Michael Schulzer

Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies

Alzheimers disease (AD) lesions are characterized by the presence of numerous inflammatory proteins.This has led to the hypothesis that brain inflammation is a cause of neuronal injury in AD and that anti-inflammatory drugs may act as protective agents. Seventeen epidemiologic studies from nine different countries have now been published in which arthritis, a major indication for the use of anti-inflammatory drugs, or anti-inflammatory drugs themselves have been considered as risk factors for AD. Both factors appear to be associated with a reduced prevalence of AD. The small size of most studies has limited their individual statistical significance, but similarities in design have made it possible to evaluate combined results. We have used established methods of statistical meta-analysis to estimate the overall chance of individuals exposed to arthritis or anti-inflammatory drugs developing AD as compared with the general population. Seven case-control studies with arthritis as the risk factor yielded an overall odds ratio of 0.556 (p < 0.0001), while four case-control studies with steroids yielded odds ratios of 0.656 (p = 0.049) and three case-control studies with nonsteroidal anti-inflammatory drugs (NSAIDs) yielded an odds ratio of 0.496 (p = 0.0002). When NSAIDs and steroids were combined into a single category of anti-inflammatory drugs, the odds ratio was 0.556 (p < 0.0001). Population-based studies were less similar in design than case-control studies, complicating the process of applying statistical meta-analytical techniques. Nevertheless, population-based studies with rheumatoid arthritis and NSAID use as risk factors strongly supported the results of case-control studies. These data suggest anti-inflammatory drugs may have a protective effect against AD. Controlled clinical trials will be necessary to test this possibility. NEUROLOGY 1996;47: 425-432

Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures

PURPOSE To determine if intraocular pressure plays a part in the pathogenic process of normal-tension glaucoma. METHODS One eye of each eligible subject was randomized either to be untreated as a control or to have intraocular pressure lowered by 30% from baseline. Eyes were randomized if they met criteria for diagnosis of normal-tension glaucoma and showed documented progression or high-risk field defects that threatened fixation or the appearance of a new disk hemorrhage. The clinical course (visual field and optic disk) of the group with lowered intraocular pressure was compared with the clinical course when intraocular pressure remained at its spontaneous untreated level. RESULTS One hundred-forty eyes of 140 patients were used in this study. Sixty-one were in the treatment group, and 79 were untreated controls. Twenty-eight (35%) of the control eyes and 7 (12%) of the treated eyes reached end points (specifically defined criteria of glaucomatous optic disk progression or visual field loss). An overall survival analysis showed a statistically significant difference between the two groups (P < .0001). The mean survival time +/-SD of the treated group was 2,688 +/- 123 days and for the control group, 1,695 +/- 143 days. Of 34 cataracts developed during the study, 11 (14%) occurred in the control group and 23 (38%) in the treated group (P = .0075), with the highest incidence in those whose treatment included filtration surgery. CONCLUSIONS Intraocular pressure is part of the pathogenic process in normal-tension glaucoma. Therapy that is effective in lowering intraocular pressure and free of adverse effects would be expected to be beneficial in patients who are at risk of disease progression.

The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma

PURPOSE In a companion paper, we determined that intraocular pressure is part of the pathogenesis of normal-tension glaucoma by analyzing the effect of a 30% intraocular pressure reduction on the subsequent course of the disease. We report an intent-to-treat analysis of the study data to determine the effectiveness of pressure reduction. METHODS One eligible eye of 145 subjects with normal-tension glaucoma was randomized either to no treatment (control) or to a 30% intraocular pressure reduction from baseline. To be eligible for randomization, the normal-tension glaucoma eyes had to show documented progression of field defects or a new disk hemorrhage or had to have field defects that threatened fixation when first presented for the study. Survival analysis compared time to progression of all randomly assigned patients during the course of follow-up from the initial baseline at randomization. In a separate analysis, data of patients developing cataracts were censored at the time that cataract produced 2 lines of Snellen visual acuity loss. RESULTS Visual field progression occurred at indistinguishable rates in the pressure-lowered (22/66) and the untreated control (31/79) arms of the study (P = .21). In an analysis with data censored when cataract affected visual acuity, visual field progression was significantly more common in the untreated group (21/79) compared with the treated group (8/66). An overall survival analysis showed a survival of 80% in the treated arm and of 60% in the control arm at 3 years, and 80% in the treated arm and 40% in the controls at 5 years. The Kaplan-Meier curves were significantly different (P = .0018). The analyses gave different results because of a higher incidence of cataract in the group that underwent filtration surgery. CONCLUSIONS The favorable effect of intraocular pressure reduction on progression of visual change in normal-tension glaucoma was only found when the impact of cataracts on visual field progression, produced largely by surgery, was removed. Lowering intraocular pressure without producing cataracts is beneficial. Because not all untreated patients progressed, the natural history of normal-tension glaucoma must be considered before embarking on intraocular pressure reduction with therapy apt to exacerbate cataract formation unless normal-tension glaucoma threatens serious visual loss.

Effect of school-based physical activity interventions on body mass index in children: a meta-analysis

Background: The prevalence of childhood obesity is increasing at an alarming rate. Many local governments have enacted policies to increase physical activity in schools as a way to combat childhood obesity. We conducted a systematic review and meta-analysis to determine the effect of school-based physical activity interventions on body mass index (BMI) in children. Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials up to September 2008. We also hand-searched relevant journals and article reference lists. We included randomized controlled trials and controlled clinical trials that had objective data for BMI from before and after the intervention, that involved school-based physical activity interventions and that lasted for a minimum of 6 months. Results: Of 398 potentially relevant articles that we identified, 18 studies involving 18 141 children met the inclusion criteria. The participants were primarily elementary school children. The study duration ranged from 6 months to 3 years. In 15 of these 18 studies, there was some type of co-intervention. Meta-analysis showed that BMI did not improve with physical activity interventions (weighted mean difference –0.05 kg/m2, 95% confidence interval –0.19 to 0.10). We found no consistent changes in other measures of body composition. Interpretation: School-based physical activity interventions did not improve BMI, although they had other beneficial health effects. Current population-based policies that mandate increased physical activity in schools are unlikely to have a significant effect on the increasing prevalence of childhood obesity.

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease

Clinical symptoms of Parkinsons disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three‐dimensional mode by using each tracer on 35 patients and 16 age‐matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug‐naive and drug‐treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11C]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L‐amino acid decarboxylase is up‐regulated, whereas the plasma membrane DA transporter is down‐regulated in the striatum of patients with PD. Ann Neurol 2000;47:493–503.

EMSY Links the BRCA2 Pathway to Sporadic Breast and Ovarian Cancer

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.

Unequal intraocular pressure and its relation to asymmetric visual field defects in low-tension glaucoma.

Fifty-nine low-tension glaucoma patients were reviewed with respect to asymmetry of intraocular pressure (IOP) and visual field defects. In the presence of unequal IOP the visual field damage is almost always greater on the side with higher mean IOP. However, only 13 of 47 patients with asymmetric visual field defects had a mean IOP difference between the two eyes of greater than or equal to 1 mmHg. Although in the case of IOP asymmetry visual field damage is greater in the eye with higher mean IOP, other factors must also play an important role in the development of visual field defects in low-tension glaucoma.

Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover

Motor fluctuations are a major disabling complication in the treatment of Parkinsons disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinsons disease with a follow‐up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed “wearing‐off” fluctuations during the follow‐up period had a different pattern of levodopa‐induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow‐up. Thus, 1 hour post‐levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent “wearing‐off” phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa‐related motor complications. Ann Neurol 2001;49:298–303

Reproducibility of topographic parameters obtained with the heidelberg retina tomograph.

The Heidelberg retina tomograph is a confocal scanning laser ophthalmoscope that permits recording of topographic information related to the optic nerve and retina. We studied the reproducibility of the topographic parameters obtained by recording five times sequentially the images obtained from one eye of five healthy people and five glaucoma patients. The reproducibility coefficients ranged from 60.5 to 99.4%. The results indicate that, for the parameters examined, the instrument has a high level of reproducibility.

The Normal Human Optic Nerve: Axon Count and Axon Diameter Distribution

Computerized image analysis was used to determine the normal axonal count and axon diameter distribution in 12 normal human eyes. Mean axon count per nerve was 969,279 +/- 239,740 and mean axon diameter was 0.72 +/- 0.07 micron. Multiple linear regression disclosed 4909 axons lost yearly (P = 0.08). Statistical analysis did not show a relationship between axon diameter and age or time to fixation. The inferotemporal sector of the nerve had the highest fiber density (P = 0.02). The superonasal nerve had higher mean diameters (P = 0.02). This study may provide a baseline for future pathologic studies.