Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene.

BACKGROUND: Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK1 ). SP and NK1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA. METHODS: Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed. RESULTS: Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10-4 , OR = 0.79 95% 0.68-0.90 after meta-analysis). CONCLUSIONS: This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA. SIGNIFICANCE: This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested.

Site specific osteoarthritis and the index to ring finger length ratio.

OBJECTIVE: To quantify the relationship between the index to ring finger length ratio second digit:fourth digit(2D:4D) and radiographic osteoarthritis (OA) of the knee. METHODS: Data from the Clearwater Osteoarthritis Study (COS) were analyzed. We selected a random sample of 236 subjects with knee OA (Kellgren-Lawrence scores >or=2) and compared their finger length ratio pattern with a random sample of 242 controls. Finger length measurements were recorded from digitized hand radiographs. Subjects were classified into three groups: type 1 (index finger longer than ring finger), type 2 (fingers of equal length) and type 3 (index finger shorter than ring finger). Using a case-control design, we calculated odds ratios (OR). RESULTS: The type 3 finger pattern was significantly associated with knee OA (OR 2.59, 95% confidence interval (CI) 1.54-4.37). Women demonstrated a stronger association of visual type 3 finger pattern and knee OA (OR 4.40, 95% CI 2.62-7.38) compared to men (OR 2.59, 95% CI 1.34-5.00). CONCLUSIONS: The type 3 finger length pattern is associated, to a statistically significant degree, with OA of the knee. The type 3 finger length pattern (ring finger longer than index finger) appears to be an indicator of OA predisposition. Consideration of this pattern in clinical assessments may be an added aid as clinicians screen patients for OA risk.

Driving safety in Parkinson's disease.

In this study, 39 patients with PD and 25 control subjects without neurologic disease completed testing in a driving simulator. PD patients had more total collisions on the driving simulator than control subjects (t = -3.7, p < 0.01). In PD patients, collisions were associated with Hoehn and Yahr stage (chi(2) = 12.4, p = 0.006) and correlated with Unified Parkinson's Disease Rating Scale score (r = 0.5, p < 0.01).

Body mass index growth in a sample of U.S. children: repeated measures data analysis of the Minneapolis Children's Blood Pressure Study.

Longitudinal assessments of the body mass index (BMI) in children and adolescents are limited. The purpose of the study was to describe the growth patterns of the BMI in children and young adults. Black and White children of Minneapolis Children's Blood Pressure Study (MCBPS) were 6 to 9 years old at entry and were followed for 12 years at 19 separate visits. Those with at least five visits (n = 1,302) were included for analysis, using non-linear mixed effects models in conjunction with the Gompertz curve. The growth patterns of four sex-ethnic groups were different at three levels: starting level (SL) (kg/m(2)), asymptote level (AL) (kg/m(2)), and peak growth age (PGA) (in years). In this context, SL is the average BMI level at age 6, AL is the average BMI level when growth diminishes, and PGA is the average age at which the rate of growth in the BMI peaks. The SL (16.3 +/- 0.1) for White males was significantly greater than SL in the other three sex-ethnic groups, among which there were no significant differences. There was a significant ethnic difference in AL between Black females (25.5 +/- 0.3) and White females (24.4 +/- 0.2) and a marginally significant difference in AL between Black females and Black males (24.4 +/- 0.3). For PGA, only sex differences were significant: Black females reached the peak at the earliest age at (11.5 +/- 0.1) years, followed by White females (11.7 +/- 0.1), Black males (12.6 +/- 0.1), and White males (12.8 +/- 0.1).

Regional patterns in the incidence of aplastic anemia in Thailand. The Aplastic Anemia Study Group.

The annual incidence of aplastic anemia has been determined in a rigorous and standardized epidemiologic study conducted in Thailand. A total of 374 cases were identified over a period of 3-6 years in three geographically defined and distinct regions of the country; Bangkok, Khonkaen in the northeast, and Songkla in the south. The incidence was 3.9 cases per million persons in Bangkok, 3.0 per million in Songkla, and 5.0 per million in Khonkaen. These rates are as high or higher than in any region of Europe or Israel as reported in the International Agranulocytosis and Aplastic Anemia Study, in which the methods and case definition were the same. Rates were stable over the course of the study. There were marked differences in incidence between northern and southern rural regions of Thailand, and among Bangkok suburbs. These differences, together with an unusual peak in the incidence among young people in Bangkok, suggest the possibility of occupational and environmental factors in the etiology of aplastic anemia.

Agranulocytosis in Bangkok, Thailand: a predominantly drug-induced disease with an unusually low incidence. Aplastic Anemia Study Group.

Agranulocytosis, a syndrome characterized by a marked reduction in circulating granulocytes, is strongly associated with medical drug use in Europe and the United States. Unregulated use of common pharmaceutical agents in developing countries has been suspected of causing large numbers of cases of agranulocytosis and deaths, especially among children. To elucidate the incidence and etiology of agranulocytosis in Thailand, a population-based case-control study of symptomatic agranulocytosis that resulted in hospital admission was conducted in Bangkok from 1990 to 1994. An attempt was also made to study the disease in Khonkaen (in northeastern Thailand) and Songkla (in southern Thailand), but there were insufficient cases in the latter regions, and the analysis was confined to subjects from Bangkok. In that region, the overall incidence of agranulocytosis was 0.8 per million per year; there were no deaths. As expected, the incidence was higher in females (0.9 per million), and it increased with age (4.3 per million beyond age 60). Among 25 cases and 529 controls the relative risk estimate for a combined category of all suspect drugs was 9.2 (95% confidence interval = 3.9-21), and the proportion of cases that could be attributed to drug use was 68%. For individual drugs and drug classes the data were sparse; within these limitations, the strongest association appeared to be with antithyroid drugs. One case and three controls were exposed to dipyrone, a drug known to cause agranulocytosis; with such scanty data the risk could not be evaluated. Exposure to pesticides or solvents was not associated with an increased risk. This is the first formal epidemiologic study of agranulocytosis in a developing country. As in the West, most cases are attributable to medical drug use. However, the incidence of agranulocytosis in Bangkok, and apparently, in Thailand as a whole, is unusually low, and the disease does not pose a public health risk.

Evaluation of the accuracy of on-site multi-analyte drug testing devices in the determination of the prevalence of illicit drugs in drivers.

A principal goal of this research was to conduct a field evaluation of "on-site" multi-analyte drug testing devices to determine the most accurate, efficient, and cost-effective device available for the purpose of rapidly detecting drivers under the influence of drugs. Four on-site kits were selected and evaluated for accuracy and efficiency for the detection of tetrahydrocannabinol (THC), the cocaine metabolites (COC), and opiates (OPI). From 16 December 1995 to 17 March 1996, 303 voluntary urine specimens were collected by law enforcement officers from persons arrested for driving-under-the-influence (DUI). These specimens were tested using the four selected kits and aliquots of the specimens were sent to a DHHS certified lab for "gold standard" comparison testing by immunoassay and Gas Chromatography/Mass Spectrometry. On-site kit sensitivity ranged from 82.9% to 100% for THC, 82.5% to 100% for COC, and all were at 100% for OPI. Specificity, and positive and negative predictive values were also determined. Accuracy ranged from 94.0% to 98.3% for THC, 97.4% to 98.0% for COC, and 99.7% to 100% for OPI. All four kits were in very close agreement on prevalence: 15.5% to 15.8% for THC, all were at 13.2% for COC, and all were at 0.7% for OPI. For law enforcement purposes, sensitivity may be the most important indicator in these kits.

Low drug attributability of aplastic anemia in Thailand. The Aplastic Anemia Study Group.

From 1989 to 1994, a population-based, case-control study of aplastic anemia was conducted in Thailand, including the regions of Bangkok, Khonkaen in the northeast, and Songkla in the south. An annual incidence in Bangkok of 3.7 cases per million population, about twice as high as in Western countries, has been reported. To evaluate the etiologic role of drugs, 253 subjects were compared with 1,174 hospital controls. With multivariate adjustment for confounding, a significant association was identified for exposure 2 to 6 months before admission to thiazide diuretics (relative risk estimate 7.7; 1.5 to 40). There were crude associations with sulfonamides (relative risk estimate, 7.9; P = 0.004) and mebendazole (6.3; P = 0.03) (there were insufficient data for multivariate adjustment). Excess risks for the three drugs were in the range of 9 to 12 cases per million users. There was no significant association with chloramphenicol, although the multivariate relative-risk estimate was elevated (2.7; 0.7 to 10). Other drugs that have been reported to increase the risk of aplastic anemia, such as nonsteroidal anti-inflammatory drugs and anticonvulsants, were not commonly used. There were no associations with commonly used drugs, including benzodiazepines, antihistamines, oral contraceptives, and herbal preparations. For all associated drugs, the overall etiologic fraction (the proportion of cases attributable to an exposure) was 5%, compared with 25% in Europe and Israel. Drugs are uncommon causes of aplastic anemia in Thailand, and their use does not explain the relatively high incidence of the disease in that country.

Use of household pesticides and the risk of aplastic anaemia in Thailand. The Aplastic Anemia Study Group.

BACKGROUND: Aplastic anaemia is a severe blood dyscrasia that is more common in Thailand than in Western countries. Its a etiology remains poorly understood. METHODS: A case-control study was conducted in Bangkok and two rural regions of Thailand. The effect of household pesticides was evaluated among 253 incident cases of aplastic anaemia and 1174 hospital controls. RESULTS: A total of 54% of the cases and 61% of the controls were exposed 1-6 months previously. For most individual household pesticides and for groups classified according to chemical type (organophosphates, pyrethrins, and organochlorines), the relative risk (RR) estimates approximated 1.0; upper 95% confidence limits were below 2.0 for many comparisons. A significant association was observed for exposure to combination products containing dichlorvos and propoxur, with an overall RR estimate of 1.7 (95% confidence interval [CI]: 1.1-2.6); the estimate for regular use was 1.6 (95% CI: 0.9-2.9). CONCLUSIONS: The absence of a higher risk for the regular use of dichlorvos/propoxur reduces the credibility of the apparent association, which could well have been an artefact of multiple comparisons. We conclude that most household pesticides used in Thailand do not appear to increase the risk of aplastic anaemia.

Association of seropositivity for hepatitis viruses and aplastic anemia in Thailand.

Aplastic anemia is more common in the Orient than in western countries, with an incidence in Thailand that is 2- to 3-fold higher than in Europe. Aplastic anemia after hepatitis is a well characterized clinical entity, and clinical hepatitis is also prevalent in the Far East. We performed a prospective case-control study to determine risk factors for aplastic anemia in Bangkok and two rural regions during 1989 to 1994. A total of 375 cases were identified, along with 1,174 hospital controls matched for age and sex. Historical data were collected by trained interviewers. Sera from a subset of cases (N = 177) and controls (N = 183) were tested for antibodies to hepatitis viruses A, B, and C and hepatitis B surface antigen. There was no evidence of association of aplastic anemia with hepatitis B or hepatitis C. Previous exposure to hepatitis A, as determined by immunoglobulin G (IgG) seropositivity, was significantly associated with aplastic anemia: the relative risk adjusted for confounding was 2.9 (95% confidence interval 1.2-6.7). The same association also existed for persons under age 25 years, in whom the prevalence of hepatitis A IgG was lower than in the total population. However, no patients showed evidence of recent infection with hepatitis A (immunoglobulin M [IgM] seropositivity). These results indicate that exposure to a hepatitis virus is a risk indicator for aplastic anemia in Thailand, and while itself unlikely to be etiologic, hepatitis A may be a surrogate marker for another enteric microbial agent.

Finding and treating depression in Alzheimer's patients: a study of the effects on patients and caregivers.

Unrecognized and untreated depression occurs frequently in Alzheimer's disease (AD) patients, adding to the agony already experienced by patient and caregiver. The authors screened AD patients living with a family caregiver for depression. Twelve patients with confirmed depression were treated in an open-label study with antidepressant medication, with dosage adjustment by a psychiatrist at Weeks 2, 4, 8, and 16. Data collection occurred at baseline, Week 4, and Week 16. Depression decreased significantly (p < .01). Contrary to expectations, patient functional capacity declined (p = .045). Cognition remained unchanged (p > .05). Caregiver burden, caregiver depressive symptomatology, and quality of life of patient and caregiver remained unchanged (p > .05). The authors conclude that depression in AD can be detected if a collateral source, such as the caregiver, is available. The depression can and should be treated. More research is needed to determine the impact on patient functioning, caregiver burden, caregiver depressive symptomatology, and quality of life of patient and caregiver.

Drugs in the aetiology of agranulocytosis and aplastic anaemia.

Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case-control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population-based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/10(6) in the IAAAS and 0.8/10(6) in Thailand; by contrast the incidence of aplastic anaemia was 2.0/10(6) in the IAAAS and 4.1/10(6) in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/10(6) users/wk; the most strongly associated drugs were procainamide, anti-thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/10(6) users in a 5-month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug-induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.

An association of aplastic anaemia in Thailand with low socioeconomic status. Aplastic Anemia Study Group.

The relationship of socioeconomic status to the risk of aplastic anaemia was evaluated in a case-control study conducted in Bangkok and two rural regions of Thailand (Khonkaen and Songkla). Among 152 cases and 921 controls there were significant trends of increasing risk with decreasing years of education (P = 0.01) and total household income (P = 0.0001), after control for confounding. The relative risk estimate for those with monthly incomes of < 1500 baht (about $60 U.S.) was 3.9 (95% confidence interval 2.1-7.3) compared to those with monthly incomes of at least 5000 baht (about $200). The pattern of increasing risk with decreasing income was observed in all three regions, with significant trends in Bangkok (P = 0.004) and Khonkaen (P = 0.003). This finding may partly explain the high incidence of aplastic anaemia in Thailand. Low socioeconomic status may be a surrogate for one or more environmental factors that could cause aplastic anaemia, such as infectious pathogens or toxic exposures.

Physical activity as a risk factor for osteoarthritis of the knee.

A case-control study was conducted to evaluate the association between knee osteoarthritis (OA) and physical activity (PA) among a community group aged 40 years and older. Case patients (85 males, 154 females) had radiologically confirmed knee OA with grade 2+ changes, according to Kellgren and Lawrence criteria. Control subjects (85 males, 154 females) had no radiologic evidence of knee OA. A statistically significant positive association between high PA level and knee OA was observed for women, with an age-adjusted odds ratio (OR) of 1.66 and 95% confidence interval (CI) of 1.01 to 2.72. In men no association was observed (OR = 0.95; 95% CI, 0.49 to 1.83). These associations persisted when controlling simultaneously for potential confounders including age, obesity, history of knee injury, and socioeconomic status, indicating that the OA-PA association is limited to women. One possible explanation is that risk factors for knee OA are influenced by hormones.

Short course training in epidemiology and biostatistics for graduate and undergraduate public health professionals.

The University of South Florida has developed short courses of 2 to 3 days in epidemiology and biostatistics geared to public health workers. A key focus is providing skills which will assist local and State public health units to assess their status and measure progress with respect to achieving their explicitly stated health objectives for the year 2000. The courses were developed after the identification of the training needs in health departments and other public health settings. The training objectives were (a) to enhance the biostatistics skills of professionals involved in the analysis of health data; (b) to reinforce basic knowledge of epidemiologic methods and its practical applications in public health settings, including measures of disease frequency and association, epidemic outbreak investigations, and the identification and use of surveillance data; and (c) to demonstrate the application of the risk factor approach to select the interventions needed to reach health objectives for year 2000 and how to evaluate such interventions. A total of 43 students have taken this course series. Professional staff in health departments cannot always enroll in formal training in epidemiology and biostatistics because of time limitations or a lack of a bachelor's degree. However, the need exists. An alternative to such training could be the short course program described in this paper.

Bronchodilator testing "confidence intervals" based on the level of bronchial responsiveness.

"Confidence intervals" based upon inhalation of placebo have been proposed as criteria for defining a significant response to an inhaled bronchodilator. The published intervals were derived from a clinically heterogeneous population. We calculated the difference (delta) between spirometric data before and after placebo in 109 consecutive patients referred for methacholine bronchoprovocation challenge testing. The mean delta, expressed both as a percent change and as actual volume change for both the FVC and FEV1, was not significantly different in patients with bronchial hyperresponsiveness, as compared to subjects with a negative methacholine challenge test; however, the variance of measurements in hyperresponsive subjects was significantly greater than that of the normal population. In addition, as the category of responsiveness increased from mild to moderate to severe hyperresponsiveness, so did the variance within these groups. A negative correlation between the measured PC20FEV1 and the volume and percent change was noted. We conclude that patients with hyperresponsive airways may display increased spirometric variation before and after placebo. This general approach for establishing normal limits for defining a significant response appears to be valid, but the actual values used may vary, depending on the composition of the population tested and the goals of the study. Also, the use of the term, "confidence intervals," in this context is inappropriate; and we propose, instead, the use of percentiles and the simpler terms, upper 90th or 95th percentiles.