Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine, for patients with osteoarthritis of the knee: a multi-site, randomized, double-blind, placebo-controlled phase II clinical trial.

OBJECTIVE: To examine the efficacy and safety of Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine (TCM), in patients with knee osteoarthritis (OA). DESIGN: A multi-site, randomized, double-blind, placebo-controlled phase II dose-escalation clinical trial was conducted. Eligible patients who fulfilled American College of Rheumatology criteria were randomized to receive either HLXL or placebo. Clinical assessments included measurement of knee pain and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. A Data and Safety Monitoring Board (DSMB) was established to review the data for ensuring the quality of the trial. RESULTS: In the first stage, 28 participants were randomized to receive either low-dose HLXL-Dan (2400 mg/day) or placebo for 6 weeks. The results showed no statistical difference between the two groups. The study was then re-designed following the recommendation of DSMB. Ninety-two patients were enrolled in the second stage and were randomized to receive either high-dose HLXL-Dan (4000 mg/day for week 1-2, and 5600 mg/day for week 3-8) or placebo for 8 weeks. All outcome assessments showed significant improvements for both groups after 8 weeks but no significant between-group differences. The change (mean ± SD) of WOMAC pain and WOMAC function scores of HLXL and placebo group after 8 weeks were -1.2 ± 1.7 vs -1.4 ± 1.5, and -1.1 ± 1.6 vs -1.3 ± 1.5 respectively. No serious adverse events were reported. CONCLUSION: Although safe to use, an 8-week treatment of HLXL-Dan was not superior to placebo for reduction in pain or functional improvement in patients with knee OA. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT00755326).

Immune status, and not HIV infection or exposure, drives the development of the oral microbiota.

Even with antiretroviral therapy, children born to HIV-infected (HI) mothers are at a higher risk of early-life infections and morbidities including dental disease. The increased risk of dental caries in HI children suggest immune-mediated changes in oral bacterial communities, however, the impact of perinatal HIV exposure on the oral microbiota remains unclear. We hypothesized that the oral microbiota of HI and perinatally HIV-exposed-but-uninfected (HEU) children will significantly differ from HIV-unexposed-and-uninfected (HUU) children. Saliva samples from 286 child-participants in Nigeria, aged ≤ 6 years, were analyzed using 16S rRNA gene sequencing. Perinatal HIV infection was significantly associated with community composition (HI vs. HUU-p = 0.04; HEU vs. HUU-p = 0.11) however, immune status had stronger impacts on bacterial profiles (p < 0.001). We observed age-stratified associations of perinatal HIV exposure on community composition, with HEU children differing from HUU children in early life but HEU children becoming more similar to HUU children with age. Our findings suggest that, regardless of age, HIV infection or exposure, low CD4 levels persistently alter the oral microbiota during this critical developmental period. Data also indicates that, while HIV infection clearly shapes the developing infant oral microbiome, the effect of perinatal exposure (without infection) appears transient.

Breast cancer risk in elderly women with systemic autoimmune rheumatic diseases: a population-based case-control study.

Systemic autoimmune rheumatic diseases (SARDs) are chronic inflammatory and immuno-modulatory conditions that have been suggested to affect cancer risk. Using the Surveillance, Epidemiology and End Results-Medicare-linked database, women aged 67-99 years and diagnosed with incident breast cancer in 1993-2002 (n=84 778) were compared with an equal number of age-matched cancer-free female controls. Diagnoses of SARDs, including rheumatoid arthritis (RA, n=5238), systemic lupus erythematosus (SLE, n=340), Sjogren's syndrome (n=374), systemic sclerosis (n=128), and dermatomyositis (n=31), were determined from claim files for individuals from age 65 years to 1 year before selection. Associations of SARD diagnoses with breast cancer, overall and by oestrogen receptor (ER) expression, were assessed using odds ratio (OR) estimates from multivariable logistic regression models. The women diagnosed with RA were less likely to develop breast cancer (OR=0.87, 95% confidence interval (CI)=0.82-0.93). The risk reduction did not differ by tumour ER-status (OR=0.83, 95% CI=0.78-0.89 for ER-positive vs OR=0.91, 95% CI=0.81-1.04 for ER-negative, P for heterogeneity=0.14). The breast cancer risk was not associated with any of the other SARDs, except for a risk reduction of ER-negative cases (OR=0.49, 95% CI=0.26-0.93) among women with SLE. These findings suggest that systemic inflammation may affect breast epithelial neoplasia.

Full publication of results initially presented in abstracts.

BACKGROUND: Abstracts of presentations at scientific meetings are usually available only in conference proceedings. If subsequent full publication of abstract results is based on the magnitude or direction of study results, publication bias may result. Publication bias, in turn, creates problems for those conducting systematic reviews or relying on the published literature for evidence. OBJECTIVES: To determine the rate at which abstract results are subsequently published in full, and the time between meeting presentation and full publication. To assess the association between study characteristics and full publication. SEARCH STRATEGY: We searched MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, reference lists, and author files. Date of most recent search: June 2003. SELECTION CRITERIA: We included all reports that examined the subsequent full publication rate of biomedical results initially presented as abstracts or in summary form. Follow-up of abstracts had to be at least two years. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. We calculated the weighted mean full publication rate and time to full publication. Dichotomous variables were analyzed using relative risk and random effects models. We assessed time to publication using Kaplan-Meier survival analyses. MAIN RESULTS: Combining data from 79 reports (29,729 abstracts) resulted in a weighted mean full publication rate of 44.5% (95% confidence interval (CI) 43.9 to 45.1). Survival analyses resulted in an estimated publication rate at 9 years of 52.6% for all studies, 63.1% for randomized or controlled clinical trials, and 49.3% for other types of study designs.'Positive' results defined as any 'significant' result showed an association with full publication (RR = 1.30; CI 1.14 to 1.47), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; CI 1.02 to 1.35), and 'positive' results emanating from randomized or controlled clinical trials (RR = 1.18, CI 1.07 to 1.30). Other factors associated with full publication include oral presentation (RR = 1.28; CI 1.09 to 1.49); acceptance for meeting presentation (RR = 1.78; CI 1.50 to 2.12); randomized trial study design (RR = 1.24; CI 1.14 to 1.36); and basic research (RR = 0.79; CI 0.70 to 0.89). Higher quality of abstracts describing randomized or controlled clinical trials was also associated with full publication (RR = 1.30, CI 1.00 to 1.71). AUTHORS' CONCLUSIONS: Only 63% of results from abstracts describing randomized or controlled clinical trials are published in full. 'Positive' results were more frequently published than not 'positive' results.

Factors associated with determinants of sexual functioning in midlife women.

OBJECTIVES: The present study was conducted to assess the associations between a woman's passionate love for her partner and sexual satisfaction and demographic factors, health and life-style characteristics, menopausal status, and menopausal symptoms. METHODS: A cross-sectional study was conducted among women (40-60 years) residing in Maryland (n = 846). chi(2)-tests were performed to evaluate the associations between each of the outcome variables (sexual satisfaction and passionate love for the partner) and predictor/independent variables. Logistic regression analysis was performed to determine whether significant associations from chi(2) analyses remained significant after adjustment for confounders. RESULTS: Older age (adjusted odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01, 1.07), higher education (OR 1.47; 95% CI 1.09, 1.99), and alcohol intake (OR 1.42; 95% CI 1.03, 1.95) were associated with low passion for the partner. Older age was also a significant predictor of low sexual satisfaction (OR 1.04; 95% CI 1.01, 1.07). Women experiencing vaginal dryness had higher odds of low passion for partner (OR 1.67; 95% CI 1.21, 1.31) and low sexual satisfaction (OR 1.58; 95% CI 1.14, 2.20) than women not experiencing vaginal dryness. CONCLUSIONS: Older age, higher education, alcohol intake, and vaginal dryness are significantly associated with lower levels of passionate love for the partner, while older age and vaginal dryness are significantly associated with lower levels of sexual satisfaction in midlife women.

Hormone levels in vegetarian and nonvegetarian teenage girls: potential implications for breast cancer risk.

Between September 1984 and June 1985, a total of 75 adolescent girls, 35 vegetarians residing in a Seventh-Day Adventist school and 40 nonvegetarians residing in a private non-Adventist boarding school, underwent measurement of their plasma hormone levels in the follicular and luteal phase of their menstrual cycles as well as dietary intake measured by 3-day food records, medical history, height, and weight. There were no significant differences between vegetarians and nonvegetarians in average age of the girls, weight, body mass index, age at menarche, years since the onset of menstruation, or percentage of girls with ovulatory cycles. Vegetarian girls had significantly higher levels of log follicular estradiol [2.00 +/- 0.27 (SD) versus 1.85 +/- 0.27 pg/ml, P less than or equal to 0.05] and luteal dehydroepiandrosterone sulfate (DHS) (1.88 +/- 0.71 versus 1.45 +/- 0.80 microgram/ml, P less than or equal to 0.05) than nonvegetarian girls. Follicular DHS was higher in vegetarians than in nonvegetarians (1.72 +/- 0.79 versus 1.45 +/- 0.95 microgram/ml), but the difference was not significant. The differences in follicular and luteal DHS, but not the difference in log estradiol, were significant (P less than or equal to 0.05) after controlling for ovulation, smoking, and alcohol intake with multivariable regression analysis. There were no significant differences in testosterone or in percentage free estradiol levels between vegetarians and nonvegetarians. Smoking was significantly associated with follicular and luteal DHS and with percentage free follicular estradiol, while alcohol use was significantly and inversely associated with percentage free follicular estradiol after controlling for other variables. The implications for breast cancer risk are discussed.

Culture of squamous head and neck cancer on 3T3 fibroblasts following isokinetic velocity sedimentation.

Growth in culture of squamous head and neck cancer is hampered by microbial contamination, low plating efficiency, and cellular heterogeneity within tumors. Furthermore, clumps of cells must be removed if plating efficiency is to be accurately determined. Isokinetic velocity sedimentation was applied to 44 primary tumor specimens in an effort to minimize these problems. Seven fractions were evaluated for cell number, clump number, cell viability, clonogenic growth, plating efficiency, and microbial overgrowth. Unseparated specimens were simultaneously cultured. Microbial growth was significantly associated with the highest gradient fraction. Clumps were significantly associated with the lowest gradient fraction. Colony formation was significantly associated with middle gradient isokinetic velocity sedimentation, although seven specimens grew only when fractionated, suggesting the possibility of inhibitor cells within the tumor specimen.

Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.

Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.

Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer.

PURPOSE: The study was undertaken to define the relationship between tumor response and carboplatin area under the curve (AUC) in patients with ovarian cancer; to study the relationship between carboplatin AUC and myelosuppression in the same population; to establish the true impact of carboplatin AUC, prior therapy, and pretreatment platelet and WBC counts on toxicity; and to define an optimal carboplatin exposure for treating patients with ovarian cancer. METHODS: With the equation AUC = dose/(glomerular filtration rate [GFR]+25), carboplatin AUC (course 1) was calculated for 1,028 patients (450 previously untreated) who received single-agent carboplatin (40 to 1,000 mg/m2) for advanced ovarian cancer. GFR was measured (chromium-51-edathamil [51Cr-EDTA] or creatinine clearance) in all patients. RESULTS: Regression analysis showed that carboplatin AUC, prior treatment, and Eastern Cooperative Oncology Group grade performance status (PS) are predictors of tumor response, thrombocytopenia, and leukopenia. Pretreatment platelet and WBC counts are additional predictors of thrombocytopenia and leukopenia, respectively. Although the likelihood of tumor response increased with increasing carboplatin AUC, this relationship was nonlinear. In all patient subsets, the likelihood of complete response (CR) or overall response did not increase significantly above a carboplatin AUC of 5 to 7 mg/mL x minutes. At any given carboplatin AUC, thrombocytopenia occurred more frequently than leukopenia, although both approached 100% as carboplatin AUC increased. Both thrombocytopenia and leukopenia were more frequent in pretreated than in untreated patients regardless of pretreatment count. At any carboplatin AUC, the influence of PS on likelihood of response and toxicity was profound. CONCLUSION: Carboplatin dosing by AUC will lead to more predictable toxicity, and increasing carboplatin AUC above 5 to 7 mg/mL x minutes does not improve the likelihood of response but does increase myelotoxicity. Therefore, careful evaluation of high-dose carboplatin therapy in a prospective, randomized trial is needed before such treatment becomes accepted practice.

Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) contains all known and potential atherogenic lipid particles. Therefore, non-HDL-C level may be as good a potential predictor of risk for cardiovascular disease (CVD) as low-density lipoprotein cholesterol (LDL-C). OBJECTIVES: To determine whether non-HDL-C level could be useful in predicting CVD mortality and to compare the predictive value of non-HDL-C and LDL-C levels. METHODS: Data are from the Lipid Research Clinics Program Follow-up Study, a mortality study with baseline data gathered from 1972 through 1976, and mortality ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64 years at entry were observed for an average of 19 years, with CVD death as the main outcome measure. RESULTS: A total of 234 CVD deaths in men and 113 CVD deaths in women occurred during follow-up. Levels of HDL-C and non-HDL-C at baseline were significant and strong predictors of CVD death in both sexes. In contrast, LDL-C level was a somewhat weaker predictor of CVD death in both. Differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 19% and 15%, respectively, in men. In women, differences of 0.78 mmol/L (30 mg/dL) in non-HDL-C and LDL-C levels corresponded to increases in CVD risk of 11% and 8%, respectively. CONCLUSIONS: Non-HDL-C level is a somewhat better predictor of CVD mortality than LDL-C level. Screening for non-HDL-C level may be useful for CVD risk assessment.

Changes in body weight, body composition, and energy intake in women fed high- and low-fat diets.

The effects of a 20%-fat diet (LF) on total body weight, lean body weight, and adiposity were studied in 18 premenopausal women with body mass index (BMI) of 18-44. Subjects were fed a 37%-fat (HF) control diet for 4 wk followed by the LF diet for 20 wk. Total body weight, lean body weight, and fat weight were measured at the end of the HF and LF dietary periods by hydrostatic weighing. Despite adjustments in energy intake to maintain weight throughout the study, subjects exhibited a 2.8% decrease in total body weight (P less than 0.0006), an 11.3% decrease in fat weight (P less than 0.0001), and a 2.2% increase in lean body weight (P less than 0.0149) by the end of the LF period. Similar changes were observed in obese (BMI greater than 30) and non-obese women (BMI less than 30). By the end of the LF period, energy intake had increased significantly in comparison with the HF diet (119% of the HF intake, P less than 0.0001). Results could not be explained by changes in daily activity levels and suggest that macronutrient composition plays a role in energy requirements for weight maintenance.

Insulin-like growth factor I and low-density-lipoprotein cholesterol in women during high- and low-fat feeding.

In vitro studies suggest that insulin-like growth factor I (IGF-I) may modulate hepatic production and peripheral utilization of lipoproteins. We measured blood concentrations of IGF-I; total, high-density-lipoprotein, and low-density-lipoprotein (LDL) cholesterol; and apolipoproteins in 18 women with above average cholesterol after high- and low-fat diet periods. Total cholesterol fell 6% (P less than 0.02) during the low-fat diet because of reduced concentrations of LDL cholesterol (P less than 0.01). Serum concentrations of IGF-I were inversely correlated with total and LDL cholesterol and apolipoprotein B during both high-fat (r = -0.676, P less than 0.005; r = -0.745, P less than 0.001; and r = -0.504, P less than 0.04, respectively) and low-fat (r = -0.656, P less than 0.005; r = -0.757, P less than 0.001; and r = -0.695, P less than 0.001, respectively) diets. IGF-I increased with reduced fat intake in obese subjects only. Thus, IGF-I may contribute to the regulation of LDL cholesterol in mildly hypercholesterolemic women but may not mediate the beneficial response to reduced fat intake.

Differential reduction of plasma cholesterol by the American Heart Association Phase 3 Diet in moderately hypercholesterolemic, premenopausal women with different body mass indexes.

The ability of a low-fat, low-cholesterol diet to improve the risk-factor profiles of moderately hypercholesterolemic, premenopausal women was evaluated. Nineteen women were fed a typical American diet for 1 mo, after which a low-fat diet consisting of 21% of total energy (en%) as fat, 59 en% carbohydrates, 19 en% protein, and 96 mg cholesterol/d (P:S 1.8) was given. After 5 months, total and low-density lipoprotein (LDL) cholesterol was decreased by 7% and 11%, respectively, and total triglycerides increased by approximately 30%. High-density-lipoprotein (HDL) cholesterol was decreased by 12% at month 2 and 5% at month 5 (P less than 0.05). Although HDL2 cholesterol decreased progressively throughout the diet period to -35% by month 5, HDL3 cholesterol, which decreased to -5% at month 1, increased to +7% by month 5. Of the plasma apolipoproteins only apo A-II was altered (+15%) by the diet. Body mass index correlated to baseline values and affected response to diet; only the leanest women had significant decreases in total, LDL, and HDL2 cholesterol in response to the low-fat diet.

The effect of flunarizine on essential tremor.

We investigated the effect of flunarizine treatment (10 mg/d) in 17 subjects with essential tremor in a double-blind placebo-controlled design. Tremor was assessed by clinical scoring, tremographic recordings, and subjective rating by subjects. Of the 15 subjects who completed the study, 13 showed improvement. We conclude that flunarizine is effective treatment for essential tremor.

A double-blind trial of clonazepam in the treatment of parkinsonian dysarthria.

We studied the effect of clonazepam in a double-blind trial on 12 parkinsonian patients with hypokinetic dysarthria. Speech samples were judged on 14 of the dimensions used in the Mayo Clinic dysarthria study. Of the 11 patients who completed the study, 10 showed improvement. The effective dosage of clonazepam was 0.25 to 0.5 mg/d with higher dosage than that less effective. Clonazepam has a definite role in the management of parkinsonian dysarthria.

Headache in acute cerebrovascular disease.

Headache features were compared in 51 patients with acute subarachnoid hemorrhage (SAH), 61 with intraparenchymal hemorrhage (IPH), and 160 with ischemic stroke (IS). SAH patients had more sentinel headaches, more onset headaches, and more bilateral and severe onset headaches than patients with IPH or IS. Vomiting with onset headache was more common in SAH and IPH. In stepwise logistic regression analysis, onset headache and vomiting were direct predictors of SAH, but were inversely related to IS. Sentinel headache was not a predictor of underlying stroke mechanism. The data suggest that some headache features are more frequently associated with particular stroke subtypes and that onset headache and vomiting may be important indicators of stroke mechanism.

Weekly alcohol consumption, cigarette smoking, and the risk of ischemic stroke: results of a case-control study at three urban medical centers in Chicago, Illinois.

To assess the role of current weekly alcohol consumption as a risk factor for cerebral infarction, we administered a pretested questionnaire to 205 middle-aged and elderly acute ischemic stroke patients and 410 outpatient controls matched by age, sex, race, and method of hospital payment. The frequency of hypertension (p less than 0.001) and transient ischemic attacks (p = 0.051), and mean weekly alcohol consumption (p = 0.0286) and mean pack-years cigarette exposure (p = 0.0168) were higher among stroke index cases than controls. For weekly alcohol consumption and mean pack-years cigarette exposure, there was a highly significant dose-response effect. In analyses to assess the possibility of mutual confounding effects of independent variables, we found hypertension and smoking to be independent risk factors for ischemic stroke, while alcohol consumption was not. Separate analyses by sex yielded similar results. We conclude that current weekly alcohol consumption may not be an independent risk factor for cerebral infarction in middle-aged and elderly patients.

Clinical and angiographic comparison of asymptomatic occlusive cerebrovascular disease.

We compared clinical and arteriographic features in 106 patients with symptomatic unilateral carotid territory occlusive disease to determine the frequency and distribution of occlusive arterial lesions in asymptomatic vessels. Among black patients who were predominantly from Chicago, young, and female, there were fewer transient ischemic attacks and myocardial infarcts, less claudication, and more asymptomatic lesions of the supraclinoid internal carotid artery, anterior cerebral artery stem, and the middle cerebral artery stem. Among white patients predominantly from New England, elderly, and male, there was more frequent and severe occlusive asymptomatic disease at extracranial carotid and vertebral artery sites. Knowledge of the distribution of asymptomatic lesions will help guide evaluation and treatment strategies for patients with occlusive cerebrovascular disease.

Chinese-white differences in the distribution of occlusive cerebrovascular disease.

The distribution of cerebrovascular lesions is affected by race. Blacks and Japanese have more intracranial occlusive cerebrovascular disease, while whites have more extracranial disease. Despite a high incidence of stroke in China, there are few formal studies of the distribution of vascular occlusive disease in Chinese populations. We compared clinical and angiographic features of 24 white and 24 Chinese patients with symptomatic occlusive cerebrovascular disease. In symptomatic vascular territories, whites had more severe (greater than or equal to 50% stenosis) extracranial lesions, while Chinese had more severe intracranial lesions. When we counted mild and severe lesions in a symptomatic territory, whites had more extracranial lesions while Chinese had more intracranial lesions. When we combined symptomatic and asymptomatic territories, whites had more extracranial lesions, while Chinese had more intracranial lesions. White patients reported more transient ischemic attacks. The distribution of lesions, however, was not explained by differences in incidence of transient ischemia, hypertension, diabetes, hypercholesterolemia, or ischemic heart disease between the groups. The preponderance of intracranial vascular lesions in Chinese patients is similar to that seen in blacks and Japanese. Racial differences in the occurrence of extracranial and intracranial lesions raise the possibility of a different underlying pathophysiology for the 2 locations.

Hypertension and sodium transport in 390 healthy adults in Chicago.

A total of 390 people undergoing routine examinations at the Portes Center, a screening center in Chicago, and at the Northwestern Memorial Hospital employee health service, underwent an in-depth battery of tests designed to explore the relationships of both intracellular erythrocyte sodium and sodium-lithium countertransport with age, race, gender, body mass index, pattern of alcohol intake, exogenous hormone use and the presence of hypertension. Erythrocyte sodium was significantly higher in blacks than in whites and in men than in women aged 20-39 years. Relationships of erythrocyte sodium with race and gender, as well as inverse associations with alcohol intake in men, and positive associations with age and the presence of hypertension in women were significant on multivariate analysis after control for other variables. Sodium-lithium countertransport was significantly higher in whites than in blacks and in men than in women aged 20-59 years. Associations of sodium-lithium countertransport with race and gender as well as positive associations of sodium-lithium countertransport with body mass index in men and women were significant on multivariate analysis after control for other variables. Age-related gender differences in both sodium-lithium countertransport and erythrocyte sodium, as well as the association of erythrocyte sodium with the presence of hypertension in women but not in men, suggest a hormonal interaction with sodium transport in the development of hypertension.