AD (Lewy Body variant; LBV) was associated with significantly faster rates of cognitive decline compared to pure AD in analyses that used the DRS, but only trends were identified with the MMSE. The metric properties and longitudinal characteristics of cognitive tests and the statistical methods used to calculate change are key factors in obtaining reliable estimates of change in studying cohorts of patients with AD.

In the problem of large-scale multiple testing the p-plot is a graphically based competitor to the notoriously weak Bonferroni method. The p-plot is less stringent and more revealing in that it gives a gauge of how many hypotheses are decidedly false. The method is elucidated and extended here: the bootstrap reveals bias and sampling error in the usual point estimates, a bootstrap-based confidence interval for the gauge is given, as well as two acceptably powerful blanket tests of significance. Guidelines for use are given, and interpretational pitfalls pointed out, in the discussion of a case study linking premortem neuropsychological and postmortem neuropathologic data in an HIV cohort study.

The present study examined neuropsychological (NP) functioning and associated medical, neurological, brain magnetic resonance imaging (MRI), and psychiatric findings in 389 nondemented males infected with Human Immunodeficiency Virus-Type 1 (HIV-1), and in 111 uninfected controls. Using a comprehensive NP test battery, we found increased rates of impairment at each successive stage of HIV infection. HIV-related NP impairment was generally mild, especially in the medically asymptomatic stage of infection, and most often affected attention, speed of information processing, and learning efficiency; this pattern is consistent with earliest involvement of subcortical or frontostriatal brain systems. NP impairment could not be explained on the bases of mood disturbance, recreational drug or alcohol use, or constitutional symptoms; by contrast, impairment in HIV-infected subjects was related to central brain atrophy on MRI, as well as to evidence of cellular immune activation and neurological abnormalities linked to the central nervous system.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

Previous studies have shown blood pressure reactivity to exercise predicts future resting blood pressure. Subjects in this study were 206 healthy Mexican-American and Anglo-American families with fifth or sixth grade children. A total of 539 children (mean age = 12 years) and parents (mean age = 37 years) had complete data at baseline, and 79% were remeasured 48 months later. Blood pressure was measured during a submaximal cycle ergometer fitness test. Reactivity measures included systolic blood pressure at 70% of maximal heart rate (SBP70) and slope of the blood pressure-heart rate association during exercise (SLOPE). Stability of reactivity measures over 24 months varied from .22 to .63 (all p less than 0.001). Correlates of blood pressure reactivity in parents included resting heart rate, gender, age, and sodium intake. Correlates of reactivity in children included resting heart rate, body mass index, and age. Modest but significant levels of family aggregation of blood pressure reactivity were observed. In stepwise multiple regression analyses, SBP70 at baseline predicted resting blood pressure 48 months later in parents but not in children. The present results confirm previous studies indicating systolic blood pressure reactivity to exercise is a significant predictor of later resting blood pressure.

Although antidepressants are widely prescribed as analgesics in chronic back pain, their clinical pharmacology is not well established. Norepinephrine transporter blockade seems to be essential for analgesia, but optimal concentrations are unknown. Fixed-dose studies of serotonin reuptake inhibitors are generally negative, but such studies cannot be interpreted clearly because efficacy might be detected if concentration-response relationships were known. We evaluated (1) the feasibility of conducting a controlled-concentration study of a norepinephrine (desipramine) and a serotonin reuptake (fluoxetine) inhibitor and (2) the relationship between achieved concentrations and analgesic response. This single-center, 12-week, double-blind, prospective, controlled-concentration study randomized 121 chronic back pain patients without major depression to active placebo (benztropine mesylate) or to predetermined low, medium, or high concentrations of desipramine (targets were 50, 110, and 150 ng/mL, respectively) or fluoxetine (targets were 100, 200, and 400 ng/mL, respectively). Of these, 83 completed the trial: 38 withdrew primarily due to side effects. Manipulation check revealed significant overlap of assigned and achieved concentrations related to drug intolerability. Completers' analysis of achieved concentrations revealed reduction in pain intensity was significantly greater for low-concentration desipramine (<60 ng/mL, mean Descriptor Differential Scale [DDS], 4.5) compared with placebo (DDS 6.2), higher concentrations of desipramine (>60 ng/mL, DDS 7.9), and all concentrations of fluoxetine (P < 0.05, DDS 7.1). Significant improvement in everyday function mirrored findings for pain intensity. Preliminary evidence for a low-concentration "therapeutic window" for noradrenergic analgesia may warrant additional study.

The effectiveness of a family-based cardiovascular disease risk reduction intervention was evaluated in two ethnic groups. Participants were 206 healthy, volunteer low-to-middle-income Mexican-American and non-Hispanic white (Anglo-American) families (623 individuals), each with a fifth or a sixth-grade child. Families were recruited through elementary schools. Half of the families were randomized to a year-long educational intervention designed to decrease the whole family's intake of high salt, high fat foods, and to increase their regular physical activity. Eighty-nine percent of the enrolled families were measured at the 24-month follow-up. Both Mexican- and Anglo-American families in the experimental groups gained significantly more knowledge of the skills required to change dietary and exercise habits than did those in the control groups. Experimental families in both ethnic groups reported improved eating habits on a food frequency index. Anglo families reported lower total fat and sodium intake. There were no significant group differences in reported physical activity or in tested cardiovascular fitness levels. Significant differences for Anglo-American experimental vs. control adult subjects were found for LDL cholesterol. Significant intervention-control differences ranging from 2.2 to 3.4 mmHg systolic and/or diastolic blood pressure were found in all subgroups. Direct observation of diet and physical activity behaviors in a structured environment suggested generalization of behavior changes. There was evidence that behavior change persisted one year beyond the completion of the intervention program. It is concluded that involvement of families utilizing school based resources is feasible and effective. Future studies should focus on the most cost-effective methods of family involvement, and the potential for additive effects when family strategies are combined with other school health education programs.

To determine whether cardiac mortality is abnormally high on days considered unlucky: Chinese and Japanese people consider the number 4 unlucky, white Americans do not. Examination of cardiac and non-cardiac mortality on and around the fourth of each month in Chinese and Japanese subjects and white controls. United States. All Chinese and Japanese (n=209 908) and white (n=47 328 762) Americans whose computerised death certificates were recorded between the beginning of January 1973 and the end of December 1998. Ratio of observed to expected numbers of deaths on the fourth day of the month (expected number was estimated from mortality on other days of the month). Cardiac mortality in Chinese and Japanese people peaked on the fourth of the month. The peak was particularly large for deaths from chronic heart disease (ratio of observed to expected deaths = 1.13, 95% confidence interval 1.06 to 1.21) and still larger for deaths from chronic heart disease in California (1.27, 1.15 to 1.39). Within this group, inpatients showed a particularly large peak on the fourth day(1.45, 1.19 to 1.81). The peak was not followed by a compensatory drop in number of deaths. White controls, matched on age, sex, marital status, hospital status, location, and cause of death, showed no similar peak in cardiac mortality. Our findings of excess cardiac mortality on "unlucky" days are consistent with the hypothesis that cardiac mortality increases on psychologically stressful occasions. The results are inconsistent with nine other possible explanations for the findings-for example, the fourth day peak does not seem to occur because of changes in the patient's diet, alcohol intake, exercise, or drug regimens.

To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. Eighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count. In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.

Although the preclinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects, efficacy in the human pain state remains unclear. Using a human experimental pain model, the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin. In a randomized, double-blinded, placebo-controlled, crossover trial in 15 healthy volunteers, the authors evaluated concentration-response effects of low-, medium-, and high-dose smoked cannabis (respectively 2%, 4%, and 8% 9-delta-tetrahydrocannabinol by weight) on pain and cutaneous hyperalgesia induced by intradermal capsaicin. Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure, and pain, hyperalgesia, tetrahydrocannabinol plasma levels, and side effects were assessed. Five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations between pain perception and plasma delta-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects. There was no significant difference in performance on the neuropsychological tests. This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.