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Biomedical subjects

R Hirsch

Publications and source records attributed to R Hirsch.

At least 37 records · Page 2Linked to original sources

Osteoarthritis: new insights. Part 1: the disease and its risk factors.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weight-bearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability.

Age Distribution↗

Heterogeneous effects of IL-2 on collagen-induced arthritis.

IL-2 is generally considered a pro-inflammatory cytokine that exacerbates Th1-mediated disease states, such as autoimmune arthritis. Consistent with this role for IL-2, recent studies from our laboratory demonstrate that IL-2 mRNA is markedly increased during the acute stage of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. To further define the role of IL-2 in CIA, the levels of IL-2 protein and its receptor and the effects of IL-2 administration were analyzed during CIA. IL-2 protein and IL-2R were preferentially expressed at disease onset, compared with later stages of disease. Administration of recombinant human IL-2 (rhIL-2) at, or just before, disease onset exacerbated disease; surprisingly, rhIL-2 given before disease onset inhibited CIA, associated with reduced cellular and humoral responses to type II collagen. Determination of in vivo serum levels of Th1 and Th2 cytokines in response to rhIL-2 treatment demonstrated that IFN-gamma, but not IL-4, was markedly up-regulated in response to IL-2. In mice treated with anti-IFN-gamma Ab, both early and late IL-2 administration exacerbated CIA. Thus, IL-2 can have two opposite effects on autoimmune arthritis, a direct stimulatory effect and an indirect suppressive effect that is mediated by IFN-gamma.

Acute Disease↗

On the mechanism of protection of distal joints after local gene transfer in collagen-induced arthritis.

Considerable interest has been generated by the observation that adenovirus-mediated gene delivery to a single arthritic joint results in suppression of arthritis in distal joints associated with the presence of small numbers of transduced cells in distal joints. It has been proposed that this is mediated by trafficking of transduced cells from the injected to distal joints. There are, however, alternative explanations that have not been explored, including the possibility that transgene protein or infectious virions circulate to distal sites. To investigate these possibilities, a replication-incompetent adenovirus encoding viral IL-10 (vIL-10) was administered to naive mice and to mice with collagen-induced arthritis by intraarticular, periarticular, or intravenous injection. In all cases, the ability to protect distal joints correlated with serum levels of vIL-10 protein. After intraarticular or intravenous injection, vIL-10 cDNA could be detected not only in distal joints, but also in the liver, which is the major target of circulating adenovirus, demonstrating that adenovirus circulating through the bloodstream is taken up by the joint tissue. Periarticular administration of adenovirus, which resulted in lower serum levels of vIL-10, protected only the injected paws and failed to induce trafficking immunoregulatory cells capable of suppressing distal disease. These observations suggest that circulating vIL-10 protein is the major mediator of distal protection. The presence of small numbers of transduced cells at distal sites can be accounted for by transduction of distal synovium after entry of adenovirus virions into the circulation.

Adenoviridae↗

[Patients without referral treated in the emergency room: patient characteristics and motives].

OBJECTIVES: To determine the motives of patients to directly visit the Emergency Department for medical treatment without seeing their family practitioner first and to establish the characteristics of this group. DESIGN: Prospective, descriptive. METHOD: Of the surgical patients attending the Emergency Room (ER) of Utrecht University Hospital, the Netherlands, between 1st April and 25th June 1997, the demographic and diagnostic data of the non-referred patients were compared with those of patients referred by the general practitioner (GP). The non-referred patients were asked about their reasons to attend without referral. RESULTS: A total of 1026 patients visited the ER at their own initiative: 603 males and 423 females. The most frequent reasons for the direct visits were 'had not thought of their family practitioner' (48%) and 'wants help that can only be provided in a hospital' (30%). The self-referring patients differed from the 962 referred patients in severity of the trauma: 76% versus 39% had a relatively minor trauma; sort of trauma: 19% versus 4% had a sport trauma; place of residence: 57% versus 45% lived in the near vicinity of the hospital. Of the self-referring patients 57% visited the hospital out of office hours, versus 39% of the referred patients. CONCLUSION: A large part of the non-referred patients visited the ER unnecessarily and should actually have consulted their GP. These were mainly young adults with minor injuries or sports injuries who lived close to the hospital. Important factors were unfamiliarity with or lack of understanding of the existing regulations.

Adolescent↗

Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer.

Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory proteins that can suppress collagen-induced arthritis (CIA). These and related proteins have shown efficacy in the treatment of human rheumatoid arthritis; however, neither alone is able to completely suppress disease. Furthermore, they have short half-lives, necessitating frequent administration. To determine the ability of these proteins to act synergistically following gene transfer, arthritis was induced in DBA/1 male mice by immunization with type II collagen on days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors, or a control vector lacking a transgene. Significant synergism was observed with the combination of vIL-10 and sTNFR-Ig, with a substantial reduction in both the incidence and severity of disease as well as inhibition of progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10 alone inhibited disease when given before disease onset, but had minimal effect on established disease. Both proteins inhibited spleen cell proliferation and IFN-gamma secretion in response to stimulation with type II collagen, but only vIL-10 reduced the synovial mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act synergistically in suppressing CIA and suggest that gene transfer offers a potential therapeutic modality for the treatment of arthritis.

Adenoviridae↗

Adeno-associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium.

Treatments for rheumatoid arthritis and other inflammatory arthropathies are often ineffective at preventing joint destruction. Long-term genetic modification of the cells lining the joint space (synoviocytes) in vivo represents a potential method for the treatment of these chronic conditions. However, a vector capable of efficiently transducing synoviocytes in vivo for a persistent period has not been available. The present report describes the genetic modification of synoviocytes in vivo using recombinant adeno-associated virus. High-titer adeno-associated virus encoding the gene for Escherichia coli beta-galactosidase was injected into the knee joints of mice. Synovial tissues were then examined for beta-galactosidase transgene expression by in situ staining and by fluorometry. High-efficiency, persistent transgene expression was observed in the synovium with no evidence of vector-induced inflammation. Expression was observed for at least 7 months and was higher in arthritic than nonarthritic mice. Gene transfer of murine IL-4 to the joints of mice with collagen-induced arthritis led to detectable levels of IL-4 in the joint and protection from articular cartilage destruction. These data suggest that adeno-associated virus may be a useful vector for gene delivery to the synovium for the treatment of inflammatory arthropathies.

Animals↗

A sensitive method for the determination of iodine containing diagnostic agents in aqueous matrices using LC-electrospray-tandem-MS detection.

Iodinated contrast media belong to the most frequently applied compounds in medicine. They exhibit a high polarity and are very persistent against metabolism by the organism and environmental degradation. A sensitive method for the determination of five iodinated contrast media in aqueous matrices is described. Solid phase extraction utilizing Isolute ENV+ material was used for sample enrichment. The contrast media were partially separated on a RP-C18 column, and detection was achieved using electrospray-tandem MS (API III plus and API 365) allowing the sensitive quantitation of these compounds down to the lower ng/L range. The recovery rates generally exceeded 70%, for spiked surface water as well as tap water. The analytes were detected in native samples such as municipal sewage treatment plant (STP) effluent, the river Rhine and even in tap water.

Chromatography, High Pressure Liquid↗

Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation.

BACKGROUND: Cardiopulmonary bypass seems to be a major cause for both intraoperative microemboli and cerebral hypoperfusion. This study investigates high intensive transient signals (HITS) in transcranial Doppler ultrasound (TCD) and serum levels of the neurobiochemical marker protein S-100 in patients who underwent coronary artery bypass operation without cardiopulmonary bypass (off-pump CABG) in comparison with the conventional procedure using cardiopulmonary bypass (CPB). The results are related to the neuropsychologic outcome in both surgical groups. METHODS: Forty patients were randomized in 2 groups (20 conventional and 20 off-pump CABG). Neurocognitive status was assessed preoperatively and postoperatively. Venous serum levels of S-100 protein were measured before and after coronary operation, HITS were measured in the middle cerebral artery during the operation. RESULTS: The median value of HITS was 394.5 (0 to 2217) in the conventional versus 11 (0 to 50) in the off-pump group, p less than 0.0001. Postoperative S-100 serum levels were: 3.76 (0.13 to 11.2) microg/L (conventional) versus 0.13 (0.04 to 1.01) microg/L (off-pump), p less than 0.0001. Postoperative cognitive testing showed significantly different results with a postoperative impairment of 90% of the patients in the conventional group versus no impairment in the off-pump group. CONCLUSIONS: Cognitive impairment seems to be strongly associated to CPB and the occurrence of micro-emboli. The off-pump technique appears to be promising in order to eliminate the source of these neuropyschologic impairments following CABG operation.

Cardiopulmonary Bypass↗

Transplant coronary artery disease in pediatric heart transplant recipients.

BACKGROUND: Transplant coronary artery disease (TxCAD) contributes to a large percentage of late morbidity and mortality among adult heart transplant recipients. Intracoronary ultrasound (ICUS) is a sensitive tool in the diagnosis of TxCAD in adult patients and has allowed analysis of factors contributing to disease development. Experience with ICUS in pediatrics, however, has been limited. By using ICUS we sought to determine the overall prevalence of TxCAD in pediatrics and to characterize factors associated with its development in this population. METHODS: Eighty-six studies were performed in 51 pediatric patients a median of 3.4 years after heart transplantation. Evaluation included angiography and ICUS in 83 and angiography alone in 3 studies. Donor and recipient characteristics were obtained. The ICUS images were analyzed for intimal thickening and compared with coronary angiograms. The presence of any intimal thickening on ICUS was considered TxCAD. An intimal index and point of maximal intimal thickening (MIT) were measured. Vessel disease was graded 0 to 4 based on these results. Four patients had evidence of vasculopathy by angiography, whereas 32 patients (63%) had evidence of intimal proliferation by ICUS. Grade 2 or greater disease was present in 19 (37%) patients. A positive correlation was found when comparing time from transplant with intimal index and MIT (p < 0.001). No other factors were found to predict the development of disease. The overall prevalence of disease was 74% in patients studied at least 5 years after transplant. Intracoronary ultrasound can be performed safely in pediatric patients. Transplant coronary artery disease is common in infants and children after heart transplantation, although its prevalence appears to be less than in adult recipients at similar time intervals. We found no factor other than time from transplant was associated with development of disease.

Adolescent↗

The patterns and prevalence of hand osteoarthritis in a population of disabled older women: The Women's Health and Aging Study.

OBJECTIVE: To describe the prevalence of hand osteoarthritis (OA) by joint site, joint count and severity in a representative population of older disabled women. METHODS: 1,002 moderately to severely disabled women aged > or = 65 years were selected from a representative population of community-dwelling women. Hand OA was established using a reproducible algorithm based on self-reported pain, standardized physical examinations, hand photographs, and physician questionnaire responses. OA was categorized as either symptomatic disease, intermittently symptomatic/ asymptomatic disease, possible disease, or no disease. RESULTS: Symptomatic OA, requiring the presence of hand pain on most days for at least 1 month, occurred in approximately 23% of disabled older women in each age group, and most reported pain in the moderate to severe range. The prevalence of intermittently symptomatic/ asymptomatic OA was higher with increasing age. Finally, the most commonly affected hand OA sites were the distal interphalangeal (DIP) and the first carpometacarpal (CMC1) joint groups. CONCLUSION: These findings demonstrate the very high prevalence of clinical hand OA in disabled older women and show that a large proportion of hand OA results in substantial symptoms.

Aged↗

T-cell and T-cell receptor abnormalities in the immunopathogenesis of juvenile rheumatoid arthritis.

Several lines of indirect evidence suggest that the pathologic autoimmune responses in juvenile rheumatoid arthritis may be antigen-driven and T cell-mediated. These include (1) activation markers expressed on synovial T cells suggestive of previous activation in vivo; (2) persistent oligoclonally expanded T-cell populations accumulating preferentially in the synovial compartment; (3) some T-cell receptor complementarity-determining region 3 sequence similarities between different clones in an individual patient; and (4) T-cell derived cytokines of predominantly Th1 type. Whether T-cell contribution is limited to only early stages of the disease (as appears to be the case in collagen-induced arthritis) or T cells are required for the perpetuation of the inflammation at later stages as well, still remains to be determined.

Arthritis, Juvenile↗

Maternal characteristics and toddler temperament in infantile anorexia.

OBJECTIVE: To explore the association between specific maternal characteristics, maternal perceptions of toddler temperament, and infantile anorexia. METHOD: Three groups of toddlers (aged 12-37 months) participated in this study: toddlers with infantile anorexia (n = 34), picky eaters (n = 34), and healthy eaters (n = 34). Mothers completed questionnaires that assessed their own eating attitudes, marital satisfaction, and their toddlers' temperament, and an interview that explored their attachment representations. Mothers and toddlers were videotaped during a feeding session, and toddlers were weighed and measured. RESULTS: Temperament ratings differentiated between infantile anorexics and healthy eaters (p < .0001), with infantile anorexics receiving higher difficulty, irregularity, negativity, dependence, and unstoppable ratings. Mothers of anorexics showed greater attachment insecurity than mothers of healthy eaters (p < .05), but they demonstrated neither overt eating pathology nor less marital satisfaction than the other groups. Thirty-nine percent of variance in feeding conflict was explained by toddlers' diagnoses, temperament ratings, and maternal characteristics. Twenty-one percent of variance in toddlers' weights was explained by temperament ratings and feeding conflict. CONCLUSION: Maternal characteristics and perceptions of their toddlers' temperament characteristics should be addressed in treatment for infantile anorexia.

Anorexia↗

The prevalence of functional limitations and disability in older persons in the US: data from the National Health and Nutrition Examination Survey III.

OBJECTIVE: To provide estimates by sex and age and by sex and race/ethnicity of the proportion of older Americans who have difficulty with functional limitations and daily activities. SETTING: The Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. DESIGN: A cross-sectional nationally representative survey. PARTICIPANTS: All persons aged 60 and older who completed a household interview (N = 6,866) during NHANES III (conducted 1988-1994). MEASUREMENTS: The self-reported physical and functional disability questions from NHANES III included: lower-extremity function, instrumental activities of daily living, basic activities of daily living, needing help with personal and routine daily activities, and use of assistive devices for walking. RESULTS: Non-Hispanic black and Mexican-American men and women generally reported significantly (P < .01) more disability than did non-Hispanic white men and women. Disability was greater for minority women than for men. For both men and women, the prevalence in disability increased significantly (P < .01) with age for each measure. CONCLUSIONS: These sex-age and sex-race/ethnicity national estimates of disability indicate that minority women may represent a vulnerable subpopulation.

Activities of Daily Living↗

Reliability and prevalence of physical performance examination assessing mobility and balance in older persons in the US: data from the Third National Health and Nutrition Examination Survey.

OBJECTIVE: This report provides reliability and prevalence estimates by sex, age, and race/ethnicity of an observed physical performance examination (PPE) assessing mobility and balance. SETTING: The Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. DESIGN: A cross-sectional nationally representative survey. PARTICIPANTS: All persons aged 60 and older (n = 5,403) who performed the PPE either in the mobile examination center (MEC) or in the home during NHANES III (conducted 1988-1994). MEASUREMENTS: The PPE included timed chair stand, full tandem stand, and timed 8-foot walk. RESULTS: Timed chair stand and 8-foot timed walk were reliable measurements (Intraclass Correlations > 0.5). Women were significantly slower (P < .001) than men for both timed chair stands and timed walk. Non-Hispanic white men and women did the maneuvers in significantly less time than non-Hispanic black men and women and Mexican Americans women (P < .001). CONCLUSIONS: Lower extremity functions measured by timed chair stand and walk are reliable. Women at every age group were more physically limited than men.

Activities of Daily Living↗

The Ross operation: initial Israeli experience.

BACKGROUND: The need for aortic valve replacement in children and young adults poses a special problem to cardiologists and surgeons. Replacing the sick aortic valve with the patient's pulmonary valve as described by Ross has proven to be a good option in this special age group. OBJECTIVE: To review our initial experience in order to assess the short-term results. METHODS: From January 1996 to June 1999, 40 patients (age 8 months to 41 years) underwent aortic valve replacement with pulmonary autograft. Indications for surgery were congenital aortic valve disease in 30 patients, bacterial endocarditis in 5, rheumatic fever in 3, and complex left ventricular outflow tract obstruction in 3. Trans-esophageal echocardiography was performed preoperatively and post-bypass in all patients, and transthoracic echocardiography was done prior to discharge and on follow-up. RESULTS: There was no preoperative or late mortality. All patients remain in functional class I (New York Heart Association) and are free of complications and medication. None showed progression of autograft insufficiency or LVOT obstruction. Homograft insufficiency in the pulmonary position has progressed from mild to moderate in one patient, and three developed mild homograft stenosis. CONCLUSIONS: The Ross procedure can be performed with good results in the young population and is considered an elegant surgical alternative to prosthetic values and homografts.

Adolescent↗

The accuracy of self-report of physician diagnosed rheumatoid arthritis in moderately to severely disabled older women. Women's Health and Aging Collaborative Research Group.

OBJECTIVE: To determine the accuracy of self-report of physician diagnosed rheumatoid arthritis (RA) in moderately to severely disabled older women. METHODS: A total of 1002 participants in the Women's Health and Aging Study were included. These women were > or =65 years old, had an average of 4 chronic illnesses, and represented the one-third most disabled women living in the community. Self-report of a physician's diagnosis of RA was compared to cases of "definite" RA that were adjudicated using an algorithm modeled on the American College of Rheumatology criteria for RA. RESULTS: The sensitivity of self-report of physician diagnosed RA was 77%, with 90.6% specificity and 99% negative predictive value, kappa = 0.46. The positive predictive value was 34% and likely reflected the low prevalence of RA in this sample (3.1%). Five of the 6 women who did not correctly report RA were under the care of a rheumatologist. CONCLUSION: The accuracy of self-report of a physician's diagnosis of RA in this sample of disabled women with multiple chronic illnesses matched that observed in the general adult population of previous studies. Accuracy was enhanced by including report of receiving care by a rheumatologist.

Aged↗

Mid-term clinical and echocardiographic follow up of patients with CarboMedics valves in the tricuspid position.

BACKGROUND AND AIM OF THE STUDY: Debate continues regarding tricuspid valve replacement (TVR) with a mechanical prosthesis. Experience with bileaflet prostheses is limited; hence the study aim was to explore early and mid-term outcome and hemodynamic data in patients with bileaflet CarboMedics prosthetic valves in the tricuspid position. METHODS: The study population included 25 patients (21 females, four males; mean age 50.5 +/- 13.4 years) who underwent TVR with a CarboMedics valve over a six-year period. Routine clinical examinations and details of transthoracic echocardiography (TTE) were reviewed. Additional TTE, transesophageal echocardiography (TEE) and fluoroscopy were performed as indicated. The number of previous cardiac operations was zero, one and two in 36%, 32% and 32% of patients, respectively. Previous tricuspid surgery was performed in eight cases (32%); concurrent mitral valve replacement was performed in 17 (68%). The hospital mortality rate was 24% and late mortality rate 12%. Seventeen early survivors (13 females, four males) were followed up for 46 +/- 28 months (range: 4-96 months). RESULTS: Among early survivors, the mean and peak transvalvular gradients were 4.0 +/- 1.7 and 7.9 +/- 3.3 mmHg, respectively. Commonly observed INR levels were >2.5 in seven patients (41%), and >3.0 in only three (18%). Five patients (29% of mid-term survivors) experienced a total of 13 episodes of obstructive valve thrombosis, mostly with inappropriate anticoagulation. One patient required emergency re-do surgery; the others responded initially to thrombolysis or intensified antithrombotic treatment, but experienced at least two additional relapses. Aside from thrombotic episodes, all patients but two were in NYHA functional class II-III, and all but four required diuretics. CONCLUSION: TVR with bileaflet mechanical valves carries a high perioperative mortality and mid-term morbidity. Among patients with poor or fair anticoagulation, these valves were associated with a high incidence of obstructive valve thrombosis. If poor patient compliance is anticipated, insertion of a bioprosthesis should be encouraged.

Echocardiography↗

A divalent major histocompatibility complex/IgG1 fusion protein induces antigen-specific T cell activation in vitro and in vivo.

Activation of antigen-specific T cell clones in vivo might be possible by generating soluble MHC molecules; however, such molecules do not induce effective T cell responses unless cross-linked. As a first step in generating a soluble MHC molecule that could function as an antigen-specific immunostimulant, the extracellular domains of the murine H-2Kb MHC class I molecule were fused to the constant domains of a murine IgG1 heavy chain, resulting in a divalent molecule with both a TCR-reactive and an Fc receptor (FcR)-reactive moiety. The fusion protein can be loaded with peptide and can induce T cell activation in a peptide-specific, MHC-restricted manner following immobilization on plastic wells or following cross-linking by FcR+ spleen cells. The fusion protein induces partial T cell activation in vivo in a mouse transgenic for a TCR restricted to H-2Kb. This fusion protein molecule may be useful to study peptide-MHC interactions and may provide a strategy for boosting in vivo antigen-specific T cell responses, such as to viral or tumor antigens.

Animals↗