The STR/ort mouse model of spontaneous osteoarthritis - an update.

Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes.

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DESIGN: Prospective randomized controlled trial. SETTING: Multicenter community-based clinical trials network. PATIENTS: One-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. INTERVENTIONS: Randomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. MAIN OUTCOMES MEASURES: Plasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. RESULTS: The average baseline CD4 cell count was 230 x 10(6) cells/l and the median HIV-1 RNA was 28,085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: -0.53 log, 95% confidence interval, -0.77 to -0.29; P = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. CONCLUSION: In patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens. The Terry Beirn Community Programs for Clinical Research on AIDS.

The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific ('signature') protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.

Acyclovir use and survival among human immunodeficiency virus-infected patients with CD4 cell counts of < 500/mm3. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

To examine the relationship between acyclovir use and survival in AIDS, we performed a retrospective analysis of data collected through an observational cohort of the 17-site Community Program for Clinical Research on AIDS (CPCRA), under the sponsorship of the National Institute of Allergy and Infectious Diseases. Data were analyzed regarding 2,368 patients with CD4+ lymphocyte counts of < 500/mm3, and 7,836 follow-up visits were conducted from September 1990 to July 1994. Factors associated with use of acyclovir were studied by stratified analysis of variance and Mantel-Haenzel chi 2 tests. The association between acyclovir and survival was studied with use of the proportional hazards regression model. Individuals reporting acyclovir use were more likely to be white, male, and homosexual; to have a history of herpes simplex and zoster; and to have lower CD4+ T cell counts than those who did not. After adjustments for differences in baseline factors, acyclovir use was not associated with prolonged survival.

Data analysis issues for protocols with overlapping enrollment.

Many persons with HIV require and take several medications. The efficacy and safety of many of these medications are uncertain. Usually limited data on drug interactions are available. Thus simultaneous and sequential enrolment of patients into multiple studies is desired for reasons of science and efficiency. This paper discusses the analysis of data arising from coenrolment in multiple studies sponsored by the Community Programs for Clinical Research on AIDS (CPCRA). Factorial designs and those in which patients are sequentially instead of simultaneously randomized are compared. Approaches to data analysis, based on intention-to-treat, for individual and pairs of trials are described. An antiretroviral trial and a trial for prophylaxis of Pneumocystis carinii pneumonia (PCP) are used for illustration. We conclude that such analyses may yield useful information on drug interactions and that a more vigorous coenrolment policy should be pursued in AIDS research.

Considerations in choice of a clinical endpoint for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).

In most clinical trials of antiretroviral therapy for patients infected with HIV, the major outcome variable has been the combined clinical endpoint of any new or recurrent AIDS defining event. We review features of combined endpoints and use data from the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) to evaluate this outcome measure in terms of relevance, diagnostic certainty and sensitivity. We conclude that this endpoint is not relevant because: (i) the 19 different events constituting the combined endpoint are equally weighted in analyses even though they vary considerably in terms of risk of death; and (ii) events after the first are ignored, thus the event profile of patients is not taken into account in making treatment comparisons. We also conclude that power may be low with use of this endpoint if treatments under study do not have an immediate impact on disease progression, if some events which occur soon after randomization represent a disease process that has already begun to incubate, or if treatment differences for the various events constituting the combined endpoint are differentially effected by treatment. Since the ease and certainty of diagnosis of each of the 19 events also vary, we recommend that survival be the primary endpoint of antiretroviral trials, and that all opportunistic events experienced by patients, not just the first, be collected and summarized. Trial reports should include comparisons of incidence of each event by treatment group so that readers can rank events as they please. A single summary measure which considers severity and the entire event profile, as described here, would also be useful for assessing the impact of treatments on quality of life. Further research on approaches for weighting and combining multiple outcome measures is needed.

Primary prophylaxis with pyrimethamine for toxoplasmic encephalitis in patients with advanced human immunodeficiency virus disease: results of a randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS.

Pyrimethamine, 25 mg thrice weekly, was evaluated as primary prophylaxis for toxoplasmic encephalitis (TE) in a double-blind, randomized clinical trial in patients with human immunodeficiency virus (HIV) disease, absolute CD4 lymphocyte count of < 200/microL (or prior AIDS-defining opportunistic infection), and the presence of serum IgG to Toxoplasma gondii. Leucovorin was coadministered only for hematologic toxicity. There was a significantly higher death rate among patients receiving pyrimethamine (relative risk [RR], 2.5; 95% confidence interval [CI], 1.3-4.8; P = .006), even after adjusting for factors predictive of survival. The TE event rate was low in both treatment groups (not significant). Only 1 of 218 patients taking trimethoprim-sulfamethoxazole but 7 of 117 taking aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia developed TE (adjusted RR for the trimethoprim-sulfamethoxazole group, 0.16; 95% CI, 0.01-1.79; P = .14). Thus, for HIV-infected patients receiving trimethoprim-sulfamethoxazole, additional prophylaxis for TE appears unnecessary.

Risk factors for death from different types of stroke. Multiple Risk Factor Intervention Trial Research Group.

UNLABELLED: The objective of this study was to investigate risk factors for death from different types of stroke among men screened for the Multiple Risk Factor Intervention Trial (MRFIT). A total of 353,340 men were screened by 20 centers for the MRFIT in 1973 to 1975; vital status has been ascertained over an average of 12 years of follow-up (range: 11 to 13 years). Death certificates were coded using the International Classification of Diseases (ICD), ninth revision. Deaths from stroke were classified as death from subarachnoid hemorrhage (ICD code 430), death from intracranial hemorrhage (ICD codes 431 and 432), death from nonhemorrhagic stroke (ICD codes 433 through 438), and death from any type of stroke (ICD codes 430 through 438). RESULTS: During an average of approximately 12 years of follow-up, 765 deaths from stroke were identified; 139 of these deaths were attributable to subarachnoid hemorrhage; 227, to intracranial hemorrhage; and 399 were classified as nonhemorrhagic stroke. Blood pressure and cigarette smoking were strongly related to each type of stroke. Systolic blood pressure was a stronger predictor than diastolic blood pressure. With the exception of subarachnoid hemorrhage, death rates from each type of stroke increased with age and were higher for black men. The positive association of age and race with subarachnoid hemorrhage was much weaker than for the other types of stroke and was not significant. Income was inversely associated with risk of death from nonhemorrhagic stroke and was not associated with either subarachnoid or intracranial hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity of clindamycin as prophylaxis for AIDS-associated toxoplasmic encephalitis. Community Programs for Clinical Research on AIDS.

A double-blind, placebo-controlled trial was set up to compare clindamycin and pyrimethamine as prophylaxis for toxoplasmic encephalitis (TE) in HIV-infected patients at risk of the disorder. Interim analysis showed that clindamycin-treated patients were 4.4 (95% confidence interval 1.3-15.2) times more likely to experience an adverse effect that necessitated withdrawal of the study drug than those who received placebo. Diarrhoea and rash were reported in 16 (31%) and 11 (21%), respectively, of 52 patients treated with clindamycin (300 mg twice daily) compared with 2 (6%; p = 0.06) and none (p = 0.01) of the 32 placebo-treated patients. The clindamycin arm of the trial was prematurely terminated, although recruitment to the pyrimethamine arm continues.

Cigarette smoking and mortality. MRFIT Research Group.

METHODS: The relationship of cigarette smoking and smoking cessation to mortality was investigated among men screened for and also among those randomized to the Multiple Risk Factor Intervention Trial (MRFIT). RESULTS: Among the 361,662 men screened for the MRFIT, cigarette smoking was an important risk factor for all-cause, coronary heart disease (CHD), stroke, and cancer mortality. These risks, on the log relative scale, were strongest for cancers of the lung, mouth, and larynx. The excess risk associated with cigarette smoking was greatest for death from CHD. Overall, approximately one-half of all deaths were associated with cigarette smoking. Among the 12,866 randomized participants, weak positive associations with duration of cigarette smoking habit and tar and nicotine levels were found with all-cause mortality. For both SI and UC men, substantial differences in subsequent CHD (34-49%) and all-cause (35-47%) mortality were evident for men who reported cigarette smoking cessation by the end of the trial compared with those continuing to smoke. There was no evidence that lung cancer death rates were lower among cigarette smokers who quite compared with those who continued to smoke in this 10-year follow-up period. CONCLUSION: The data are consistent with results of previous epidemiologic studies indicating that the benefits of smoking cessation on CHD are rapid, while for lung cancer, the benefit is not evident in a 10-year follow-up period.

The epidemiology of pulmonary function and COPD mortality in the multiple risk factor intervention trial.

The potential determinants of the changes in chronic obstructive pulmonary disease (COPD) mortality were evaluated using both the Multiple Risk Factor Intervention Trial (MRFIT) screenees, the longitudinal analysis of the participants, and the differences in special intervention (SI) and usual care (UC) groups. COPD was the underlying cause for only one third of all death certificates listing COPD. Small changes in classification will have a major impact on reported COPD death rates. Cigarette smoking is clearly the primary determinant of COPD mortality. Decreased pulmonary function is an independent risk factor for coronary heart disease (CHD) mortality. Smoking cessation results in a slower rate of decline in pulmonary function over time, especially among heavy smokers. Careful evaluation of smoking cessation, including repeat chemical measures, suggest that the percentage of long-term quitters, especially among heavy smokers has been overestimated. The low percentage of quitters substantially reduced the power to detect an intervention effect. The increased cigarette smoking among recent older cohorts, and failure to substantially reduce smoking, especially among heavy smokers, may be an important factor accounting for the failure to note a decline in COPD mortality among older persons.

Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease.

Among the 356,222 men screened for the Multiple Risk Factor Intervention Trial who had no history of hospitalization for heart attack at entry, more than 2,000 coronary deaths occurred during 6 years of follow-up. With this large data set, detailed cross-tabulations clearly and simply showed the strong graded relation between blood pressure and coronary heart disease death. This risk gradient was evident in each of five age groups ranging from 35 to 57 years and for levels of diastolic blood pressure ranging from less than 75 mm Hg to greater than 115 mm Hg. Systolic blood pressure was more strongly associated with coronary heart disease death than was diastolic blood pressure, and isolated systolic blood pressure elevation was found to be an important risk factor in these middle-aged men. The risk of coronary death was increased among hypertensive men who had elevated serum cholesterol levels or who smoked cigarettes. Because less than 10% of hypertensive men had cholesterol levels in the lowest quintile (below 182 mg/dl) and were nonsmokers, a multi-intervention approach for the large majority of hypertensive persons is clearly indicated. Risks of death were also substantially increased among those hypertensive men who already had end-organ damage, emphasizing the importance of early treatment to prevent such damage. These findings have implications for the design of prevention trials and clinical practice, as it is clear that systolic as well as diastolic blood pressure should be considered in treating hypertensive patients. Additionally, treatment goals should be directed at preventing not only death but many other morbid events, clinical and subclinical, that are associated with elevated blood pressure and that are preventable with appropriate treatment.

Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial.

The large cohort of white men (317,871) 35 to 57 years old at initial screening for possible enrollment into the Multiple Risk Factor Intervention Trial (MRFIT) was examined with regard to initial blood pressure levels and subsequent coronary heart disease (CHD), stroke, and all-cause mortality. The overall prevalence of isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg, was 0.67% among white men screened for MRFIT and increased with age (0.31% among 35- to 39-year-olds to 1.7% among 55- to 57-year-olds). The 6 year CHD and all-cause mortality rates in men over 50 were highest in those with ISH compared with both subjects with diastolic hypertension and those with normal pressure. The relative risk of death from stroke in those with ISH, compared with that in those with SBP less than 160 mm Hg and those with DBP less than 90 mm Hg, was 3.0 (95% confidence interval 1.3 to 6.8). In addition, at any level of DBP, the level of SBP appeared to be the major determinant of all-cause and CHD mortality. The determinants of ISH in individuals under 60 years of age as well as the possible efficacy of its treatment should be evaluated further.

Serum cholesterol levels and cancer mortality in 361,662 men screened for the Multiple Risk Factor Intervention Trial.

Several prospective studies have demonstrated an association between low serum cholesterol level and subsequent mortality from cancer. This finding was explored in the large cohort (361,662) of men aged 35 to 57 years who were screened for possible randomization to the Multiple Risk Factor Intervention Trial. Mortality follow-up revealed a significant excess of cancer in the lowest decile of serum cholesterol level during the early years of follow-up, which attenuated over time. In contrast, the association between high serum cholesterol and coronary heart disease did not diminish during the average of seven years of follow-up. These findings are consistent with the inference that the association between low serum cholesterol level and cancer is at least in part due to an effect of preclinical cancer on serum cholesterol level. A subset of the cohort (12,866 men) participated in the randomized Multiple Risk Factor Intervention Trial protocol, which called for annual measurements of serum cholesterol level. Among the 150 of these men who died of cancer during the trial, cholesterol level fell 22.7 mg/dL (0.59 mmol/L) more than in the survivors over an equivalent period. These data are consistent with the foregoing inference.

Effectiveness of a pinhole method for visual acuity screening.

Visual acuity screening was performed in the home in an adult population, using a standardized, retroilluminated chart. A pinhole disk was utilized to retest those subjects who initially failed the screening. All subjects failing the screening with the pinholes, and an equal number of age-matched subjects passing the screening (controls), were asked to have a complete ophthalmologic examination, including a protocol refraction in an eye clinic (clinic examination). Without use of the pinhole disk, 14.4% of subjects failed to read a 20/40 line. Use of the pinholes reduced the failure rate to 6.9%. Fifty-seven percent of those failing and 55% of controls had the clinic examination. Determination of best-corrected visual acuity after protocol refraction in the clinic indicated that the false-positive rate (the percentage of subjects who failed the screening but had visual acuity of 20/40 or better on the clinic examination) for the screening was 26%, and the false-negative rate (the percentage of subjects who passed the screening but had visual acuity of worse than 20/40 on the clinic examination) was 1.5%. Use of a pinhole disk is highly effective for visual acuity screening, reducing the false-positive rate by more than half.

An evaluation of the Social Security Administration master beneficiary record file and the National Death Index in the ascertainment of vital status.

To evaluate the relative utility of the Social Security Administration and National Death Index as sources of mortality data, the vital status of 12,866 participants in the Multiple Risk Factor Intervention Trial was identified from these sources and compared to the known mortality experience. The SSA correctly identified 87.8 per cent of the 409 deaths that occurred between 1974 and 1980. Underreporting of deaths by the SSA occurred for participants with certain demographic characteristics, especially marital status. For the years 1979 and 1980, the period for which the SSA and NDI have comparable data, the SSA correctly identified 93.2 per cent and the NDI correctly identified 98.4 per cent of the 191 known deaths. The NDI matching process resulted in a large number of false positive matches.