Prostaglandins with antiproliferative activity induce the synthesis of a heat shock protein in human cells.

Prostaglandins (PGs) A1 and J2 were found to potently suppress the proliferation of human K562 erythroleukemia cells and to induce the synthesis of a 74-kDa protein (p74) that was identified as a heat shock protein related to the major 70-kDa heat shock protein group. p74 synthesis was stimulated at doses of PGA1 and PGJ2 that inhibited cell replication, and its accumulation ceased upon removal of the PG-induced proliferation block. PGs that did not affect K562 cell replication did not induce p74 synthesis. p74 was found to be localized mainly in the cytoplasm of PG-treated cells, but moderate amounts were found also in dense areas of the nucleus after PGJ2 treatment. p74 synthesis was not necessarily associated with cytotoxicity or with inhibition of cell protein synthesis. The results described support the hypothesis that synthesis of the 70-kDa heat shock proteins is associated with changes in cell proliferation. The observation that PGs can induce the synthesis of heat shock proteins expands our understanding of the mechanism of action of these compounds whose regulatory role is well known in many physiological phenomena, including the control of fever production.     

In situ hybridization analysis for herpes simplex virus nucleic acids in Alzheimer disease

Histological sections of brain from patients showing evidence of advanced pathology of Alzheimer disease (AD) were examined for the presence of herpes simplex type-1 (HSV-1) nucleic acids by a sensitive in-situ hybridization technique. Samples from neurologically normal patients were examined in parallel. Sensitivity of the assay was verified by the detection of HSV-1 nucleic acids in neurons of trigeminal ganglia taken from cases of AD and normal controls. This indicated that the hybridization reaction was sufficiently sensitive to detect latent HSV-1 infections. Positive hybridization in the brain was only detected in a confirmed case of herpes simplex virus encephalitis. These results appear to confirm previous reports that HSV-1 infection is not directly involved in the pathology associated with AD.     

Positron emitters for the study of tumor metabolism

Positron emission tomography with metabolically active substances is a noninvasive imaging modality to determine tumor metabolism. Quantification of tumor metabolism provides valuable information, e.g., for the differential diagnosis of malignancies. Radiolabeled therapeutic substances can be traced with PET. Measurement of fluorouracil metabolite concentrations provides data about the accumulation pattern of the cytostatic agent and allows assessment of the therapeutic outcome.     

Association of tuberculosis and M. tuberculosis-specific antibody levels with HLA

In the search for HLA-linked immune response genes that control susceptibility to tuberculosis, we performed HLA typing and measured antibody titers to well-defined Mycobacterium tuberculosis antigenic determinants in 101 patients with sputum smear-positive pulmonary tuberculosis and 64 healthy controls from Surabaya, Indonesia. HLA-DR2 and DQw1 were associated with sputum smear-positive pulmonary tuberculosis (attributable risk = 36% and 39%, respectively), while DQw3 was associated even more strongly with the control group (preventive fraction = 57%). Antibody titers to the TB71 and TB72 epitopes of the 38-kDa protein, present only on tubercle bacilli, were strongly associated with DR2 (Pcorr = .001 and .024, respectively). The association of both the disease and the antibody response to the 38-kDa antigen of M. tuberculosis with Class II HLA genes HLA-DR2 indicates that Ir-gene-mediated regulation of the immune response to this antigen may be of pathogenic significance for the development of sputum smear-positive tuberculosis.     

Skeletal muscle blood flow and venous capacitance in patients with severe sepsis and systemic hypoperfusion

Alterations in peripheral vascular tone are presumed to contribute to circulatory failure during severe sepsis. Decreased venous tone with venous pooling may decrease effective circulatory blood volume, while decreased arterial tone with redistribution of systemic blood may compromise tissue nutrient flow. We compared forearm arterial and venous tone and forearm blood flow in ten patients with and ten patients without sepsis. The FVT, MVC, and FBF were measured by air plethysmography. In the septic patients, MCV was 1.4 +/- 0.1 ml compared with 3.1 +/- 0.2 ml in nonseptic patients (p less than 0.01). The FVT was 13.4 +/- 1.0 mm Hg/ml in septic patients versus 7.0 +/- 0.5 mm Hg/ml in nonseptic patients (p less than 0.01). The ratio of FBF to cardiac output was 0.28 +/- 0.07 percent in septic patients and 0.31 +/- 0.07 percent in nonseptic patients. These data suggest that increased peripheral venous capacitance and redistribution of skeletal muscle blood flow are not present in patients with sepsis.     

The association of circulating endotoxin with the development of the adult respiratory distress syndrome

Despite extensive investigation, the pathogenesis of the adult respiratory distress syndrome (ARDS) remains uncertain. As yet, there is no clear explanation of why some patients at risk for ARDS develop the syndrome, whereas others do not. Neutrophils and complement fragments have been implicated in the acute lung injury, but it is clear from published data that evidence of complement activation alone predicts neither the development nor the severity of ARDS. We investigated whether the combination of endotoxin, a leukocyte-priming agent, and complement fragments, leukocyte-stimulating agents, was associated with the development of ARDS. Ninety-eight patients were identified as being either at risk for the development of ARDS or having ARDS, and serial blood samples were obtained. There was no correlation between C5 fragments and the development of ARDS. C3 fragment levels were increased in 89% of the patients with ARDS, but they were also increased in 62% of patients at risk. Endotoxin was detected in 74% of the plasma samples obtained from patients at risk who subsequent developed ARDS and in 64% of the plasma samples obtained from the patients with ARDS. In contrast, only 22% of the plasma samples obtained from the patients at risk who did not develop ARDS had measurable endotoxin. We suggest that the combination of endotoxin and complement fragments may be one mechanism involved in the development of ARDS.