Biomedical subjects
R Stern
Publications and source records attributed to R Stern.
Hyaluronan-binding properties of human serum hemopexin.
Hemopexin, the heme-binding serum glycoprotein, exhibits a complex electrophoretic pattern on two-dimensional immunoelectrophoresis on agarose gels into which hyaluronic acid is incorporated in the first and monospecific anti-hemopexin in the second dimension. This heterogeneity reflects a range of interactions of hemopexin isoforms with hyaluronic acid. Electrophoretic patterns of individual human sera greatly differ in their contents of hyaluronan-interacting hemopexin species. Hemopexin itself has no hyaluronidase activity.
The application of health care surrogate laws to older populations: how good a match?
OBJECTIVE: The Health Care Surrogate Act (HCSA) in Illinois has been proposed as a model for state laws naming surrogate medical decision-makers for those without advance directives (ADs). Our objective was to determine if the HCSA identifies the same surrogate as older persons would choose for themselves. If not, is the discrepancy between legally identified surrogate and preferred surrogate troublesome to respondents? Because it is documented that black Americans have a variety of family structures, some of which may not be reflected in the HCSA list, we also wished to determine if discrepancies between surrogates named by the law and those desired by patients are associated with black or white race. DESIGN, SETTING AND PARTICIPANTS: A convenience sample of 144 patients aged 65 and older, without cognitive impairment, was interviewed at the geriatrics clinic of an academic medical center. MAIN OUTCOME MEASURES: Respondents without ADs who had a different stated choice for surrogate medical decision-maker than the surrogate defined by the Illinois HCSA, based on their existing family. RESULTS: Twenty-six percent of respondents without ADs chose a surrogate that differed from the surrogate defined by the HCSA. However, 67% of those with a different choice for surrogate than defined by law were not troubled by the discrepancy. The proportion of black subjects (25%) and white subjects (31%) who had surrogate discrepancies was not significantly different (P = .6). CONCLUSION: Because the Illinois HCSA named surrogates who would be agreeable to the majority of our respondents, it appears that it may be a useful model for state surrogacy laws.
Lithium in the treatment of mood disorders.
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Urinary hyaluronic acid is a Wilms' tumor marker.
Wilms' tumor is a renal neoplasm that is histologically similar to fetal kidney tissue. Both Wilms' tumor and the fetal kidney have high levels of the glycosaminoglycan hyaluronic acid (HA) in the extracellular matrix. Preliminary studies suggest that urinary HA levels are elevated in Wilms' tumor patients. To test the utility of urinary HA as a Wilms' tumor marker, the authors compared HA levels in urine specimens from 105 Wilms' tumor patients with those of 17 age-matched controls. Preoperative urine samples (n = 92), early postoperative samples, obtained from 1 to 3 weeks after surgery (n = 63), and late postoperative samples, obtained from 1 to 6 months after surgery (n = 58) were collected from patients at 30 institutions between 1989 and 1993. The HA levels were determined in triplicate by a competitive enzyme-linked immunosorbent binding assay. Seventy-four percent of the preoperative urine specimens contained elevated HA levels compared with the controls. The preoperative HA levels were significantly higher than the early postoperative (P < .01), late postoperative (P < .01), and control levels (P < .01). There was significant correlation between preoperative HA levels and clinical tumor staging. The mean preoperative HA level for patients with histological evidence of nephroblastomatosis was higher than that for patients without nephroblastomatosis. In the late postoperative period, patients with relapse or persistent disease had higher levels of urinary HA than did the disease-free patients (P < .05). In Wilms' tumor patients, urinary HA levels are elevated preoperatively and decline progressively after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of the central dopaminergic index of plasma HVA in schizophrenia.
Under fasting conditions, the dopamine (DA) metabolite homovanillic acid (HVA) in plasma originates mainly from central DA neurons or from central and peripheral noradrenergic (NA) neurons. The latter source contributes, in addition to HVA, the norepinephrine metabolites, for example, 3-methoxy-4-hydroxyphenylglycol (MHPG). It has been shown in primates that the association between HVA and MHPG in plasma or urine under varying rates of NA metabolism can be used to obtain an estimate of the central DA neuronal contribution of HVA to plasma or urine. This estimate is called the central dopaminergic index (CDI). Two studies presented here examine the applicability of this model in schizophrenia patients. The results were consistent with the proposed model and suggested that only about 30 percent of the total plasma HVA concentrations in our patients were derived from central DA neurons. A convenient modification of this model is proposed for future studies. Since the CDI of plasma HVA is not likely to be confounded by NA activity, this tool may prove useful in disentangling the roles played by the DA and NA systems in schizophrenia.
Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM.
The migration of smooth muscle cells is a critical event in the pathogenesis of vascular diseases. We have investigated the role of hyaluronan (HA) and the hyaluronan receptor RHAMM in the migration of adult bovine aortic smooth muscle cells (BASMC). Cultured BASMC migrated from the leading edge of a single scratch wound with increased velocity between 1 and 24 h. Polyclonal anti-RHAMM antisera that block HA binding with this receptor abolished smooth muscle cell migration following injury. HA stimulated the random locomotion of BASMC and its association with the cell monolayer increased following wounding injury. Immunoblot analysis of wounded monolayers demonstrated a novel RHAMM protein isoform that appeared within one hour after injury. At the time of increased cell motility after wounding, FACS analysis demonstrated an increase in the membrane localization in approximately 25% of the cell population. Confocal microscopy of injured monolayers confirmed that membrane expression of this receptor was limited to cells at the wound edge. Collectively, these data demonstrate that RHAMM is necessary for the migration of smooth muscle cells and that expression and distribution of this receptor is tightly regulated following wounding of BASMC monolayers.
Molecular cloning of a mammalian hyaluronidase reveals identity with hemopexin, a serum heme-binding protein.
Hyaluronan is the most abundant glycosaminoglycan of the extracellular matrix and is a critical substrate for cellular attachment and locomotion. Little is known about the class of enzymes, termed hyaluronidases, that are responsible for hyaluronan catabolism in mammals. We have determined a partial amino acid sequence from a purified preparation of porcine liver hyaluronidase and have used this information as the basis for cloning complementary DNA that encodes the corresponding protein. When expressed in a recombinant baculovirus system, the protein exhibited hyaluronidase activity in a substrate-gel assay. The deduced sequence of this mammalian hyaluronidase is that of a 459-amino-acid polypeptide bearing four potential N-glycosylation sites as well as a copy of a proposed hyaluronan binding motif. Remarkably, amino acid sequence comparisons and immunologic cross-reactivities strongly suggest that the cloned protein is identical to hemopexin, an abundant, heme-binding serum protein. Although hemopexin has not previously been reported to possess any enzymatic activity, it includes a conserved domain found in collagenases, stromelysins, and other enzymes that metabolize the extracellular matrix. We conclude that hemopexin is the predominant hyaluronidase expressed in mammalian liver.
Metastatic squamous cell cancer after psoralen photochemotherapy.
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Circadian variation of cardiopulmonary disease onset in the general population: an emergency care system perspective from Berlin.
STUDY HYPOTHESIS: The objective of the present study was to determine the circadian pattern of onset of acute pulmonary emergencies in the general population and to analyze the influence of age and sex on these patterns. METHODS: Analysis of all 47,082 emergency calls during the years 1987 and 1988 of the Berlin emergency medical system. Analysis of circadian variation in incidence of subgroups with the leading symptom of respiratory distress, chest pain, or sudden unconsciousness. All cases of nontraumatic sudden death were analyzed. All missions were evaluated with regard to sex and age dependence. RESULTS: There is a circadian variation in acute cardiopulmonary emergencies with the highest incidence between 6 AM and noon. This applies to subpopulations of chest pain (9,068), respiratory distress (13,732), sudden unconsciousness (7,829), resuscitation attempts (4,787), and persons found dead without resuscitation attempts (4,780). Cases of chest pain, respiratory distress, and resuscitations show a second evening peak. Patients 65 years old or less have the highest rates in the afternoon, whereas those aged over 65 show a single morning peak (P < .0001). These relations are independent of sex and presenting complaint. CONCLUSION: Unselected populations show circadian variations in the incidence of cardiopulmonary emergencies. Age-related differences suggest different pathophysiological age-dependent mechanisms, eg, hormonal factors or lifestyle-dependent trigger mechanisms. Emergency medical systems should adjust the availability of emergency services to the distinct circadian differences of life-threatening cardiovascular and pulmonary diseases.
Age-dependent changes of hyaluronan in human skin.
Hyaluronan is a major component of the extracellular matrix of skin. The large volume of water of hydration associated with hyaluronan may be a mechanism for maintaining the normal hydration of skin. As such, decreasing levels of hyaluronan deposition might underlie the changes associated with the aging process. To test this hypothesis, hyaluronan levels were determined in extracts of skin obtained at autopsy from individuals of different ages. However, no significant differences in hyaluronan concentrations were found. The distribution of hyaluronan polymer sizes in various extracts did not change as a function of age as measured by size exclusion chromatography. However, major differences in hyaluronan extractability did occur as a function of age. Sequential extraction was performed utilizing 1) 0.1% Triton X-100, 2) 4 M guanidine-HCl, and 3) papain digestion, to release species of hyaluronan progressively more tightly associated with tissue. With advancing age, hyaluronan polymers became progressively more tissue associated. The proportion of hyaluronan released after papain digestion increased from 7% of the total in fetal to 23% of the total in senescent skin. Finally, histolocalization of hyaluronan was examined in full-thickness sections of human skin of different ages. Major differences in compartmentalization were found. We conclude that neither the concentration nor polymer size of hyaluronan changes as a function of age. However, enhanced association with tissue occurs, presumably through hyaluronan-binding proteins and alterations in the histolocalization of hyaluronan. Such observations may underlie some of the changes in human skin that occur with aging.
Ethical aspects of dementia research: informed consent and proxy consent.
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[Stress factors in acute myocardial infarct: the role of physical exertion and unusual life events].
OBJECTIVE: It is controversial whether the onset of myocardial infarction is a "random" event or whether there are triggering factors of the disease. Previous reports on possible triggers were based on case studies or inadequately controlled studies. The TRIMM study (Triggers and Mechanisms of Myocardial Infarction) was designed to determine the influence of physical activity and other external factors on the acute risk of myocardial infarction. METHODS: At Klinikum Steglitz, Berlin, all consecutive patients with myocardial infarction were included. In the Augsburg area, all patients with myocardial infarction in a prospectively defined cohort (n = 330,000) were registered by monitoring 26 hospitals. Information on the circumstances and possible triggers of the disease was obtained by standardized interviews. The control group was matched for age, sex, precinct, and time of a control event. The statistical analysis included a case-control comparison of patients with control subjects and a case-crossover comparison comparing the average exposure to a possible trigger with the time of the last exposure prior to the onset of disease. RESULTS: From January 1989 to December 1991, 1194 patients (74% men, 61 +/- 9 years) were enrolled 13 +/- 6 days after myocardial infarction. During the initial three hours after awakening, the occurrence of myocardial infarction was almost threefold compared to other times of day. A multivariate analysis yielded a twofold risk of myocardial infarction during physical exertion, statistically independently of time of day. 7.1% of patients had engaged in exertional physical activity at onset of the event, as opposed to 3.9% of control subjects. The case-crossover analysis demonstrated a relative risk of 2.1 (1.6-3.1) of exertional physical activity within 1 hour prior to myocardial infarction. Patients whose average frequency of physical exertion was < 4 versus > or = to 4 times per week had relative risks of 6.9 versus 1.3 (p < 0.01). Unusual life events within 24 hours and 24 hours to 4 weeks prior to the event occurred with similar frequencies and control subjects. CONCLUSIONS: Physical exertion appears to increase the acute risk of myocardial infarction in patients with coronary heart disease, particularly in untrained individuals. Unusual life events, however, are of less importance for the acute risk of disease. These findings are important for further investigation of triggering mechanisms of myocardial infarction and for improving preventive strategies.
Self-administration of Salmonella endotoxin.
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Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors.
Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.
Calcium and kidney stones.
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[The therapy of androgenetic alopecia with minoxidil].
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Age-dependent change in the hyaluronic acid content of the human chorioretinal complex.
OBJECTIVE: Hyaluronic acid (HA) has a key role in the structure and organization of the extracellular matrix. We sought to identify the distribution of HA in human eye tissue with regard to age using a biotinylated HA-binding protein. METHODS: Fetal and adult (from donors ranging from 28 to 94 years of age) eye tissues were fixed less than 24 hours post mortem and embedded in JB-4 medium (Polysciences, Warrington, Pa). Sections of 2-microns thickness were used. Control sections were pretreated either with Streptomyces hyaluronidase or HA-binding protein inactivated by HA. The binding of the protein to HA was detected with avidinbiotin alkaline phosphatase and developed by incubation with naphthol as-mx phosphate and Texas Red Salt (Pierce, Rockford, Ill). RESULTS: Specific staining for HA was observed in fetal eyes in the choroid, Bruch's membrane, sclera, retinal pigment epithelium, and developing retina from the vitreoretinal interface to the inner plexiform layer. Specific staining decreased with age in the choroid, retinal pigment epithelium, and Bruch's membrane. Hyaluronic acid-specific staining was undetectable in tissues from donors over 50 years of age. CONCLUSIONS: The localization of HA in the chorioretinal complex and its disappearance after the fifth decade of life may play a role in aging and age-related retinal disorders.