Inhibition of erythropoietin production by cytokines and chemotherapy may contribute to the anemia in malignant diseases.
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Biomedical subjects
Publications and source records attributed to M Wolff.
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The prevalence of increased serum immunoreactive erythropoietin (Epo) was determined in a prospective study of 49 patients with renal cell carcinoma. Measured by a monoclonal antibody based commercial enzyme-linked immunoassay, the Epo concentration was above the normal range, determined in nonanemic humans, in four of the renal carcinoma patients. Since three of these were anemic, their increased Epo level was considered to be appropriate. The high estimate of serum Epo (218 U/l) in the fourth patient, who was not anemic, was not confirmed when tested by radioimmunoassay. Thus, in contrast with earlier studies, our results indicate that increased Epo is not a clear serological renal cell carcinoma marker. In addition, when monolayer cell cultures of 14 different established human renal carcinoma lines were screened, none of these released immunoreactive Epo in measurable amounts.
The various methods of measurement of dentinal hypersensitivity are based upon the types of stimuli used to elicit a pain response in teeth, which include thermal, tactile, evaporative, electrical and osmotic. Pulpal inflammation in its early stages reduce the threshold of pain response to these stimuli but electrical stimulation may make it possible to assess the possible contribution of such inflammation to sensitivity determinations. Although the magnitude of each stimulus is quantifiable, patient response is subjective, which necessarily makes measurements of dentinal sensitivity semisubjective. Various methods of testing dentinal sensitivity are discussed, along with their advantages and disadvantages. The teeth most suited for measurement in clinical studies are the canines and premolars. This is because approx. 80% of the sensitivity lesions are associated with these teeth, which have similar thicknesses of root dentine. Data from several studies involving the same subjects indicate that individual measurements readily return to baseline and that the commonly seen placebo effect is probably due to some as yet unidentified factor in desensitizing formulations. Possible roles of salivary and plaque environmental factors in the development of dentinal sensitivity are discussed, as well as methods for their measurement.
An outbreak of gastrointestinal disease and haemolytic uraemic syndrome caused by Escherichia coli O157:H7 was investigated. The outbreak occurred in a day care centre located in northern Germany in August 1992 and involved 39 children and two adults. Furthermore, four asymptomatic infections were detected among the staff. Initial and secondary cases were reported over a 30-day interval, with cases occurring in three waves. Person-to-person contact and environmental contamination were assumed to be the main mode of transmission. The source of the outbreak has remained unknown but it is likely that primary or secondary contamination of the day care centre's kitchen, too, played a role in the spread of infections. The organisms were isolated from two open packs of deep-frozen stuffed cabbage rolls and turkey scallops in batter, and furthermore from swabs from two kitchen utensils. Of the 39 cases with diarrhoea, three developed a haemolytic uraemic syndrome; one of the latter patients died. In 8 of the cases as well as in four healthy adult employees, E. coli O157:H7 was isolated from stool samples, and in two stool culture-negative cases the presence of IgM antibody to O157 LPS indicated recent infection. The E. coli O157:H7 isolates from the cases and the kitchen were of identical phage type and yielded identical biochemical reactions. All E. coli O157:H7 isolates harboured stable slt-II genes. However, slt-I genes could only be demonstrated in the primary cultures and were lost during subcultivation. This is the largest outbreak caused by enterohaemorrhagic E. coli O157:H7 that has been documented in Germany so far. The high infectivity of the organism which was demonstrated by person-to-person transmission and propagation within certain groups of children stresses the need for strict hygienic measures and early case reporting when such infections occur in susceptible settings like day care centres, nursing homes, or hospitals.
The value of rapid T1- and T2-weighted fast field (T1-FFE, T2-FFE) gradient-echo sequences and T2 weighted turbo-spin echo (TSE) sequences in the diagnosis of focal liver lesions using 0.5 Tesla was compared with conventional spin-echo sequences (SE). Amongst 88 liver lesions T1-SE sequences showed 98%, T2-TSE sequences showed 92%, T2-SE sequence showed 84%, T1-FFE sequence showed 78% and T2-FFE sequence showed 69%. Direct comparison has shown that TSE sequences are able to demonstrate significantly more lesions (p < 0.05) than T2-SE sequences. Quantitative assessment has shown that the tumor/liver contrast/noise ratio in the T1-SE sequence was 118% higher than in the T1-FFE sequence (p < 0.001). Comparison of T2 weighted sequences has shown that the tumour/liver contrast/noise ratio was 45% higher in the TSE sequence than in the T2-SE and 239% higher than in the T2-FFE sequence (p < 0.001). The results indicate that the TSE sequence should be used instead of the conventional T2-SE sequence because of the reduced time (about 40%), due to improved image quality and increased demonstration rate of liver lesions. Neither T1-FFE nor T2-FFE are suitable, when using moderate field strength, to replace T1-SE or TSE sequences.
Ten cases of salmonellal splenic abscesses recently documented in various Latin American countries are discussed. All patients were adults; the mean age was 32.6 years, and there was a predominance of males (seven). Predisposing conditions were identified in four cases. All 10 cases were documented by diagnostic imaging techniques; in one case, exploratory diagnostic laparotomy was also performed. Splenectomy was performed on eight patients, while two other patients responded to long courses of intravenous antimicrobial therapy alone. One patient died as the result of perioperative splenic rupture, and two patients underwent second laparotomies because of left subphrenic abscesses. Except for one human immunodeficiency virus-infected individual, all patients were immunocompetent and had large solitary lesions. Salmonella typhi was the predominant organism isolated and was recovered in six of the 10 cases.
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The Navajo are known to be at high risk for hepatitis A virus (HAV) infection. This study investigated the safety and immunogenicity of an investigational, alum-adjuvanted, formalin-inactivated HAV vaccine (VAQTA) developed by Merck Research Laboratories in Navajo children. One hundred two of 212 children, ages 4 to 12 years, were HAV-seronegative (< 10 mIU/ml by an enhanced sensitivity modification of the HAVAB; Abbott). Ninety of these children received the HAV vaccine. Study participants were given vaccines containing various viral protein concentrations: Group A (n = 18), 6 units; Group B (n = 36), 13 units; and Group C (n = 36), 25 units HAV protein (1 unit approximately 1 ng viral protein antigen). Three-dose (0, 8, 24 weeks) and two-dose (0, 24 weeks) regimens were compared in subgroups within B and C. The vaccine was well-tolerated and there were no serious adverse reactions; no vaccinee developed hepatitis A. After 1 dose 82 to 100% of children seroconverted (> or = 10 mIU/ml, modified HAVAB; Abbott) and 100% seroconverted after 2 doses. After 1 dose the geometric mean titer for antibody was: Group A, 22 mIU/ml; Group B, 18 mIU/ml; and Group C, 38 mIU/ml. After 3 doses geometric mean titers increased to 10,106 mIU/ml in Group A, 7258 mIU/ml in Group B and 11,856 mIU/ml in Group C. Further field studies are indicated to evaluate its use in high risk populations, such as the Navajo.
Polychlorinated biphenyls (PCBs) are synthetic chemicals, manufactured in volume from about 1929 to the 1970s. Environmental contamination by PCBs has been documented in various substances, including human tissue. PCBs have been measured in human tissue by a variety of analytical methods. PCB levels have been reported as an approximation of total PCB content expressed in terms of a commercial mixture, by identification and quantification of chromatographic peaks, or by qualitative and quantitative characterization of specific congeners. Until recently, the coplanar mono-ortho- and di-ortho substituted PCBs, which are especially toxic and present in significant concentration in humans from industrial countries, had not been measured in human tissues. Examples of various types of commonly used analyses are presented in general population subjects and in persons who experienced special exposure. In this paper, the usefulness of PCB blood determinations following potential exposure is demonstrated, and their application in health studies is illustrated from a number of case studies. Coplanar PCB, mono-ortho-substituted and di-ortho-substituted PCB levels in human blood are presented and compared with polychlorinated dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in the U.S. population. Dioxin toxic equivalents for the two groups of chemicals are calculated and compared. It is found that mono-ortho-substituted and, to a lesser extent, coplanar PCBs, contribute substantially to dioxin toxic equivalents (TEq) in blood from U.S. adults. Because of substantial PCB contribution to dioxin toxic equivalents, total dioxinlike toxicity can only be determined if dioxins, dibenzofurans, and dioxinlike PCBs are measured.(ABSTRACT TRUNCATED AT 400 WORDS)
A new therapeutic approach involves the discovery by the "Stony Brook group," that tetracyclines, but not other antibiotics, can inhibit host-derived collagen-destructive enzymes. This newly discovered property of tetracyclines is unrelated to the antimicrobial activity of these drugs. Examples support the hypothesis that this unexpected property of tetracyclines provides a new approach to treating periodontal diseases as well as a variety of medical disorders.
Effects of thyroid hormones on the production of erythropoietin (Epo) were investigated in isolated perfused rat kidneys and in the human hepatoma cell line, HepG2. Epo protein was measured by radioimmunoassay. L-triiodothyronine and L-thyroxine stimulated hypoxia-induced Epo formation both in the kidney and in HepG2 cells in a dose-dependent fashion. Quantitation of Epo mRNA by competitive polymerase chain reaction (PCR) showed that hypoxic HepG2 cells had three-fold higher Epo messenger RNA levels when treated with thyroid hormones for 3 hours. Measurements of oxygen consumption revealed that this effect was not due to an increase in the degree of hypoxia. Thus, apart from the known direct effect on erythroid precursors, thyroid hormones appear to stimulate erythropoiesis by a noncalorigenic increase in Epo production.
Campylobacter fetus is a rare cause of endocarditis and endoaortitis: the authors believe this to be the second reported case of infection of an intracardiac prosthesis. The patient was a man who had already undergone replacement of the aortic valve and ascending aorta, and a gastrectomy, which were predisposing factors. The portal of entry was not found. The diagnosis was confirmed by positive blood cultures and transoesophageal echocardiography. The outcome was rapidly fatal despite antibiotic therapy and surgery, because of the seriousness of the lesions (pseudo-aneurysm of the aorta ruptured into the right atrium), the precarity of the terrain and surgical difficulties.
OBJECTIVE: To evaluate the safety and efficacy of a natural platelet-activating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome. DESIGN: Prospective, randomized, placebo-controlled, double-blind, phase III, multicenter clinical trial. SETTING: Twenty-one academic medical center intensive care units in France. PATIENTS: Two hundred sixty-two patients with sepsis syndrome who received standard supportive care and antimicrobial therapy, in addition to the administration of platelet-activating factor receptor antagonist or placebo. INTERVENTIONS: Patients received either a 120-mg dose of platelet-activating factor receptor antagonist intravenously every 12 hrs over a 4-day period or placebo. MAIN OUTCOME MEASUREMENTS: All patients were evaluated for 28-day, all-cause mortality. RESULTS: The 28-day mortality rate was 51% for the placebo group and 42% for the platelet-activating factor receptor antagonist group (p = .17). However, the efficacy of platelet-activating factor receptor antagonist was significantly greater in patients with Gram-negative sepsis (test for interaction, p = .03). In a separate analysis of patients with and without Gram-negative sepsis, the 28-day mortality rate was 57% for the patients receiving placebo (30 deaths of 53 patients) and 33% for patients receiving platelet-activating factor receptor antagonist (22 deaths of 67 patients; p = .01). Platelet-activating factor receptor antagonist also significantly (p = .01) reduced the mortality rate among patients with Gram-negative sepsis who were in shock at entry into the study (mortality rate was 65% for placebo vs. 37% for platelet-activating factor receptor antagonist) and among patients > 60 yrs of age (mortality rate was 74% for placebo vs. 31% for platelet-activating factor receptor antagonist). A Cox proportional-hazards model identified five independent prognostic factors: a) adequacy of antibiotic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram-negative sepsis population was stratified by age and these five prognostic factors were controlled for, the relative risk of death of the platelet-activating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving platelet-activating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet-activating factor receptor antagonist groups in the absence of Gram-negative sepsis. There were no differences in adverse events between the placebo and the treated groups. CONCLUSION: The studied platelet-activating factor receptor antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram-negative sepsis.
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This report describes the clinical spectrum and outcome of the hemophagocytic syndrome (HS) in 5 HIV infected patients. All 5 patients presented with fever, hepatomegaly and/or splenomegaly, confusion or coma and respiratory symptoms. Severe anemia was associated with thrombocytopenia and with neutropenia in 4 cases. Diffuse intravascular coagulopathy was present in 2 cases. Liver function tests were abnormal in three patients. The diagnosis of HS was made 2 to 12 weeks after the onset of symptoms and required in most patients repeated examinations of the bone-marrow, showing infiltration by histiocytes with prominent phagocytosis of blood cells. In one case this infiltration was not seen in the bone-marrow but only in the liver and the spleen. Varicella, mycobacterium infection, oesophageal candidiasis, Kaposi sarcoma were observed in the evolution of 3 patients. Anaplastic large cell Ki-1 lymphoma was present in one case. Four patients died as a result of complications of HS. The one patient with lymphoma survived.
To determine the range of tissues in which the human epidermal growth factor (EGF) receptor promoter is active, we created 12 independently derived lines of mice expressing a transgene consisting of human EGF receptor promoter and enhancer sequences fused to the bacterial chloramphenicol acetyltransferase (CAT) gene. Analysis for the presence of CAT activity in these transgenic mice revealed that the human EGF receptor promoter construct was consistently active in the thymus and spleen. Thymocytes separated from thymic stromal cells of EGF receptor-CAT mice demonstrated no CAT activity suggesting that expression in the thymus is confined to the thymic stroma, which consists mainly of epithelial cells. Thus, it should be possible to use the EGF receptor promoter construct described in this study to direct expression of a variety of foreign genes to the nonlymphocytic cells of the thymus and spleen so that the effect of these genes on the maturation and proliferation of thymocytes may be addressed.
The possibility of demonstrating erythropoietin at the light microscopic level was examined in homogenous cultures of the erythropoietin-producing human hepatoma cell lines HepG2 and Hep3B. Immunoperoxidase staining was applied in combination with several mono- and polyclonal antibodies. Sufficiently strong colour responses were obtained with all three polyclonal antibodies and with one of three monoclonal antibodies raised against recombinant human erythropoietin. The staining intensity was increased in hypoxic versus nonhypoxic hepatoma cultures. Intracellular erythropoietin immunoreactivity was confirmed by Western blot analysis of HepG2 extracts. The effect of oxygen supply on erythropoietin gene expression was confirmed by competitive polymerase chain reaction of erythropoietin mRNA and by radioimmunoassay of secreted erythropoietin.
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