Biomedical subjects
Publications and source records attributed to S Hoffman.
The tumors can progress rapidly from superficial lesions of the epidermis, which are nearly all curable by excision, to invasive cancers unresponsive to current therapy. New strategies for regional and systemic spread include multiagent chemotherapy combined with biologic response modifiers, such as alpha-interferon or interleukin-2. On the early evidence, some of these approaches are promising.
The disease is perhaps the clearest instance of a cancer for which early treatment is crucial. Increasing knowledge of risk factors (including brief, intense sun exposure and sunburn damage early in life) aids the identification of persons at highest risk--one reason for physicians not to be pessimistic about the value of urging patients to limit their sun exposure.
BACKGROUND: Although more than 1 percent of black women 80 years of age or older have hip fractures each year, little is known about risk factors for hip fracture in these women. METHODS: We carried out a case-control study involving 144 black women admitted with a first hip fracture to 1 of 30 hospitals in New York and Philadelphia. The control were 218 black women living in the community who were matched to the case patients according to age and ZIP Code or telephone exchange and 181 hospitalized black women matched according to age and hospital. Information was obtained through personal interviews and was studied by multivariable logistic-regression analysis. RESULTS: When the case patients were compared with the control subjects from the community, the women in the lowest quintile for body-mass index had a markedly increased risk of hip fracture as compared with the women in the highest quintile (odds ratio, 13.5; 95 percent confidence interval, 4.2 to 43.3). Postmenopausal estrogen therapy for one year or more was protective for women under 75 years of age (odds ratio, 0.1; 95 percent confidence interval, < 0.1 to 0.5). Factors associated with an increased risk of hip fracture included a history of stroke (odds ratio, 3.1; 95 percent confidence interval, 1.2 to 8.1), use of aids in walking (odds ratio, 5.6; 95 percent confidence interval, 2.7 to 11.5), and consumption of seven or more alcoholic drinks per week (odds ratio, 4.6; 95 percent confidence interval, 1.5 to 14.1). The results were similar when the case patients were compared with the hospitalized control subjects. CONCLUSIONS: Among black women thinness, previous stroke, use of aids in walking, and alcohol consumption are associated with an increased risk of hip fracture. Postmenopausal estrogen therapy protects against hip fracture in women under 75 years of age.
Reports from several laboratories have suggested that interleukin 6 (IL-6) may play a role in the process of bone resorption. We have extended these studies by examining the role of IL-6 in fetal rat long bone (FRLB) resorption stimulated by a variety of agents, including parathyroid hormone (PTH); 1,25 dihydroxyvitamin D3 (1,25(OH)2D3); interleukin 1 (IL-1); tumour necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS). This model of bone resorption does not require the generation of osteoclasts in order to elicit a resorptive response and allowed us to assess whether IL-6 can directly affect osteoclastic bone resorption. We confirmed previous studies which showed that exogenous recombinant murine or human IL-6 does not stimulate bone resorption and demonstrated that IL-6, when added prior to the addition of parathyroid hormone, caused a significant but somewhat variable inhibition at 120 hours. Exogenous PGE2 stimulated both IL-6 production and resorption in FRLB cultures in a concentration-dependent manner. Endogenous production of IL-6 in fetal rat long bone (FRLB) cultures was stimulus dependent and generally correlated with prostaglandin E2 (PGE2) levels in the same cultures. However, endogenous IL-6 production did not correlate with the extent of bone resorption, except when IL-1 and PGE2 were used as stimuli. Addition of indomethacin and diclofenac to IL-1 stimulated cultures demonstrated that both the IL-6 production and bone resorption were largely PGE-2 dependent. Neutralizing anti-IL-6 antibodies inhibited IL-6 activity in FRLB cultures but did not affect bone resorption, even in the IL-1 stimulated cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
Nonsurgical management of a penile fracture can result in penile deformity due to plaque, and impaired tumescence due to corporeal fibrosis and altered erectile hemodynamics. We describe the correction of penile deformity and impaired tumescence by extensive resection of corporeal fibrosis and insertion of a unilateral unitary inflatable prosthesis. A possible role is proposed for correcting penile angulation secondary to unilateral disease using a unilateral unitary inflatable penile prosthesis.
Cytotactin, cytotactin binding (CTB) proteoglycan, and several other extracellular matrix (ECM) proteins and proteoglycans are described as antiadhesion molecules because they inhibit cell spreading and attachment to normally permissive ECM proteins. For cytotactin and CTB proteoglycan, this effect appears to be due to the binding of these proteins to their cell-surface receptors, which initiates a transmembrane signal that inhibits cell spreading. In contrast, the binding of fibronectin or laminin to its cell-surface receptors promotes cell spreading. Cell behavior may be regulated in a variety of systems by the interplay between these two opposing signals. For example, eosinophils on laminin spreading, form numerous foci containing filamentous actin, and remain viable in culture. In contrast, eosinophils on a mixture of laminin and cytotactin do not spread or form foci containing filamentous actin and the maintenance of viability is inhibited. In another system designed to model the immune surveillance of tumors, monocytes migrate in response to tumor necrosis factor through a gel comprised of a mixture of basement membrane proteins (Matrigel). Migration is blocked if the gel is coated with cytotactin. This result is of particular significance because cytotactin is expressed at high levels in the stroma of adult breast tissue surrounding tumors but only at low levels in normal breast tissue. These observations suggest that inflammation and the immune surveillance of tumors are among the processes regulated by cytotactin.
rcsp, encoding amino acids 21-398 of Plasmodium falciparum circumsporozoite protein (CSP), under control of tacP was integrated into the chromosomal delta aroC locus of attenuated delta aroC, delta aroD Salmonella typhi CVD 908. By immunoblot and ELISA, rCSP expression was greater from a multicopy plasmid than from the single chromosomal gene. CVD 908 omega (delta aroC1019::tacP-rcsp) was well tolerated by 10 volunteers who were fed two doses of 5 x 10(7) organisms 8 days apart. Seven subjects excreted the vaccine strain for 1-3 days. All subjects developed serologic responses to O and H antigens of the live vector, whereas 3 vaccinees responded to the foreign antigen: 1 developed an 80-fold rise in serum anti-sporozoite antibody, another had a 4-fold rise in antibody to a recombinant portion of CSP (residues 309-345), while a third vaccinee developed CSP-specific CD8+ cytotoxic T lymphocyte activity. This is the first report of attenuated S. typhi eliciting a human serologic or a cytotoxic T lymphocyte response to a foreign protein. Improved foreign gene expression should enhance immunogenicity.
Position of the leg while using the KT-1000 knee arthrometer may be an important variable in attaining accurate and reliable measurements. The purpose of this study was to compare the anterior translation of the tibia on the femur with the tibia in neutral, internal rotation (IR), and external rotation (ER). Additionally, data were analyzed to determine the intratester and intertester reliability of the KT-1000 knee arthrometer with the leg in neutral. Data were collected from 50 subjects by two testers and one recorder, according to MEDmetric protocol. Tester 1 performed three pulls or one sequence in neutral, IR, and ER. A second sequence was performed in neutral. Tester 2 performed two sequences in the neutral position. Data in each sequence were averaged and evaluated. Intertester reliability was calculated at r = .64 (poor), while intratester reliability for tester 1 was r = .90 (high) and for tester 2 was r = .86 (good). A repeated measure, one-way ANOVA was used, and results demonstrated a statistical difference of p < .0001, with the difference found between IR when compared with ER and neutral. In conclusion, differences in tibial translation occurred between neutral, IR, and ER of the lower extremity. This may prove valuable for clinicians using the KT-1000.
OBJECTIVE: To examine synchronous changes in soluble interleukin-2 receptor (sIL-2R) levels, daily indicators of emotional stress, joint inflammation, and reported pain in patients with rheumatoid arthritis (RA). METHODS: Fourteen patients were studied on each of 6 occasions, 2 weeks apart. Measures included daily ratings of mood disturbance, undesirable events, and joint pain; clinical examination of joint swelling; and serum assays of sIL-2R. Pooled within-person correlations among these variables were calculated. RESULTS: Consistent with the results of previous research, joint inflammation covaried directly with sIL-2R levels. Changes in mood disturbance were unrelated to changes in joint inflammation, but increases in mood disturbance were linked with decreases in sIL-2R levels and increases in reported joint pain. CONCLUSION: These findings provide preliminary evidence that psychoimmune processes may be implicated in short-term changes in RA disease activity.
The relationship between parity, lactation and the occurrence of hip fracture was investigated in a case-control study of white women. The cases were patients (n = 174) aged 45 years and over with a radiologically confirmed first hip fracture sampled from among admissions to 30 hospitals in New York and Philadelphia between September 1987 and July 1989. Controls (n = 174) were selected from general surgical and orthopedic services during the same time period and were frequency-matched to cases by age and hospital. Ever having a live birth was associated with reduced odds of hip fracture, controlling for age and hospital of recruitment (odds ratio = 0.65; 95% confidence interval = 0.41-1.04). When body mass index was also controlled, each birth was associated on average with a 9% reduction in the odds of hip fracture (odds ratio = 0.92 [0.78-1.08]), although the trend was not statistically significant. After adjusting for number of births, lactation was not associated with hip fracture (adjusted odds ratio for 12 months of lactation or less = 0.80 [0.42-1.55]; adjusted odds ratio for more than 12 months = 1.08 [0.45-2.60]).
A unique, open group therapy conducted at a university counseling service is described. This model differs from other approaches in that the participants "can come or not come." Method, impressions and conclusions are presented.
Eosinophils (Eo) participate in the inflammatory response to parasites, allergins, toxins, and epitopes recognized by autoimmune antibodies. Nonetheless, little attention has heretofore been paid to the interactions of Eo with extracellular matrix (ECM) proteins during their migration through the subendothelial basement membrane and into the surrounding tissue. Therefore, we have studied the adhesion of Eo to specific ECM proteins and the effect of this adhesion on Eo viability and maturation. Control Eo (from normal donors) adhere no better to substrates coated with laminin (LM), fibronectin (FN), cytotactin (CT), or collagen types I or IV (Col IV) than they do to human serum albumin coated substrates. In contrast, Eo activated in vitro with IL-5 or in vivo in patients with eosinophilia bind well to LM, FN and Col IV. LM is by far the most avid ligand among these molecules. For example, 43% of input cells bind to a substrate bearing 200 fmol/cm2 of LM; a similar level of adhesion to FN requires 30 times as much absorbed protein. Antibody inhibition experiments suggest that the alpha 6 beta 1 integrin heterodimer is the predominant LM receptor on these cells. Flow cytometry showed similar levels of these subunits on control and activated Eo, suggesting that Eo adhesion to LM is not regulated simply by cell surface integrin concentration. The effects of ECM proteins on Eo behavior were also examined. A LM-coated substrate (with no added cytokine) was found to be almost as effective as IL-5 in maintaining Eo viability while an equally adhesive FN-coated substrate had much less effect. Normally, even in the presence of 10% serum, no Eo survive a 5-day incubation in vitro unless IL-3, IL-5, or GM-CSF is added to the medium. Conditions that inhibit adhesion to LM (anti-integrin antibodies in the medium or CT on the substrate) and certain anti-cytokine antibodies inhibited the promotion of Eo viability by LM. During incubation on LM, Eo become hypodense, as they do in the presence of IL-5, indicating that they have become activated. These observations suggest that the interactions of Eo and ECM proteins may be important both for their potential to direct Eo migration and for their ability to regulate Eo viability, cytokine production, and maturation.
Two extracellular matrix proteins of brain tissue, neuronectin (NEC1) and cytotactin (CT), are disulfide-bonded multimers of M(r) 180,000-250,000 subunits. The previously known distribution of these molecules is, however, very different. Human NEC1 is found throughout the white matter of rostral segments of the adult central nervous system (CNS) but not in rostral gray matter or in caudal CNS segments, including the cerebellum. In contrast, CT is absent or expressed at a low level in the adult chicken cerebrum but highly expressed in the cerebellum. Despite these differences in distribution, results obtained with antibodies that recognize NEC1 and CT in several vertebrate species indicate that these molecules are identical or at least closely related: (1) alpha NEC1 antibodies recognize proteins affinity-purified with CT-binding proteoglycan; (2) proteins recognized by alpha NEC1 and alpha CT antibodies in cells constitutively expressing the molecules, cells in which expression is induced by growth factors and phorbol ester and cells treated with tunicamycin (to block glycosylation) are identical in subunit composition and mobility on SDS gels; (3) the removal of NEC1 from culture supernatants by immunoprecipitation removes all molecules reactive with alpha CT antibodies and vice versa; (4) immunoblots of brain extracts with alpha NEC1 and alpha CT antibodies yield identical results. Having demonstrated the structural similarity between NEC1 and CT, we reexamined their distribution in the CNS. Surprisingly, the temporal and spatial distribution pattern of NEC1/CT varied greatly among species. Immunohistochemical and immunoblot experiments with adult human CNS tissues revealed significant levels of NEC1/CT in rostral but not caudal segments. In contrast, in cows and pigs the molecule is found throughout the CNS. Adult rat and mouse brains show regionally restricted expression of NEC1/CT in several areas of the cerebrum--distinct from those showing NEC1/CT in the human--and in the molecular layer of the cerebellum. Tests with fetal and newborn tissues revealed that CNS development in humans, cows and pigs is not accompanied by the marked decline in NEC1/CT levels or the changes in subunit composition found in the chicken CNS. The marked species diversity in temporospatial expression patterns suggests that intrinsic and/or extrinsic elements controlling the expression of NEC1/CT have diverged during vertebrate evolution.
The need to develop a blood substitute is now urgent because of the increasing concern over blood-transmitted viral and bacterial pathogens. Cell-free haemoglobin solutions and human haemoglobin synthesized in Escherichia coli and Saccharomyces cerevisiae have been investigated as potential oxygen-carrying substitutes for red blood cells. But these haemoglobins cannot be used as a blood substitute because (1) the oxygen affinity in the absence of 2,3-bisphosphoglycerate is too high to allow unloading of enough oxygen in the tissues, and (2) they dissociate into alpha beta dimers that are cleared rapidly by renal filtration, which can result in long-term kidney damage. We have produced a human haemoglobin using an expression vector containing one gene encoding a mutant beta-globin with decreased oxygen affinity and one duplicated, tandemly fused alpha-globin gene. Fusion of the two alpha-globin subunits increases the half-life of this haemoglobin molecule in vivo by preventing its dissociation into alpha beta dimers and therefore also eliminates renal toxicity.
Scores on a measure of self-defeating personality were associated with depression and suicidal preoccupation in a sample of 58 college students.
BACKGROUND: This study compares patient and provider satisfaction with medical care and waiting time in a large family medicine residency program. Few published studies have dealt with both patient and provider perceptions. METHODS: Telephone interviews were conducted with 156 adult, English-speaking patients who were randomly selected from daily appointment schedules. The patients were asked to rate their satisfaction with 10 aspects of medical care and to estimate the length of time they waited to see their physicians. Sixty-five family health care providers responded to the same survey items through a self-administered questionnaire. RESULTS: In general, 97% of patients and 89% of providers were satisfied with the overall medical care provided at the family health center. Approximately 8% of patients and 22% of providers were dissatisfied with waiting time, and 11% of patients and nearly 60% of providers were dissatisfied with appointment scheduling. Patients' estimates of waiting time for care (mean = 16.1 minutes) were significantly shorter than providers' estimates (mean = 27.5 minutes). Patients who were dissatisfied with the length of waiting time estimated waiting 41.8 minutes, while satisfied patients estimated waiting 13.3 minutes (P less than .001). CONCLUSIONS: Family medicine patients reported higher levels of satisfaction with medical care than did providers. Both groups were the least satisfied with access to care.
BACKGROUND: Although even in the elderly most falls are not associated with fractures, over 90 percent of hip fractures are the result of a fall. Few studies have assessed whether the risk factors for falls are also important risk factors for hip fracture. METHODS: To examine the importance of risk factors for falls in the epidemiology of hip fracture, we performed a case-control study of 174 women (median age, 80 years) admitted with a first hip fracture to 1 of 30 hospitals in New York and Philadelphia. Controls, matched to the case patients according to age and hospital, were selected from general surgical and orthopedic surgical hospital services. Information was obtained by direct interview. RESULTS: As measured by the odds ratio, increased risks for hip fracture were associated with lower-limb dysfunction (odds ratio = 1.7; 95 percent confidence interval, 1.1 to 2.8), visual impairment (odds ratio = 5.1; 95 percent confidence interval, 1.9 to 13.9), previous stroke (odds ratio = 2.0; 95 percent confidence interval, 1.0 to 4.0), Parkinson's disease (odds ratio = 9.4; 95 percent confidence interval, 1.2 to 76.1), and use of long-acting barbiturates (odds ratio = 5.2; 95 percent confidence interval, 0.6 to 45.0). Of the controls, 44 (25 percent) had had a recent fall. The case patients were more likely than these controls to have fallen from a standing height or higher (odds ratio = 2.4; 95 percent confidence interval, 1.0 to 5.7). Of those with hip fracture the younger patients (less than 75 years old) were more likely than the older ones (greater than or equal to 75 years old) to have fallen on a hard surface (odds ratio = 1.9; 95 percent confidence interval, 1.04 to 3.7). CONCLUSIONS: A number of factors that have been identified as risk factors for falls are also associated with hip fracture, including lower-limb dysfunction, neurologic conditions, barbiturate use, and visual impairment. Given the prevalence of these problems among the elderly, who are at highest risk, programs to prevent hip fracture should include measures to prevent falls in addition to measures to slow bone loss.
The expression of cytotactin, the cytotactin-binding (CTB) proteoglycan, and the neural cell adhesion molecule, N-CAM, was examined during the development of the avian endocardial cushion tissue (ECT). N-CAM was present in the cardiac mesoderm from its earliest time of development. At the time when endothelial cells converted to mesenchyme and began to migrate, they ceased their expression of N-CAM. Cytotactin and CTB proteoglycan were present in the cardiac jelly (into which the ECT cells migrate) in patterns that were correlated with cell migration. At early times of migration (stage 18), the region of the cardiac jelly near the endocardium contained cytotactin in the vicinity of the migrating cells. During later migration (stage 22), cytotactin remained associated with the leading zone of cell migration, but its expression began to decrease in areas where cells had accumulated. After ECT cell migration had ceased, cytotactin expression decreased, remaining high only in the peripheral portion of the aorticopulmonary septum and absent from its ridges. CTB proteoglycan was expressed during early migration at high levels in and adjacent to the myocardium. By stage 22, its distribution had become more uniform throughout the ECT regions and in the myocardium. The combined results of this study suggest that cytotactin, CTB proteoglycan, and N-CAM each play a distinct, critical role in pattern formation in the early heart.