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1.  Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants 
Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.
To identify novel genetic variants associated with resting heart rate in African Americans.
Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P ≤ 2.5 × 10−8).
Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98 × 10−15). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.
An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.
PMCID: PMC3718037  PMID: 23183192
African Americans; Heart rate; Single nucleotide polymorphisms; Meta-analysis
2.  The Risk of Parkinson Disease Associated with Urate in a Community-Based Cohort of Older Adults 
Neuroepidemiology  2011;36(4):223-229.
Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.
The association of baseline urate (μmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 μmol/l), middle (300–500 μmol/l), and high (>500 μmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.
Women had significantly lower urate concentrations than did men [316.8 μmol/l (SD 88.0) vs. 367.4 μmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 μmol/l (OR 1.69, 95% CI 1.03–2.78) but not for urate >500 μmol/l (OR 1.55, 95% CI 0.72–3.32) in men. A negative linear term was significant for urate <500 μmol/l, and across the entire range a convex quadratic term was significant.
Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.
PMCID: PMC3124452  PMID: 21677446
Parkinson disease; Risk factors; Oxidative stress; Epidemiology; Uric acid
3.  Association of heat shock proteins with all-cause mortality 
Age  2012;35(4):1367-1376.
Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9417-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3705092  PMID: 22555621
Heat shock proteins; HEAT shock factor 2; All-cause mortality
4.  Post Hoc Parkinson's Disease: Identifying an Uncommon Disease in the Cardiovascular Health Study 
Neuroepidemiology  2010;35(4):241-249.
Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis.
We used combinations of self-report, International Classification of Diseases − 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD.
We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8–1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26–0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29–0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null.
Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.
PMCID: PMC2978249  PMID: 20881426
Cardiovascular Health Study; Cohort study; Epidemiology; International Classification of Diseases, 9th edition; Smoking; Parkinson's disease
5.  Physical activity predicts gray matter volume in late adulthood 
Neurology  2010;75(16):1415-1422.
Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation.
In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline.
Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold.
Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
= modified Mini-Mental State Examination;
= Cardiovascular Health Study Cognition Study;
= Digit Symbol Substitution Test;
= gray matter;
= mild cognitive impairment;
= odds ratio;
= physical activity;
= Statistical Parametric Mapping;
= total intracranial volume;
= voxel-based morphometry;
= white matter.
PMCID: PMC3039208  PMID: 20944075
6.  Executive Function, Memory, and Gait Speed Decline in Well-Functioning Older Adults 
In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive deficits in aging may account for gait slowing over time.
Multiple cognitive tasks were administered at baseline in 909 participants in the Health, Aging, and Body Composition Study Cognitive Vitality Substudy (mean age 75.2 ± 2.8 years, 50.6% women, 48.4% black). Usual gait speed (m/s) over 20 minutes was assessed at baseline and over a 5-year follow-up.
Poorer performance in each cognitive task was cross-sectionally associated with slower gait independent of demographic and health characteristics. In longitudinal analyses, each 1 SD poorer performance in global function, verbal memory, and executive function was associated with 0.003–0.004 m/s greater gait speed decline per year (p =.03–.05) after adjustment for baseline gait speed, demographic, and health characteristics.
In this well-functioning cohort, several cognitive tasks were associated with gait speed cross-sectionally and predicted longitudinal gait speed decline. These data are consistent with a shared pathology underlying cognitive and motor declines but do not suggest that specific executive cognitive deficits account for slowing of usual gait in aging.
PMCID: PMC2949334  PMID: 20581339
Aging; Cognitive function; Gait speed
7.  Concurrent Change in Dehydroepiandrosterone Sulfate and Functional Performance in the Oldest Old: Results From the Cardiovascular Health Study All Stars Study 
The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.
DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996–1997 and 2005–2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005–2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.
After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.
In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
PMCID: PMC2920580  PMID: 20466773
Aging; Biomarker; Dehydroepiandrosterone sulfate; Function
8.  Moderate alcohol consumption and risk of functional decline: is there a causal relationship? The Health, Aging, and Body Composition Study 
Moderate alcohol intake has been associated with better physical performance and reduced likelihood of functional limitations. Causal inference has been difficult as most studies are cross-sectional. Our study investigated the prospective relationship between alcohol consumption and the risk of incident mobility limitation.
The analysis included 3,061 participants in the Health ABC study, community-dwelling adults aged 70–79 without mobility disability at baseline. Study outcomes were the incidence of mobility limitation, defined as self-report at two consecutive semi-annual interviews of any difficulty either walking a quarter of a mile or climbing stairs, and the incidence of mobility disability, defined as severe difficulty or inability to perform these tasks at two consecutive reports. Weekly alcohol intake was assessed at baseline and categorized as follows: former, never or occasional (<1 drink/week), light (1 to 7 drinks per week for men; 1 to 3 drinks per week for women), moderate (8 to 14 drinks per week for men; 4 to 7 drinks per week for women), and heavy (> 14 drinks per week for men; > 7 drinks per week for women). Crude incidence rates were calculated per 100 person-years; Cox proportional-hazard regression analysis was used to estimate Hazard Ratios (HR) and 95% Confidence Interval (CI).
During a follow-up time of 6.5 years, participants consuming moderate levels of alcohol had the lowest incidence of mobility limitation (6.4 per 100 person-years (P-Y); men: 6.4 per 100 P-Y; women 7.3 per 100 P-Y) and mobility disability (2.7 per 100 P-Y; men: 2.5 per 100 P-Y; women: 2.9 per 100 P-Y). Adjusting for demographic characteristics, moderate alcohol intake was associated with reduced risk of mobility limitation (HR:0.70;CI:0.55–0.89) and mobility disability (HR:0.66; CI:0.45–0.95), compared to never or occasional consumption. Additional adjustment for life-style related variables substantially reduced the strength of the association (HR:0.85;CI:0.66–1.08) and mobility disability (HR:0.81; CI:0.56–1.18). Conversely, adjustment for diseases and health status indicators did not importantly affect the strength of the associations, suggesting that life-style is most important in confounding the studied relationship.
Globally taken, these results suggest caution in attributing a direct benefit of moderate alcohol intake on functional ability.
PMCID: PMC3149890  PMID: 19737328
9.  Effects of exercise on mobility in obese and non-obese older adults 
Obesity (Silver Spring, Md.)  2009;18(6):1168-1175.
Coupled with an aging society, the rising obesity prevalence is likely to increase the future burden of physical disability. We set out to determine whether obesity modified the effects of a physical activity intervention designed to prevent mobility disability in older adults. Older adults at risk for disability (N = 424, age range: 70-88 years) were randomized to a 12 month physical activity (PA) intervention involving moderate intensity aerobic, strength, balance and flexibility exercise (150 min per week) or a successful aging (SA) intervention involving weekly educational workshops. Individuals were stratified by obesity using a body mass index ≥ 30 (n = 179). Mobility function was assessed as usual walking speed over 400 meters and scores on a short physical performance battery (SPPB), which includes short distance walking, balance tests and chair rises. Over 12 months of supervised training, the attendance and total amount of walking time was similar between obese and non-obese subjects and no weight change was observed. Non-obese participants in the PA group had significant increases in 400 meter walking speed (+1.5%), while their counterparts in the SA group declined (−4.3%). In contrast, obese individuals declined regardless of their assigned intervention group (PA: −3.1%; SA: −4.9%). SPPB scores, however, increased following PA in both obese (PA: +13.5%; SA: +2.5%) and non-obese older adults (PA: +18.6%; SA: +6.1%). A moderate intensity PA intervention improves physical function in older adults, but the positive benefits are attenuated with obesity.
PMCID: PMC3114403  PMID: 19834467
10.  Neurologic abnormalities in HTLV-I– and HTLV-II–infected individuals without overt myelopathy 
Neurology  2009;73(10):781-789.
Human T-lymphotropic virus (HTLV) type I is the causative agent of HTLV-associated myelopathy (HAM)/tropical spastic paraparesis, and a number of HAM cases with HTLV-II infection have also been reported. However, despite some reports, it is unclear whether HTLV-I or -II infection is associated with other neurologic manifestations.
An analysis of medical histories and screening neurologic examinations from a prospective cohort of 153 HTLV-I, 388 HTLV-II, and 810 HTLV-seronegative individuals followed up for means of 11.5, 12.0, and 12.2 years was performed. Participants diagnosed with HAM were excluded. We calculated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race or ethnicity, income, educational attainment, body mass index, alcohol and cigarette consumption, injection drug use, diabetes, and hepatitis C virus status, using generalized estimating equations for repeated measures.
HTLV-I and -II participants were more likely than seronegative participants to have leg weakness (ORs 1.67 [95% CI 1.28–2.18] and 1.44 [1.16–1.78]), impaired tandem gait (ORs 1.25 [95% CI 1.07–1.47] and 1.45 [1.27–1.64]), Babinski sign (ORs 1.54 [95% CI 1.13–2.08] and 1.51 [1.18–1.93]), impaired vibration sense (ORs 1.16 [95% CI 1.01–1.33] and 1.27 [1.14–1.42]), and urinary incontinence (ORs 1.45 [95% CI 1.23–1.72] and 1.70 [1.50–1.93]). For both HTLV-I and -II participants, higher odds of sensory neuropathy by monofilament examination were no longer significant after adjustment for confounding.
These results provide strong evidence that human T-lymphotropic virus (HTLV)-I and -II are associated with a spectrum of predominantly motor abnormalities in patients without overt HTLV-associated myelopathy. Further investigation of the clinical course and etiology of these abnormalities is warranted.
= adult T-cell leukemia/lymphoma;
= confidence interval;
= human T-lymphotropic virus–associated myelopathy;
= HTLV Outcomes Study;
= human T-lymphotropic virus;
= odds ratio;
= adjusted odds ratio.
PMCID: PMC2739606  PMID: 19738173
11.  Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly 
Background and aims
Glycosylated hemoglobin (HbA1c) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA1c may be associated with an increased risk of death and cardiovascular mortality in older adults.
Methods and results
We evaluated the association between HbA1c with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals ≥65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA1c and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA1c groups were: 4.4% per year, 4.3% per year and 4.6% per year for tertile 1 (≤5.6%), tertile 2 (5.61–6.20%) and tertile 3 (≥6.21%), respectively. In unadjusted and fully adjusted analyses, baseline HbA1c was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95% confidence interval 0.91–1.47] and hazard ratio: 1.31 [95% confidence interval 0.90–1.93], respectively for the highest HbA1c tertile compared with the lowest).
These results suggest that HbA1c does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.
PMCID: PMC2888268  PMID: 19364638
Glycosylated hemoglobin; Hemoglobin A1c; Cardiovascular disease; Mortality; Elderly
12.  Predictors of maintaining cognitive function in older adults 
Neurology  2009;72(23):2029-2035.
Although several risk factors for cognitive decline have been identified, much less is known about factors that predict maintenance of cognitive function in advanced age.
We studied 2,509 well-functioning black and white elders enrolled in a prospective study. Cognitive function was measured using the Modified Mini-Mental State Examination at baseline and years 3, 5, and 8. Random effects models were used to classify participants as cognitive maintainers (cognitive change slope ≥0), minor decliners (slope <0 and >1 SD below mean), or major decliners (slope ≤1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner.
Over 8 years, 30% of the participants maintained cognitive function, 53% showed minor decline, and 16% had major cognitive decline. In the multivariate model, baseline variables significantly associated with being a maintainer vs a minor decliner were age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55–0.77 per 5 years), white race (OR = 1.72, 95% CI 1.30–2.28), high school education level or greater (OR = 2.75, 95% CI 1.78–4.26), ninth grade literacy level or greater (OR = 4.85, 95% CI 3.00–7.87), weekly moderate/vigorous exercise (OR = 1.31, 95% CI 1.06–1.62), and not smoking (OR = 1.84, 95% CI 1.14–2.97). Variables associated with major cognitive decline compared to minor cognitive decline are reported.
Elders who maintain cognitive function have a unique profile that differentiates them from those with minor decline. Importantly, some of these factors are modifiable and thus may be implemented in prevention programs to promote successful cognitive aging. Further, factors associated with maintenance may differ from factors associated with major cognitive decline, which may impact prevention vs treatment strategies.
= Modified Mini-Mental State Examination;
= body mass index;
= Center for Epidemiologic Studies–Depression Scale score;
= confidence interval;
= C-reactive protein;
= Health, Aging and Body Composition;
= interleukin;
= myocardial infarction;
= odds ratio;
= Rapid Estimate of Adult Literacy in Medicine;
= tumor necrosis factor.
PMCID: PMC2692177  PMID: 19506226
13.  Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects 
Thorax  2005;61(1):10-16.
Inflammatory markers are increased in chronic obstructive pulmonary disease (COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance.
The Health Aging and Body Composition (Health ABC) study is a prospective observational cohort of well functioning individuals aged 70–79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease (OLD).
Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p<0.0001), higher systemic interleukin (IL)‐6 levels (2.6 pg/ml v 2.2 pg/ml, p<0.0001), and higher C‐reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p<0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL‐6 (adjusted regression coefficients (β) = −5.3 (95% CI −9.1 to−1.5) and −3.1 (95% CI −4.3 to −1.9), respectively). IL‐6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (β = −6.4 (95% CI −12.8 to −0.03) and −3.4 (95% CI −5.4 to −1.3), respectively, for IL‐6 and β = −10.1 (95% CI −18.7 to −1.5) and −3.8 (95% CI −7 to −0.6), respectively, for TNF). IL‐6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups.
In well functioning elderly subjects with or without OLD, IL‐6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.
PMCID: PMC2080698  PMID: 16284220
C‐reactive protein; chronic obstructive lung disease; muscle dysfunction; systemic inflammation; interleukin 6; tumour necrosis factor; exercise capacity
14.  Protective role of appendicectomy on onset and severity of ulcerative colitis and Crohn’s disease 
Gut  2002;51(6):808-813.
Background and aims: Recent studies on appendicectomy rates in ulcerative colitis and Crohn’s disease have generally not addressed the effect of appendicectomy on disease characteristics. The aims of this study were to compare appendicectomy rates in Australian inflammatory bowel disease patients and matched controls, and to evaluate the effect of prior appendicectomy on disease characteristics.
Methods: Patients were ascertained from the Brisbane Inflammatory Bowel Disease database. Controls matched for age and sex were randomly selected from the Australian Twin Registry. Disease characteristics included age at diagnosis, disease site, need for immunosuppression, and intestinal resection.
Results: The study confirmed the significant negative association between appendicectomy and ulcerative colitis (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.14–0.38; p<0.0001) and found a similar result for Crohn’s disease once the bias of appendicectomy at diagnosis was addressed (OR 0.34, 95% CI 0.23–0.51; p<0.0001). Prior appendicectomy delayed age of presentation for both diseases and was statistically significant for Crohn’s disease (p=0.02). In ulcerative colitis, patients with prior appendicectomy had clinically milder disease with reduced requirement for immunosuppression (OR 0.15, 95% CI 0.02–1.15; p=0.04) and proctocolectomy (p=0.02).
Conclusions: Compared with patients without prior appendicectomy, appendicectomy before diagnosis delays disease onset in ulcerative colitis and Crohn’s disease and gives rise to a milder disease phenotype in ulcerative colitis.
PMCID: PMC1773455  PMID: 12427781
ulcerative colitis; Crohn’s disease; appendicitis; appendicectomy
15.  Molecular diagnosis is important to confirm suspected pseudoachondroplasia 
Journal of Medical Genetics  2000;37(1):64-65.
PMCID: PMC1734440  PMID: 10691412
16.  Oral contraceptives and breast cancer among African-american women and white women. 
The higher incidence of breast cancer among African-American women younger than 50 as compared to white women points to the need to examine exposures that are common among younger women, including exposure to oral contraceptives (OC). We examined patterns of OC use and their associations with breast cancer in a population-based, case-control study conducted in North Carolina between 1993 and 1996. The study population was comprised of 858 cases and 789 controls, of whom 40% were African-American women. There was little evidence that breast cancer was associated with OC use among older women (age >50) of either race, most of whom discontinued use in the distant past. Among younger women, there was a modest, but nonsignificant, increase in risk associated with ever use of OCs for both African-American and white women. There was a trend of increasing risks with more recent use among African-American women, whereas no such trend was apparent for white women. Overall, we found more substantial age differences than race differences in patterns of OC use and the risk of breast cancer associated with their use. The similarity of the associations between African-American and white women suggest that racial differences in breast cancer incidence are not likely to be attributable to OC use.
PMCID: PMC2593962  PMID: 11560288
17.  Issues in studying the effectiveness of health services for children. 
Health Services Research  1998;33(4 Pt 2):1041-1058.
OBJECTIVES: To discuss issues in studying the effectiveness of health services for children, suggest areas in which more research is needed, and recommend strategies for future research. PRINCIPAL FINDINGS: Issues that should be considered include the choice of perspective, which will help determine the interventions studied and the measures of effectiveness and cost-effectiveness chosen. Unique challenges in this area include the fact that serious measurable morbidity is relatively uncommon in children, that causal relationships between services and outcomes may be difficult to establish, and that standard measures of cost-effectiveness may fail to accurately measure important benefits, such as reduced parental anxiety. More research is needed on high-risk and health-promoting behaviors, on critical parent behaviors, on classifying children by vulnerability status, on modes of delivery of preventive care, and on violence prevention. RECOMMENDATIONS: Group-randomized designs and observational research designs that take advantage of natural variations in practice may be increasingly useful in effectiveness studies. Parent- and patient-reported measures of health status and quality of life should be made briefer and more practical for routine use, and better measures of cost-effectiveness are needed. Future research efforts can best be supported by the concerted efforts of various constituencies, including health plans, providers, patients, researchers, and the government.
PMCID: PMC1070303  PMID: 9776948
18.  Obstacles and approaches to clinical database research: experience at the University of California, San Francisco. 
With increasing availability of clinical data in machine-readable form, and decreasing cost of storing and manipulating that data, retrospective research using clinical databases has become more feasible. Nonetheless, much of the potential for clinical research using these data remains unrealized. Obstacles to clinical database research include difficulty accessing data, difficulty using retrospective data to draw valid inferences about medical tests and treatments, and a shortage of investigators trained and interested in using a clinical database to answer their questions. At the University of California, San Francisco, we have developed a Clinical Database Research Program (CDRP) to try to overcome these obstacles. The CDRP maintains a relational database of patient data obtained from diverse sources and a small staff dedicated to providing such data to researchers. The CDRP staff also provides support for design and analysis of studies using the database--the development of methods for such studies is our primary research interest. Finally, to increase the number of investigators using the database for research, we are integrating training in clinical epidemiology and clinical research methods into residency and fellowship training, and offering an elective in clinical database research for trainees who wish to undertake a specific project.
PMCID: PMC2247798  PMID: 7949992
19.  Caution over journal supplements. 
BMJ : British Medical Journal  1993;307(6912):1140-1141.
PMCID: PMC1679148  PMID: 8251818
20.  Coughs cause systemic blood flow. 
Thorax  1984;39(3):192-195.
Although it is known that rhythmic coughing can preserve consciousness during ventricular fibrillation, the arterial pressure transients which result have not yet been shown to reflect forward blood flow in man. The effectiveness of cough in causing forward flow in eight normal volunteers with bradycardia was studied. They coughed between cardiac cycles, using an audio and visual display of the electrocardiogram. The force of the cough was varied and measured with an oesophageal balloon. Blood flow was recorded with a Döppler velocity probe over the radial artery and a finger or ear photoplethysmograph. Motion artefact on the Döppler record due to coughing was excluded by transiently obstructing the brachial artery. We compared the areas under 5-10 consecutive Döppler and photoplethysmograph pulse flow tracings due to the cough and heart beat with those due to the immediately preceding heart beat alone. They were significantly increased. This augmentation was greater in those flow pulses accompanied by a more vigorous cough. It is concluded that coughing is associated with an effort dependent forward flow pulse in the arterial circulation.
PMCID: PMC459760  PMID: 6710427
21.  The problem of tricyclic antidepressant poisoning. 
Postgraduate Medical Journal  1979;55(646):528-532.
In the year May 1976 to April 1977, 489 enquiries about the management of tricyclic antidepressant poisoning received at the London Centre of the National Poisons Information Service were followed-up. One hundred and sixty-four patients (33.5%) were unconscious, convulsions occurred in 62 (12.7%), hypotension in 31 (6.3%), respiratory depression in 28 (5.7%), tachydysrhythmias in 17 (3.5%) and cardiac arrest in 12 patients (2.5%). Sixteen patients died (3.3%). No statistically significant differences were found between individual antidepressants although poisoning with amitriptyline-like drugs resulted in a significantly higher proportion of unconscious patients than poisoning with imipramine-like drugs (P less than 0.01). There were more asymptomatic children than adults and more unconscious adults than children. Tricyclic antidepressant poisoning is a major clinical problem in general medical and paediatric practice.
PMCID: PMC2428080  PMID: 514929
23.  Paracetamol poisoning in children. 
British Medical Journal  1978;2(6135):478-479.
PMCID: PMC1606740  PMID: 678931
24.  Choosing an antidepressant. 
British Medical Journal  1978;1(6116):859.
PMCID: PMC1603491  PMID: 638494
25.  Poisoning with maprotiline and mianserin. 
British Medical Journal  1977;2(6081):260.
PMCID: PMC1631398  PMID: 884460

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