Biomedical subjects

Daniel Rabinowitz

Publications and source records attributed to Daniel Rabinowitz.

16 recordsLinked to original sources

PubMed2006

Early presynaptic changes during plasticity in cultured hippocampal neurons.

Long-lasting increase in synaptic strength is thought to underlie learning. An explosion of data has characterized changes in postsynaptic (pstS) AMPA receptor cycling during potentiation. However, changes occurring within the presynaptic (prS) terminal remain largely unknown. We show that appearance of new release sites during potentiation between cultured hippocampal neurons is due to (a) conversion of nonrecycling sites to recycling sites, (b) formation of new releasing sites from areas containing diffuse staining for the prS marker Vesicle-Associated Membrane Protein-2 and (c) budding of new recycling sites from previously existing recycling sites. In addition, potentiation is accompanied by a release probability increase in pre-existing boutons depending upon their individual probability. These prS changes precede and regulate fluorescence increase for pstS GFP-tagged-AMPA-receptor subunit GluR1. These results suggest that potentiation involves early changes in the prS terminal including remodeling and release probability increase of pre-existing synapses.

Animals↗

PubMed2006

Estimation of the mean from sums with unknown numbers of summands.

Using dye intensity measurements at synaptic terminals to examine neurotransmitter release leads to the problem of estimating an expectation when, instead of observing independent random variables with the same expectation, one observes, with error, independent random sums of independent variables with the same expectation--but with the number of summands in the random sums unobserved. Here, a relatively convenient nonparametric approach to estimation is presented. Data from an experiment in which cationic styrylpyridinium dye FM4-64 was used in cultured mouse hippocampal neurons are used to illustrate the approach.

Animals↗

PubMed2006

A method for estimating penetrance from families sampled for linkage analysis.

When a gene variant is discovered to segregate with a disease, it may be of interest to estimate the risk (or the age-specific risk) of the disease to carriers of the variant. The families that contributed to the discovery of the variant would typically contain multiple carriers, and so, especially if the variant is rare, might prove a valuable source of study subjects for estimation of the risk. These families, by virtue of having brought the gene in question to the attention of researchers, however, may not be representative of the relationship between carrier status and the risk of the disease in the population. Using these families for risk estimation could bias the observed association between the variant and the risk. The purpose here is to present an approach to adjusting for the potential bias while using the families from linkage analysis to estimate the risk.

Age of Onset↗

PubMed2005

Long-acting somatostatin analog therapy of acromegaly: a meta-analysis.

CONTEXT: Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials. OBJECTIVE: We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and tumor shrinkage. DATA SOURCES: A search of literature was conducted through 2003, primarily via PubMed. STUDY SELECTION: Inclusion criteria, met in 44 trials, included at least 3 months of secondary octreotide long-acting release (LAR) or lanreotide slow release (SR) therapy or of primary octreotide LAR, lanreotide SR, or sc octreotide therapy and clearly reported data on biochemical efficacy and/or tumor shrinkage. Fifty other trials screened did not meet analysis inclusion criteria. DATA EXTRACTION: Data were extracted by three independent observers. DATA SYNTHESIS: Among subjects not selected for somatostatin analog responsiveness before study entry, both GH efficacy criteria and IGF-I normalization were met in a greater proportion of those treated with octreotide LAR vs. lanreotide SR (GH: B = 0.2310, P = 0.016; IGF-I: B = 0.2325, P = 0.007). Prestudy selection for somatostatin analog responsiveness was not a significant predictor of meeting GH efficacy criteria (B = 0.0992; P = 0.12). Preselection was a positive predictor of IGF-I normalization rate (B = 0.1213; P = 0.04), which was greater among preselected than unselected subjects (B = 0.1472; P = 0.0475). IGF-I normalization occurred in a greater proportion of secondary octreotide LAR- vs. primary octreotide-treated subjects (B = 0.2056; P = 0.009). The odds of tumor shrinkage more than 10% were lower in the unselected vs. preselected subjects. However, the effect of drug type was an important predictor of shrinkage; such that regardless of preselection or not, the odds of shrinkage with lanreotide SR were lower than with octreotide LAR (P = 0.003). Shrinkage greater than 10% occurred in a higher percentage of primary octreotide LAR-treated vs. primary octreotide sc-treated subjects (odds ratio = 9.4; P < 0.0001). The overall rate of tumor increase was 1.4%. CONCLUSIONS: In this meta-analysis, we have shown that the efficacy of octreotide LAR is greater than lanreotide SR among subjects unselected for prior somatostatin analog responsiveness. Preselection is a significant positive predictor of IGF-I normalization and is associated with increased odds of tumor shrinkage, which is also greatest with octreotide LAR. Biochemical efficacy is similar, but tumor shrinkage is greater when these drugs are given as primary vs. secondary therapy.

Acromegaly↗

PubMed2005

Health expenditures for privately insured adults enrolled in managed care gatekeeping vs indemnity plans.

OBJECTIVES: We assessed the ability of managed care gatekeeping strategies (i.e., requiring a designated primary care provider to authorize referrals) to control health care costs in the mid-1990s. METHODS: We analyzed expenditure data from 8195 privately insured adults sampled in the nationally representative 1996 Medical Expenditure Panel Survey. Managed care gatekeeping plan enrollees included those in health maintenance organizations and other plans requiring a primary care gatekeeper. All others were considered indemnity plan enrollees. RESULTS: In 1996, total per capita annual health expenditures for adult gatekeeping enrollees were about $50 less than those of indemnity enrollees, primarily owing to lower out-of-pocket expenditures. After multivariate adjustment, mean per capita expenditures were approximately 6% lower for gatekeeping enrollees than for indemnity enrollees. CONCLUSIONS: In the private sector, gatekeeping strategies resulted in modest cost savings over indemnity plans.

Adult↗

PubMed2004

The common insertional polymorphism in the APOC1 promoter is associated with serum apolipoprotein C-I levels in Hispanic children.

We examined the effect of APOC1-317insCGTT allele status (HpaI RFLP, deletion [H1] and insertion [H2] alleles) on serum apolipoprotein (apo) C-I level in 362 Hispanic children in the Columbia University BioMarkers Study. The H2 allele was present in 147 subjects (40.6%). Serum apoC-I was 20% lower in the presence of the H2 allele in APOE epsilon3/epsilon3 homozygotes (P=0.003) but did not differ by H2 status in epsilon4 carriers. Insufficient numbers of epsilon2 carriers (N=45) were present for analysis. In multivariate analysis in the epsilon3/epsilon3 context, after adjusting for potential covariate effects and familial aggregation, the mean effect of H2/* versus H1/H1 on apoC-I level, was estimated to be 2.15+/-0.55mg/dl (P<0.0025). Plasma triglyceride level was weakly correlated with serum apoC-I level (Pearson's r=0.17, P<0.001) but was highly correlated with serum apoC-III (Pearson's r=0.74, P<0.0001). Nevertheless, presence of the H2 allele was not significantly associated with serum apoC-III level. Thus, the effect of APOC1 genotype on serum apoC-I level was not due to apoC-I level serving as a surrogate for triglyceride level. The APOC1-317insCGTT allele is a commonly polymorphic genetic marker that is associated with serum apoC-I level in the APOE epsilon3/epsilon3 context. These findings suggest that the mechanism of the previously described association with plasma TG is, at least in part, related to the correlation of the polymorphism with the level of expression of apoC-I.

Adolescent↗

PubMed2004

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

Adolescent↗

PubMed2003

Sources of variability in blood pressure measurement using the Dinamap PRO 100 automated oscillometric device.

The Dinamap automated oscillometric device (GE Medical Systems Information Technologies, Inc., Milwaukee, Wisconsin) for blood pressure measurement is widely employed in epidemiologic studies because it is easy to use and because it eliminates observer variability. In this study, the authors assessed the variability in observed blood pressures associated with use of the Dinamap monitor and estimated the contributions of various factors to that variability. In 60 volunteers (30 aged 23-35 years and 30 aged 54-82 years) from New York, New York, the authors obtained 30 simultaneous paired blood pressure measurements in both arms at 1-minute intervals, using three separate Dinamap PRO 100 devices allocated to arm and subject according to a balanced incomplete block design. Variability, defined as the between-arm difference in blood pressure measurements, was analyzed using a mixed-effects linear regression model. A total of 1,800 paired blood pressure measurements were obtained between September 2001 and June 2002. The mean ages of the two groups were 28.3 years (standard deviation, 4.0) and 71.7 years (standard deviation, 8.0). A diagnosis of hypertension was present in 53% of the older subjects and none of the younger subjects. Fifty percent of paired simultaneous blood pressure measurements obtained were in agreement within 4 mmHg for systolic blood pressure or within 3 mmHg for diastolic blood pressure. Residual variability, attributable to the intrinsic inaccuracy of the device, accounted for 64-82% of the total systolic and diastolic blood pressure variability. The majority of variability in blood pressure measurement was due to the device as used under the study conditions.

Adult↗

PubMed2003

Adjusting for population heterogeneity: a framework for characterizing statistical information and developing efficient test statistics.

The focus of this work is the TDT-type and family-based test statistics used for adjusting for potential confounding due to population heterogeneity or misspecified allele frequencies. A variety of heuristics have been used to motivate and derive these statistics, and the statistics have been developed for a variety of analytic goals. There appears to be no general theoretical framework, however, that may be used to evaluate competing approaches. Furthermore, there is no framework to guide the development of efficient TDT-type and family-based methods for analytic goals for which methods have not yet been proposed. The purpose of this paper is to present a theoretical framework that serves both to identify the information which is available to methods that are immune to confounding due to population heterogeneity or misspecified allele frequencies, and to inform the construction of efficient unbiased tests in novel settings. The development relies on the existence of a characterization of the null hypothesis in terms of a completely specified conditional distribution of transmitted genotypes. An important observation is that, with such a characterization, when the conditioning event is unobserved or incomplete, there is statistical information that cannot be exploited by any exact conditional test. The main technical result of this work is an approach to computing test statistics for local alternatives that exploit all of the available statistical information.

Data Interpretation, Statistical↗

PubMed2003

Systematic regulation of spine sizes and densities in pyramidal neurons.

Dendritic spines receive most excitatory inputs in the CNS. Recent evidence has demonstrated that the spine head volume is linearly correlated with the readily releasable pool of neurotransmitter and the PSD size. These correlations can be used to functionally interpret spine morphology. Using Golgi impregnations and light microscopy, we reconstructed 23000 spines from pyramidal neurons in layers 2/3, 4, 5 and 6 of mouse primary visual cortex and CA1 hippocampal region and measured their spine head diameters and densities. Spine head diameters and densities are variable within and across cells, although they are similar between apical and basal dendrites. When compared to other regions, layer 5 neurons have larger spine heads and CA1 neurons higher spine densities. Interestingly, we detect a correlation between spine head diameter and interspine distance within and across cells, whereby larger spines are spaced further away from each other than smaller spines. Finally, in CA1 neurons, spine head diameters are larger, and spine density lower, in distal apical dendrites (>200 microm from soma) compared to proximal regions. These results reveal that spine morphologies and densities, and therefore synaptic properties, are jointly modulated with respect to cortical region, laminar position, and, in some cases, even the position of the spine along the dendritic tree. Individual neurons also appear to regulate their apical and basal spine densities and morphologies in concert. Our data provide evidence for a homeostatic control of excitatory synaptic strength.

Animals↗

PubMed2003

Evidence for distinct genetic influences on generalized and localization-related epilepsy.

PURPOSE: Determining the existence of syndrome-specific genetic factors in epilepsy is essential for phenotype definition in genetic linkage studies, and informs research on basic mechanisms. Analysis of concordance of epilepsy syndromes in families has been used to assess shared versus distinct genetic influences on generalized epilepsy (GE) and localization-related epilepsy (LRE). However, it is unclear how the results should be interpreted in relation to specific genetic hypotheses. METHODS: To assess evidence for distinct genetic influences on GE and LRE, we examined concordance of GE and LRE in 63 families containing multiple individuals with idiopathic or cryptogenic epilepsy, drawn from the Epilepsy Family Study of Columbia University. To control for the number of concordant families expected by chance, we used a permutation test to compare the observed number with the number expected from the distribution of individuals with GE and LRE in the study families. RESULTS: Of the families, 62% were concordant for epilepsy type, and 38% were discordant. In all analyses, the proportion of concordant families was significantly greater than expected. CONCLUSIONS: This suggests that some genetic influences predispose specifically to either GE or LRE. Because of the ascertainment bias resulting from the selection of families containing multiple individuals with epilepsy, we could not test whether there are also shared genetic influences on these two epilepsy subtypes. Population-based studies will be needed to explore these results further.

Epilepsies, Partial↗

PubMed2003

Body mass index and hospitalization in the elderly.

OBJECTIVES: To explore the association between body mass index (BMI) and hospital usage in the elderly. DESIGN: Retrospective cohort study. SETTING: Medicare Current Beneficiary Survey (1992-94). PARTICIPANTS: Eight thousand seven hundred fifty-four noninstitutionalized individuals aged 65 to 100 without cancer at baseline and with available data on height and weight. MEASUREMENTS: BMI categorized by quintiles and by the 1998 National Heart Lung and Blood Institute (NHLBI) BMI classification. Poisson regression was used for multivariate analyses relating BMI to number of hospitalizations, adjusting for sex, age, smoking status, and heart disease. RESULTS: During 20464 years of observation, 1199 individuals had 4096 hospitalizations and 34190 hospital days. Individuals in the lowest BMI quintile had a higher risk of hospitalization than those in the middle BMI quintile (RR=1.22; 95% confidence interval=1.1-1.4); stratified analyses by age revealed that this association remained for individuals aged 65 to 75. Using the NHLBI classification, underweight, overweight, mild obesity, and moderate to severe obesity were related to higher risk of hospitalizations than normal BMI in individuals aged 65 to 75. In individuals older than 75, underweight, overweight, and mild obesity were not related to a higher risk of hospitalizations. Moderate to severe obesity was related to a higher risk of hospitalization in individuals aged 75 to 89, which represented only 1.5% of the sample. CONCLUSION: BMI is not a predictor of hospitalization for most individuals aged 75 and older.

Aged↗

PubMed2003

Does gatekeeping control costs for privately insured children? Findings from the 1996 medical expenditure panel survey.

OBJECTIVE: Gatekeeping requirements were widely adopted by health insurers in an attempt to control costs in the mid-1990s, but empirical evidence demonstrating decreased health expenditures for children enrolled in such plans is lacking. METHODS: We analyzed data from 3254 children with private health insurance sampled in the 1996 Medical Expenditure Panel Survey (MEPS) to compare total per capita health expenditures among gatekeeping versus indemnity plan enrollees. This sample represents 40.4 million privately insured American children. Total expenditures were defined as payments from all sources, including third-party and out-of-pocket payments, but excluding administrative costs. MEPS data are based on information provided by patients, health care providers, and hospitals. Gatekeeping plans included all children enrolled in health maintenance organizations or other plans requiring a primary care gatekeeper. All others were considered indemnity plan enrollees. RESULTS: Mean total per capita annual expenditures for children in gatekeeping versus indemnity plans differed by <1% (887 dollars vs 881 dollars, respectively). Third-party payments by gatekeeping plans on behalf of their beneficiaries were 636 dollars versus 595 dollars by indemnity plans. Out-of-pocket payments were on average 62 dollars less for gatekeeping enrollees than for indemnity enrollees. After multivariate adjustment, mean per capita expenditures were approximately 4% lower for gatekeeping enrollees than for indemnity enrollees. CONCLUSION: In 1996, total per capita annual health expenditures for children in gatekeeping plans were approximately 8 dollars less than for those in indemnity plans. These data indicate that gatekeeping is not an effective cost-containment method for children.

Child↗

PubMed2002

Concordance of disease form in kindreds ascertained through affected individuals.

When designing or conducting genetic epidemiological studies of a disease with several distinct forms, it is useful to know whether susceptibilities to the different forms are conferred by different genes or whether there are genes that confer susceptibility to multiple forms. A natural approach to exploring these issues is to examine how the disease forms cluster in kindreds. When inclusion in the study is based on the affection status of multiple relatives, however, distorted patterns of familial clustering of disease form can be evident. The purpose here is to present statistical methods for adjusting for this distortion. In particular, approaches to testing two null hypotheses are presented: a null hypothesis that corresponds to all genes acting in the same way on the relative risk of the different disease forms, and a null hypothesis that corresponds to each gene conferring susceptibility to distinct disease forms. The approaches are illustrated through an application to the generalized and localization-related forms of epilepsy.

Cluster Analysis↗

PubMed2002

Relation of antibiotic use to risk of myocardial infarction in the general population.

There are conflicting reports of an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary artery disease (CAD); randomized trials of antibiotics for the secondary prevention of CAD are currently underway. Physicians may be tempted to believe that their choice of antibiotic class in treating any infection may alter the risk of CAD. Our objective was to determine if the use of antibiotics with antichlamydial activity in the general population reduces the risk of myocardial infarction. A healthcare claims database with 354,258 patients with continuous health and pharmacy coverage for at least 2 years between January 1, 1991 and December 31, 1997 was used for the analyses. Hazard ratios were derived from proportional hazards models with time-dependent covariates, relating antibiotic prescription to first claim related to incident first myocardial infarction during the observation period, adjusting for previous CAD, age, sex, diabetes, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease. There were a total of 1,684,091 person-years of observation and 16,139 incident myocardial infarctions. The adjusted hazard ratios were 1.10 (95% confidence intervals [CI] 1.04 to 1.16) for macrolides, 1.20 (95% CI 1.13 to 1.26) for quinolones, 1.10 (95% CI 0.96 to 1.21) for cephalosporins, 1.00 (95% CI 0.96 to 1.06) for tetracyclines, 1.01 (95% CI 0.96 to 1.06) for penicillins, and 1.13 (95% CI 0.98 to 1.30) for trimetroprim-sulfamethoxazole. The hazard ratios for individual antibiotics with activity against C. pneumoniae within each group were similar. Use of antibiotics with activity against C. pneumoniae does not reduce the risk of myocardial infarction in the general population.

Anti-Bacterial Agents↗

PubMed2002

Testing for familial correlation in age-at-onset.

The analysis of family-study data sometimes focuses on whether a dichotomous trait tends to cluster in families. For traits with variable age-at-onset, it may be of interest to investigate whether age-at-onset itself also exhibits familial clustering. A complication in such investigations is that censoring by age-at-ascertainment can induce artifactual familial correlation in the age-at-onset of affected members. A further complication can be that sample inclusion criteria involve the affection status of family members. The purpose here is to present an approach to testing for correlation that is not confounded by censoring by age-at-ascertainment and may be applied with a broad range of inclusion criteria. The approach involves regression statistics in which subjects's covariate terms are chosen to reflect age-at-onset information from the subjects's affected family members. The results of analyses of data from a family-study of panic disorder illustrate the approach.

Journal Article↗