Biomedical subjects
Publications and source records attributed to M Hochberg.
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OBJECTIVES: To determine whether alendronate sodium treatment is associated with upper gastrointestinal (GI) tract adverse experiences (AEs)-particularly those of the stomach, duodenum, or esophagus-in the Fracture Intervention Trial, and to assess the relationship between alendronate use and upper GI tract events among women at increased risk for these outcomes. DESIGN: Randomized, double-blind, placebo-controlled trial with a mean follow-up of 3.8 years. Women were initially randomized to receive alendronate sodium, 5 mg/d, or placebo. After 2 years, the alendronate sodium dose was increased to 10 mg/d. PARTICIPANTS: A total of 6459 women aged 54 to 81 years recruited from 11 US clinical centers. All participants had low hip bone mineral density. Women with major upper GI tract disease (recent ulcers, upper GI tract bleeding, or use of daily medication for dyspepsia) were excluded. Regular nonsteroidal anti-inflammatory drug users were not excluded. MEASUREMENTS: Self-reported upper GI tract AEs were ascertained by interview every 3 months. Serious upper GI tract AEs were confirmed and classified by review of hospital records and endoscopy reports, if available. Upper GI tract AEs were further analyzed in 2 specified groups-gastroduodenal and esophageal-to examine events that might be related to upper GI tract mucosal irritation. Gastric and duodenal perforations, ulcers, and bleeding events were combined for analysis of these clinically important outcomes. RESULTS: The overall incidence of upper GI tract events was similar in the alendronate and placebo groups (47.5% vs. 46.2%; relative risk [RR], 1.02; 95% confidence interval [CI], 0.95-1.10). The incidence of gastroduodenal perforations, ulcers, and bleeding events was 1.6% in the alendronate group and 1.9% in the placebo group (RR, 0.86; 95% CI, 0.59-1.24). The incidence of nonspecific upper GI tract conditions, such as abdominal pain, dyspepsia, nausea, and vomiting, was also similar in the 2 groups. Esophageal events occurred in 10.0% and 9.4% of patients in the alendronate and placebo groups, respectively (RR, 1.06; 95% CI, 0.91-1.24). Esophagitis not reported as reflux was more common in the alendronate group (0.7%) than in the placebo group (0.4%), but not significantly so (RR, 1.71; 95% CI, 0.90-3.39). Alendronate use was not associated with a significant increase in upper GI tract events among women at increased risk for these events (those aged > or =75 years with previous upper GI tract disease or using nonsteroidal anti-inflammatory drugs). CONCLUSION: In these older women, upper GI tract complaints, particularly dyspepsia and abdominal pain, were common, but alendronate treatment was not associated with an increased incidence of upper GI tract events, even in high-risk subgroups.
OBJECTIVES: To review all randomized trials of analgesics and anti-inflammatory therapy in osteoarthritis (OA) of the hip. To determine which non-steroidal, anti-inflammatory drug (NSAID) is the most effective, and which NSAID is the most toxic. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register and Medline up to August 1994. Reference lists of all trials were also manually searched. SELECTION CRITERIA: All randomized controlled trials comparing non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics in patients with Osteoarthritis. The trials selected for inclusion were identified by one reviewer (TT) and rechecked by a second (MH). DATA COLLECTION AND ANALYSIS: Qualitative assessments were performed using a quality scoring system designed for NSAID trials in rheumatoid arthritis. Both the design and analysis aspects of the trials were evaluated, each aspect being rated on a scale of 0 to 8. A quantitative method, which calculates the ratio of improvement produced by one NSAID to that produced by another, was used to rate the relative efficacy of different NSAIDs with respect to pain relief. Toxicity comparisons were made according to the reviewer findings. All quality assessments were carried out independently by two reviewers (TT, BS). All data abstraction was carried out by one reviewer (TT) and rechecked by two other reviewers (BS, GW). A consensus was reached on discrepancies. MAIN RESULTS: Forty-three trials were identified, and of these, 39 evaluated NSAIDs, while four evaluated only analgesics. The median design and analysis scores were two and four respectively. Six NSAIDs were included in at least five trials. Of these, indomethacin was rated more effective in five of its seven comparisons, but more toxic in seven of 12 comparisons. Only five of the 29 (17%) NSAID comparisons found statistically significant differences in efficacy. Of the 43 RCTs identified only 17 had statistical data available for future pooling for this meta-analysis. In the case where data was missing, authors of the trials will be contacted for inclusion of data in future reviews. REVIEWER'S CONCLUSIONS: NSAID trials in patients with OA of the hip appear to be weakened by the lack of standardization of case definition of OA, and also by the lack of standardization of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA can be offered at this time based on this analysis.
UNLABELLED: Osteoarthritis (OA) has been characterized as a slowly evolving degenerative disease affecting cartilage and bone, with a multifactorial etiology that may differ depending on the joint site. Because OA has been considered a disease of the elderly, few population-based studies have examined its frequency and characteristics in persons under the age of 45. OBJECTIVE: In this cross-sectional study, we examined X-rays of both knees and the dominant hand in a population of younger black and white pre- and perimenopausal women in southeastern Michigan (N = 1053) for evidence of osteoarthritis, and reported these outcomes according to the risk factors of age, body size, injury, and smoking behavior. DESIGN: Sixteen joints of the dominant hand as well as both knee joints (weight bearing) were evaluated using the Kellgren and Lawrence Atlas of Standard Radiographs of Arthritis. RESULTS: By age 40, radiographically-defined osteoarthritis emerges in both the hands and knees. These age characteristics are observed in both black and white women, however prevalence of knee OA was higher in black females (23.1%) compared with white females (8.5%), and although prevalence of hand OA was more comparable between black (25.5%) and white females (19.2%), the joint sites affected differed. The major risk factors reported in studies of older populations are present in this younger population where OA is newly emerging. CONCLUSIONS: This study provides strong evidence that primary prevention of OA must be implemented in young adulthood to curtail the emergence of radiographically-defined OA at the mid-life.
The evidence from randomised, controlled trials of the ability of antiresorptive treatments to reduce the risk of fractures in postmenopausal women with osteoporosis is reviewed and summarised. The aminobisphosphonates, alendronic acid and risedronic acid, and the selective estrogen receptor modulator raloxifene have all been shown to reduce the incidence of radiographic vertebral fractures. Only alendronic acid and risedronic acid have been shown to reduce the incidence of non-spine fractures in women with postmenopausal osteoporosis. There is evidence of antifracture efficacy for calcium plus vitamin D, primarily in a nursing home setting or in people with low intakes of these nutrients. Furthermore, since both the placebo and active treatment groups received calcium and vitamin D in most controlled trials of antiresorptive agents, it appears that the other agents provide benefits beyond those of calcium and vitamin D alone. There is insufficient published evidence from randomised controlled trials to convincingly support the antifracture efficacy of other agents, including calcitonin, estrogen and etidronic acid, at this time. Data from observational studies suggest, however, that estrogen and etidronic acid may have antifracture efficacy in this population.
BACKGROUND: Low back pain is a highly prevalent chronic condition, yet little is known about the disabling effects of this common problem in older adults. This study examines the relationship between the presence and severity of low back pain and disability in older women. METHODS: The study population was 1,002 disabled older women participating in a population-based prospective study of disablement. Key outcome measures of disability included level of difficulty and inability to perform the following daily activities: light housework, shopping, walking one-quarter mile, climbing stairs, lifting, and activities of daily living (ADLs). RESULTS: Forty-two percent of participants reported they had low back pain for at least one month in the year before baseline. The prevalence of severe back pain decreased markedly with age (10% of those > or = 85 yr versus 23% in each of the two younger 10 yr age groups). After multivariate adjustments, women with severe back pain were 3 to 4 times more likely than other women to have a lot of difficulty with light housework or shopping. There was also an increased likelihood of difficulty with mobility tasks and basic ADLs among those with severe back pain. No associations were found between back pain and being unable to perform any of the daily activities studied, indicating possible differences in disablement processes leading to functional difficulties versus functional incapacity. CONCLUSIONS: There was a strong association between back pain and functional difficulties in older women, pointing to the need for further research using longitudinal methods.
OBJECTIVE: The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to standard care for the relief of pain and dysfunction in elderly patients with osteoarthritis (OA) of the knee. METHODS: Seventy-three patients with symptomatic OA of the knee were randomly assigned to treatment (acupuncture) or standard care (control). Analysis was performed on last score carried forward to account for patients who dropped out before completion. Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne indices at baseline and at 4, 8 and 12 weeks. Patients in the control group were offered acupuncture treatment after 12 weeks. The data for these patients are pooled with those from the original acupuncture group for within-group analysis. RESULTS: Patients randomized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received standard treatment alone. Significant differences on total WOMAC Scale were seen at 4 and 8 weeks. There appears to be a slight decline in effect at 4 weeks after cessation of treatment (12 weeks after first treatment). No adverse effects of acupuncture were reported. CONCLUSION: These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee.
Sunscreens capable of inhibiting erythema are assumed to protect against UV-induced carcinogenesis as well. However, the correlation between inflammation and carcinogenesis is uncertain, and the prevention of UV-induced erythema might in fact be biologically irrelevant as an indicator of protection against UV-induced skin cancer. Ultraviolet-B radiation promotes cutaneous immunosuppression by the release of immunoregulatory cytokines and by depletion of Langerhans cells. We investigated the ability of two different sunscreens to inhibit UVB-induced expression of epidermal interleukin (IL)-10 and depletion of Langerhans cells. Chemical and physical sunscreens were applied to the forearms of volunteers 15 min prior to 4 minimal erythemal doses of UVB exposure. Suction blisters were induced 24 h after irradiation, and RNA was extracted from the blister roofs. Reverse transcription polymerase chain reaction was performed using primers for IL-10 and CD1a. A chemical sunscreen containing octyl methoxycinnamate (12 sun protection factor [SPF]) and a physical sunscreen containing zinc oxide (16 SPF) were assayed: UVB-induced IL-10 mRNA expression was nearly totally inhibited by both sunscreens (median protection for chemical and physical sunscreens was 95% and 78%, respectively), whereas UVB-induced Langerhans cell depletion was partially prevented (47% and 50% for chemical and physical sunscreens, respectively). Langerhans cell protection by sunscreens was confirmed by estimation of cell density after ATPase staining. In contrast, both sunscreens effectively prevented the induction of UVB-induced erythema. We believe this to be the first demonstration that sunscreens can prevent the induction of cutaneous mediators of immunosuppression, and that the results indicate that the immunoprotection offered by the sunscreens is significantly lower than their ability to prevent erythema.
The purpose of this study was to examine the relationship between health status and health utility measures in 34 older claudicants and to determine which attributes of health status were significant predictors of health state valuation/preference. The MOS SF-36 was used to assess health status and the rating scale and multiattribute Health Utility Index (HUI) were used to assess utility scores. With regard to health status, the bodily pain and physical functioning subscales contributed the most to reductions in quality of life (QoL) with mean subscale scores substantially lower than reported population norms. Patients rated their health status approximately one-third below a state of perfect health on both utility measures. Moderate correlations were observed between the MOS SF-36 subscale scores and the HUI and rating scale scores. In multivariable regression models, physical functioning and mental health were the best predictors of HUI scores, whereas general health and vitality were the best predictors of rating scale scores. Approximately 50% of the variance in utility scores was explained by these attributes. This study provides further documentation that bodily pain and reductions in physical function contribute to reductions in QoL in older patients with intermittent claudication. Other attributes of health status, however, notably psychological distress, were predictive of patients' preference for health states. Recognized constructs of physical and mental health explained the substantial variation in the utility/preference assessment in this population. Furthermore, these data are consistent with those reported in the Dutch Iliac Stent Trial.
Non-Hodgkin's B-lymphomas (B-NHL) are a very heterogeneous group of B-cell neoplasias originating from the germinal centers of lymphatic follicles. Thus, they represent a suitable experimental model to study the molecular basis of certain key events which take place in the lymphatic follicles, including somatic hypermutation and heavy chain isotypic switch. An unusual B-NHL cell line ("Farage") not producing Ig polypeptide chains was previously shown to rearrange its IgH and Igkappa genes and transcribe seemingly normal size mu and kappa mRNAs. In an attempt to characterize the phenotype of Farage cells better and to elucidate the molecular basis of the failure of Farage cells to synthesize Ig chains, we sequenced its VH and Vkappa rearranged gene segments by PCR and RT-PCR. It was found that both V genes are somatically, heavily mutated compared to their germline counterparts. In addition, this rearranged VDJ gene of the heavy chain is not transcribed. Instead, the Farage cells express a low level of a new family of germline transcripts starting with a VH like sequence, continuing with a small segment of the 3'VH germline flanking region, and ending within the Cmu region. These transcripts lack D and J segments and do not contain the open reading frame of the full-length Cmu protein. Thus, Farage cells fail to produce mu heavy chains due to silencing of the expression of the conventional VDJCmu transcript and expression of unusual Cmu-germline transcripts. In contrast to the IgH genes, the rearranged VJ gene of Farage is transcribed and gives rise to a full-size kappa-mRNA. This transcript, however, is not translated to a full-length kappa-chain, as it contains a stop codon in its coding region. All the above show that Farage cells are unable to produce Ig polypeptide chains, due to somatic mutations altering the kappa-chain gene, and mutations and/or regulatory events that shutoff the transcription of the IgH gene. The heavily mutated Vkappa and Vkappa genes found, support the conclusion that the Farage cell line originated either from germinal center cells or from the mantle zone of the lymphoid follicle.
OBJECTIVES: To examine the association of acetabular dysplasia and osteoarthritis (OA) of the hip among elderly white women. METHODS: Pelvic radiographs from a sample of 165 white women aged 65 and above with radiographic hip OA and 88 white women aged 65 and above without radiographic changes of hip OA were read for evidence of acetabular dysplasia by a single trained investigator. Acetabular dysplasia was assessed using measurements of the centre edge angle and the acetabular depth, which are both reduced in this condition. Odds ratios for the association between acetabular dysplasia and hip OA were estimated using logistic regression analysis. RESULTS: Fourteen (3.4%) hips had a centre edge angle < 25 degrees, 46 (11.2%) hips had an acetabular depth of < 9 mm, and 54 (13.2%) hips had acetabular dysplasia defined as either of the above. Hips with OA had a small, but not statistically significant, increased prevalence of abnormal centre edge angle (odds ratio: 1.43; 95% confidence intervals: 0.46, 4.46), abnormal acetabular depth (1.47; 0.78, 2.77) and acetabular dysplasia (1.33; 0.74, 2.40). CONCLUSION: These results do not support the hypothesis that mild acetabular dysplasia accounts for a substantial proportion of hip OA in elderly white women. A study with a much larger sample size would be required to rule out a weak association between dysplasia and hip OA of the magnitude actually observed in our study.
OBJECTIVE: To evaluate the contributions of radiographic knee osteoarthritis (OA) and knee pain severity to self-reported disability performing upper and lower extremity tasks in a rural, population based sample. METHODS: Data from 1192 African-American and Caucasian participants in the Johnston County Osteoarthritis Project were analyzed with multiple logistic regression to examine the roles of Kellgren-Lawrence radiographic knee OA grade and knee pain severity in self-reported difficulty performing 20 activities of the Health Assessment Questionnaire. Potential confounders included age, sex, race, marital status, education, and body mass index. RESULTS: Forty-three percent reported difficulty performing at least one task. Mild knee pain was independently associated with difficulty performing 16 upper and lower extremity tasks, and moderate/severe knee pain with all 20 tasks, with little change after adjustment (p < 0.0001). In contrast, mild radiographic knee OA was associated with difficulty in only 4 mobility and transfer tasks: climbing 5 steps, taking a tub bath, getting in/out of a car, and performing chores. Moderate/severe radiographic knee OA was associated with difficulty in 17 of 20 tasks (in 10 of 17, p < 0.0001), except lifting a cup, opening car doors, and turning faucets. However, no associations between radiographic knee OA and difficulty were statistically significant after adjustment for knee pain and the above factors. CONCLUSION: Knee pain severity was the strongest risk factor for self-reported difficulty performing tasks of upper and lower extremity function. Future studies of disability should include data on knee pain severity.
Mechanical stress on the cartilage and metabolic and/or hormonal influences have been suggested as possible etiologic factors for osteoarthritis. This paper reports findings from data collected in 1992 that were used to examine associations between osteoarthritis and risk factors in 573 Caucasian women aged 24-45 years from the Michigan Bone Health Study. Radiographs of the dominant hand and both knees were evaluated using the Kellgren and Lawrence grading scale. The prevalence of osteoarthritis (grade 2 or higher) in this population was 2.8% for hands and 3.6% for knees. Using polytomous multiple logistic regression, the authors found older age, increasing bone mineral density, and decreasing testosterone levels to be significantly associated with increasing hand scores. Older age and hand injury were significantly associated with grades of 2 or higher. Increasing osteoarthritis knee scores were associated with older age, increasing bone density, increasing body mass index, and current use of hormone replacement therapy. A knee grade of 2 or higher was associated with increasing estradiol levels, knee injury, and higher blood pressure. This study indicates that age, bone density, and injury are risk factors common to the development of hand and knee osteoarthritis in this non-elderly female population.
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"Farage" is a cell line derived from a patient who had a diffuse and mixed type malignant lymphoma. In a previous study it was shown that Farage cells expressed B-cell markers, but not membrane IgM. Karyotypic analysis showed that in contrast to most follicular cell lymphomas, Farage did not have the 14;18 chromosomal translocation. In the present work Farage was further characterized by Southern and Northern blot analyses. Two rearranged heavy chain alleles and one rearranged kappa chain gene were detected. The cells expressed both mu and kappa mRNA, even though at a 3-7 fold lower level than that found in the control Daudi and DG-75 Burkitt lymphomas. Farage cells did not express the terminal deoxynucleotydyl transferase gene (TdT), nor the recombination activating genes RAG-1 and RAG-2, known as markers of the pre-B cell stage. These results show that Farage represents a mature B-cell rather than a pre-B cell. Despite the presence of C kappa and C mu RNAs, no Ig polypeptide chains were produced by Farage as judged by immunoblotting and biosynthesis labeling assays. Ig mRNAs were detected on the polysomal fraction, but at a lower level relative to Daudi cells. Our combined results suggest that in Farage cells translation of Ig mRNA is not fully blocked at the stage of translation initiation. Farage cells may express "germline" or mutated variants of Ig mRNAs. The unusual phenotype of Farage may reflect a normal as yet unknown stage of B-cell differentiation, or it may be due to an aberrant expression developed after malignant transformation.
Oct-1 is a ubiquitously expressed regulatory gene of the POU domain family. The Oct-1 protein binds to the octamer motif present in the control regions of a variety of genes such as the immunoglobulins, histone H2B and snRNAs. To learn about Oct-1 and its possible role in B-cell maturation, we have used oct-2 cDNA to screen a murine pre-B cell, cDNA library. Two cDNA clones were identical in their POU-homeo box DNA binding domain, but differed in their 3'-region. Whereas one clone (oct-1a) was very similar to its human oct-1 homologue, the other (oct-1b), contained an additional 72 bp sequence (designated E1) at the serine threonine rich coding region (position 1485 of the human oct-1), and a deletion of another 72 bp sequence (designated E2) downstream (position 1920). These changes preserve the protein reading frame. DNA blot analysis indicates that murine oct-1 is a single copy gene and that the two oct-1 isoforms oct-1 is expressed as a large approximately 10 kb transcript in all the cell are generated by alternative RNA splicing. RNA blots showed that oct-1 is expressed as a large approximately 10 kb transcript in all the cell lines tested. PCR analysis of the E1 and E2 72 bp regions, indicated the presence of a third isoform containing both E1 and E2 (Oct-1c). Oct-1a and Oct-1b were present in all cell types examined, but the level of expression was lower in liver and spleen as compared to testis, thymus and kidney. The ratio of Oct-1b to Oct-1a ranged between 0.2 to 0.5, for all tissues examined except for testis which expressed higher amounts of oct-1b and/or oct-1c. Our findings thus show that the pattern of expression of the oct-1 gene is more complex than hitherto thought.
To explore further the varied clinical expression of anti-Ro(SS-A) antibody positive patients and to determine the outcomes of these patients, we followed 100 anti-Ro(SS-A) antibody positive patients, originally seen at the Johns Hopkins Medical Institutions in 1982 and 1983, over a 10-year period. The results of this study indicate that anti-Ro(SS-A) antibody positive patients have a diverse clinical presentation and that the anti-Ro(SS-A) antibody response generally persists for years. Some of these patients appear to have a static disease process for years. However, 65% (51, including 13 deaths, of 78 patients) of the patients for whom we had follow-up data had a chronic (10 years or greater) progressive disease process. Black patients, in general, have an earlier onset of disease and may have a more severe disease than white patients. At least 25% of our anti-Ro(SS-A) antibody positive patients demonstrated a dynamic change in clinical presentation with the development of Sjögren syndrome and/or a progressive "rheumatoid-like" arthritis. Interstitial pulmonary disease, central nervous system disease, and vasculitic insults occur frequently in these patients. Renal disease occurred in 19 anti-Ro(SS-A) positive patients, and in 47% of these renal disease patients, no anti-DNA antibodies (dsDNA or ssDNA) were detected. Cutaneous manifestations are prominent in anti-Ro(SS-A) antibody positive patients with lupus. Photosensitivity and a malar dermatitis were the most common features. Twenty percent of lupus patients had discoid lesions, and 20% had SCLE lesions. Based on this study, we believe that anti-Ro(SS-A) antibody positive patients should be routinely evaluated for the emergence of systemic features. Since these systemic features are at least in part, if not solely, the result of inflammation, early treatment with steroids and/or immunosuppressive agents may minimize the damage and influence in a positive manner the significant morbidity and mortality observed in some anti-Ro(SS-A) antibody positive patients.
Radiographs of the hand, hip and knee were screened for evidence of osteoarthritis (OA). Specific sites selected for screening on the postero-anterior radiographs of the hand included the base of the thumb with distal and proximal interphalangeal joints; these regions were examined for formation of marginal osteophytes, joint space narrowing and subchondral lucency. Sites selected from antero-posterior radiographs of the hip included the acetabular and femoral portions of the joint; these regions were examined for joint space narrowing, subchondral lucency, marginal osteophytes and subchondral sclerosis. Sites selected from antero-posterior weight-bearing radiographs of the knee included distal femora and proximal tibiae including the medial and lateral compartments; these regions were examined for joint space narrowing, marginal osteophytes and subchondral sclerosis. Sites selected from axial views of the patellofemoral joint examined the medial and lateral portions; these regions were examined for joint space narrowing, osteophytes, subluxations and subchondral sclerosis. A set of photographic prints was made from the collection of radiographs. These specific features of OA were graded on each print and a subset of prints was selected that best demonstrated the spectrum of severity for each feature of OA. This resultant atlas is offered as an updated guide to standardize interpretation of radiographs prior to and during clinical trials.