Disease surveillence. Key to early intervention and epidemic control.
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Communicable Disease Control↗
Biomedical subjects
D Katz
Publications and source records attributed to D Katz.
Effects of 12-O-tetradecanoylphorbol-13-acetate on estrogen receptor activity in MCF-7 cells.
The effects of long term treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) on estrogen receptor (ER) expression in the human breast cancer cell line, MCF-7, were studied. This study demonstrates that treatment of cells with the phorbol ester blocked estrogen receptor activity. Treatment of cells with 100 nM TPA resulted in an 80% decrease in the level of ER protein and a parallel decrease in ER mRNA and binding capacity. Following removal of TPA from the medium, the level of ER protein and mRNA returned to control values; however, the receptor failed to bind estradiol. These cells also failed to induce progesterone receptor in response to estradiol. In addition, TPA treatment blocked transcription from an estrogen response element in transient transfection assays and inhibited ER binding to its response element in a DNA mobility shift assay. The estrogen receptor in treated cells was recognized by two monoclonal anti-ER antibodies and was not quantitatively different from ER in control cells. RNase protection analysis failed to detect any qualitative changes in the ER mRNA transcript. Mixing experiments suggest that TPA induces/activates a factor which interacts with the ER to block binding of estradiol. The effects of TPA on ER levels and binding capacity were concentration-dependent. Low concentrations of TPA inhibited estradiol binding without a decrease in the level of protein, whereas higher concentrations were required to decrease the level of ER protein. The effects of TPA appear to be mediated by activation of protein kinase C since the protein kinase C inhibitors, H-7 and bryostatin, block the effects of TPA on estradiol induction of progesterone receptor. TPA treatment had no effect on the level or binding capacity of the glucocorticoid receptor, indicating that the effects are not universal for steroid receptors. These data demonstrate that activation of the protein kinase C signal transduction pathway modulates the estrogen receptor pathway. The long term effect of protein kinase C activation is to inhibit estrogen receptor function through induction/activation of a factor which interacts with the receptor.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
DNA bending by thyroid hormone receptor: influence of half-site spacing and RXR.
Transcriptional activation by thyroid hormone (T3) requires interactions between the T3 receptor (TR) and T3 response elements (TREs) composed of two copies of sequences related to AGGTCA. Direct repeats of this sequence are a functional TRE when spaced by 4 but not by 5 bp (DR4 versus DR5). TR bound as monomers, homodimers and heterodimers with retinoid X receptor (RXR) to both DR4 and DR5, with an approximately 10-fold greater affinity for DR4 due to reduced dissociation of the protein-DNA complex. We explored DNA bending as an additional variable which could influence the transcriptional outcome of the TR-TRE interaction. Circular permutation indicated a large distortion of the DNA following TR binding, but phasing analysis strongly suggested that this was due only in small part to DNA bending. Phasing analysis indicated that both TR/RXR and TR homodimer induced bends of approximately 10 degrees in DR4, but caused little bending of DR5. Moreover, the TR homo- and heterodimers bent DR4 in opposite directions. These results indicate that in addition to regulating the affinity and spacing requirement for DNA binding by TR, the TR dimer partner may also modulate transcription by influencing the direction of the bending induced by TR binding to DNA, although this effect may be subtle, due to the modest degree of bending.
Animals↗
Neurofibrillary tangles in Niemann-Pick disease type C.
Niemann-Pick disease type C (NPC) is an autosomal recessive disease, belonging to a clinically heterogeneous group of lipid storage diseases, distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified cholesterol. Unlike Niemann-Pick disease types A and B, there is no primary genetic defect in sphingomyelinase in NPC. During the routine neuropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with beta-amyloid deposits. The NFT were most frequent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal ganglia, thalamus and hypothalamus. In one of the most severely affected case, the NFT were even found in the neurons in the inferior olivary nucleus and in the spinal cord. The NFT were immunostained with Alz 50, and consisted of paired helical filaments. The distribution of the neurons bearing the NFT was generally similar to that of the swollen storage neurons, and storage neurons often contained NFT in their perikarya and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NFT in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in the formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of neurons to certain slowly progressive metabolic perturbations of an as yet undefined nature.
Adolescent↗
Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation.
The thyroid hormone (T3) receptor (TR) variant TR alpha 2 is abundant in brain but does not bind T3 because of its unique C terminus. The only known function of TR alpha 2, inhibition of TR-dependent transactivation, involves competition for T3 response elements. Paradoxically, in vitro-translated TR alpha 2 bound poorly to these sites. We report here that dephosphorylation of TR alpha 2 restored its DNA binding. Mutation of C-terminal serine residues to alanine (TR alpha 2-SA) was equally effective. The C terminus of TR alpha 2 was phosphorylated in a human cell line, whereas that of TR alpha 2-SA was not. Conversely, TR alpha 2-SA was a much better inhibitor of T3 action than was wild-type TR alpha 2. The dominant negative activity of TR alpha 2-SA was less than stoichiometric with TR concentration, possibly because it was unable to heterodimerize with retinoid X receptor, which enhances the binding of other TRs. Purified casein kinase II as well as a reticulocyte casein kinase II-like activity phosphorylated TR alpha 2 on serines 474 and 475. Mutation of these two residues to alanine was sufficient to restore DNA binding. Thus, DNA binding by TR alpha 2 is regulated by phosphorylation at a site distant from the DNA-binding domain. The increased dominant negative activity of a nonphosphorylatable form of TR alpha 2 suggests that phosphorylation may provide a rapid, T3-independent mechanism for cell-specific modulation of the expression of T3-responsive genes.
Amino Acid Sequence↗
The role of lexical status on the phonetic categorization of speech in aphasia.
Recent results with normal subjects have shown that the locus of the phonetic boundary of a speech continuum may change as a function of the word/nonword status of the endpoint stimuli. This so-called lexical effect in phonetic categorization has been used as evidence for the role of top-down processing in speech perception. This study investigated whether aphasic patients show a similar influence of lexical status on phonetic categorization. Two test continua were created varying in voice-onset time: in one continuum, the two endpoint stimuli were word/nonword, i.e., "duke"--"tuke," and in the other continuum, they were nonword/word, i.e., "doot"--"toot." Twelve aphasic patients were tested including 6 Broca's aphasics and 6 Wernicke/Conduction aphasics. The subject's task was to determine whether the first sound of the stimulus was a "d" or "t." Broca's aphasics showed a large lexical effect, with the magnitude of the effect being greater than that for normals. These results suggest that the Broca's aphasics place a heavier reliance on a heuristic strategy than on the perceptual information embedded in the test stimuli in making a phonetic categorization. In contrast, Wernicke/Conduction aphasics did not show a lexical effect, suggesting that these patients are less likely than either normals or Broca's aphasics to use heuristic strategies in lexical processing. The overall results are considered in relation to current views on language-processing deficits in aphasia.
Adult↗
Human T-lymphotropic virus type I DNA in spinal cord of tropical spastic paraparesis with concomitant human T-lymphotropic virus type I-negative Hodgkin's disease.
We studied a 58-year-old black woman from Barbados who simultaneously developed myelopathy and lymphoma with human T-lymphotropic virus type I (HTLV-I) antibodies in serum and cerebrospinal fluid and died 3 years after onset. Neuropathological examination showed typical tropical spastic paraparesis (TSP). The polymerase chain reaction (PCR) demonstrated defective proviral genome retaining the HTLV-I pX and env regions in thoracic spinal cord, the level most severely affected. Defective HTLV-I in the nervous system retaining the pX region may be relevant to pathogenesis because circulating CD8+ cytotoxic lymphocytes specific for HTLV-I pX occur in HTLV-I myelopathy. This patient's lymph node biopsy specimen was consistent with Hodgkin's disease (HD), nodular sclerosis subtype, of B-cell origin. The PCR in the paraffin-embedded lymph node involved by HD failed to amplify HTLV-I proviral sequences. Complete HTLV-I proviral amplification was obtained in paraffin-embedded lymph nodes form positive controls (adult T-cell leukemia). To our knowledge the association of TSP and HD has not been reported previously. Despite claims that HD may be associated with HTLV-I, we demonstrated absence of HTLV-I-infected T cells in the lymphoid infiltrate of HD in this case, positive HTLV-I serology notwithstanding.
DNA, Viral↗
Detection of HIV-p24 antigen in body fluids by immunotrapping on Staphylococcus aureus (Cowan 1) bacteria, gold immunolabelling and backscattered electron analysis in a scanning electron microscope.
An immunosorbent electron microscopical (ISEM) method, the Protein A-coated bacteria technique/gold, (PA-CBT/G), was developed for the detection of non-particulate soluble antigens. The method is based on immunotrapping of antigens on antibody coated, glutaraldehyde cross-linked, Protein A-rich, Staphylococcus aureus bacteria. The 'trapped' antigen is then identified by colloidal-gold immunolabelling. Gold particles are observed in a scanning/transmission electron microscope by analysis of backscattered electrons. With this method it was possible to detect the presence of p24 HIV antigens in blood, semen, saliva, crevicular and cerebrospinal fluids from HIV seropositive cases. Although the PA-CBT/G identified correctly the p24 antigen in only 80% of the ELISA HIV-antigen positive sera, it detected, more frequently than ELISA, HIV-antigen in seminal and oral fluids. The PA-CBT/G method could thus be useful to fully characterise individual HIV excretion patterns in body fluids other than sera even from patients negative for HIV-antigen by ELISA.
Body Fluids↗
Long-term follow-up for recurrent stenosis: a prospective randomized study of expanded polytetrafluoroethylene patch angioplasty versus primary closure after carotid endarterectomy.
PURPOSE: To determine the effect of primary closure (PC) versus expanded polytetrafluoroethylene patch graft angioplasty (PGA) on the incidence of recurrent stenosis (> 50% lumen diameter narrowing) after carotid endarterectomy (CEA), 87 patients undergoing 100 consecutive CEA were prospectively randomized into two groups. METHODS: Forty-four patients underwent 51 PC, and 43 patients underwent 49 PGA. All patients were evaluated after operation by duplex scanning at 1.5, 12, 24, and 36 months. There were no significant differences in the demographic characteristics or operative indications for CEA between the two patient groups. Complete follow-up was achieved in 86% (75/87) of the patients during the 36-month surveillance period. RESULTS: The perioperative permanent neurologic morbidity in the PC and PGA groups was noted to be 4% and 2%, respectively (PC = 2/51 vs PGA = 1/49, p = 0.58). Three additional reversible cerebral ischemic events occurred in the postoperative period (PC = 2/51 vs PGA = 1/49, p = 0.58). Other morbidity included immediate postoperative hemorrhage requiring reexploration (1/51) in the PC group and an infected expanded polytetrafluoroethylene patch requiring removal and replacement with autogenous vein (1/49). Long-term follow-up detected a single patient with significant bilateral restenoses of his primarily closed carotid arteries. None of the patients in the PGA group had restenoses (PC = 2/51 vs 0/49, p = 0.50). In addition, no postoperative dilation of the common or internal carotid arteries or perioperative death was observed. CONCLUSIONS: In patients undergoing CEA, these data demonstrate no significant difference in the perioperative morbidity or mortality between PC and PGA. Use of the patch did not engender patients to patch rupture or aneurysmal degeneration as previously described with vein patch angioplasty procedures. This series supports effective use of either technique to achieve minimal rates of restenosis.
Adult↗
Vein harvest ischemia: a peripheral vascular complication of coronary artery bypass grafting.
Lower-extremity ischemia can lead to impaired healing of saphenous vein excision sites in patients with significant peripheral vascular disease (PVD). Five patients who required infrainguinal revascularization for wound necrosis of the harvest site after coronary artery bypass grafting are described. The male/female ratio was 2:3 with a mean age of 67 (range 45-87) years. The most commonly associated problems were insulin-dependent diabetes mellitus (80%) and congestive heart failure (60%). The saphenous vein was harvested from the thigh and leg in three patients and exclusively from the leg in the others. Manifestations of ischemia ranged from persistent ulceration to complete wound disruption threatening limb loss. Impaired healing was isolated to infragenicular wounds in all patients. Pedal pulses were not detected in any of the affected extremities. Determination of the ankle/brachial pressure indices (ABI) revealed values of < 0.5 in three affected limbs. Non-compressible vessels resulted in falsely raised ABI of > 1.0 in the remaining two limbs; however, Doppler waveform analysis in these patients demonstrated significant PVD. Aggressive wound care and antibiotic therapy were continued for mean of 9 weeks before operative intervention. Infrainguinal reconstruction included femoropopliteal (two), femorotibial (two) and popliteal-tibial bypass (one). Autologous arm and saphenous veins in addition to expanded polytetrafluoroethylene grafts were used effectively. Limb salvage and wound healing were achieved in 100% of the patients without untoward sequelae. It is concluded that unrecognized PVD in patients undergoing coronary artery bypass grafting can lead to significant morbidity. Patients at risk may be identified with a combination of history, physical examination and non-invasive testing.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes.
Regulation of development and metabolism by thyroid hormone (T3) may be influenced by a non-T3 binding T3 receptor (TR) isoform, TR alpha 2, which can inhibit transcriptional activation by legitimate TRs. Numerous mechanisms have been postulated to explain the dominant negative actions of TR alpha 2, including competition for target genes, formation of inactive heterodimers, and squelching. We have found that excess TR alpha 2 was required to inhibit TR alpha 1-mediated transactivation from multiple T3 response elements (TREs). Inhibition of T3 action by TR alpha 2 was specific for TRE-containing genes, because a GAL4/TR alpha 1 chimera, which heterodimerized with the 9-cis-retinoic acid receptor (RXR) and activated transcription from the GAL4 binding site in the presence of T3, was not inhibited by TR alpha 2. In contrast, TR alpha 2 inhibited transactivation by TR alpha/VP16, a chimeric protein containing the N-terminal DNA binding domain (DBD) of TR alpha 1 fused to the transcriptional activation domain of VP16. Indeed, TR alpha 2 inhibited the binding of TR alpha 1 monomers, homodimers, and RXR-heterodimers to DNA in vitro, whereas the TR alpha 2 C terminus alone did not. Although TR alpha 2 bound to TREs with less affinity than TR alpha 1, it bound directly to target genes in the cell nucleus. Furthermore, a TR alpha 2 mutant which binds more avidly to TREs was a more effective inhibitor of T3 action than wild type TR alpha 2. Together these data indicate that TR alpha 2 inhibits T3 action by competing for binding to TREs.
Base Sequence↗
Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis.
Magnetic resonance imaging is a highly sensitive method for the detection of the lesions of multiple sclerosis and renders possible the study and the evolution of early lesions. Previous reports on magnetic resonance imaging following gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) injection demonstrated that new lesions can be recognized by contrast enhancement. The pathological basis of these observations is uncertain. We have had the opportunity to study at autopsy the brain of a patient with chronic progressive multiple sclerosis who suffered acute worsening leading to death. Magnetic resonance imaging performed 10 days and 4 weeks prior to death showed new Gd-DTPA-enhanced lesions in the posterior hemispheric white matter adjacent to the lateral ventricles. Light microscopic examination of these areas demonstrated them to be fresh lesions comprising intense inflammatory activity and dense perivascular cuffs within an edematous lesion center and a striking parenchymal mononuclear cell infiltration at the margins of the lesions. Lesions that were demonstrated by increased signal on T2-weighted images, but were not enhanced following administration of Gd-DTPA, were all of the chronic type, either inactive or active. None of these showed the intense inflammatory activity of the acute lesions and most displayed fibrous astrogliosis.
Adult↗
The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis.
The expression of PECAM, ICAM-1, VCAM-1, and E-selectin was studied in 64 samples of human coronary arteries taken from 15 explanted hearts obtained within 5 min of transplantation. Normal artery (n = 12), predominantly fibrous plaques (n = 23), and plaques containing extracellular lipid (n = 26) and three segments showing recanalization channels were studied. All endothelial cells strongly and equally expressed PECAM; positive staining was used to check that artefactual denudation of the endothelial surface had not occurred. PECAM was also present in some lipid-filled macrophages. Normal arteries showed no VCAM-1 staining but focal segments of the endothelium were positive for ICAM-1 and E-selectin. ICAM-1 was strongly and constantly expressed by the endothelium over all types of plaques and in macrophages. E-selectin expression was confined to endothelial cells and occurred on the surface in 35 per cent of fibrous and 22 per cent of lipid-containing plaques. VCAM-1 staining of surface endothelium occurred in 39 per cent of fibrous and 20 per cent of lipid-containing plaques. A population of spindle-shaped cells of macrophage type (positive for EMB11 antigen) expressed VCAM-1 in lipid-containing plaques. Adventitial vessels adjacent to plaques showed endothelial expression of ICAM-1 and E-selectin. VCAM-1 staining of adventitial vessel endothelium was associated with local lymphoid aggregation. In conclusion, the expression of cell adhesion molecules is an important element in the inflammatory component of atherosclerosis and contributes to both monocyte and lymphocyte activation and recruitment from adventitial vessels and the arterial lumen.
Adult↗
[Mycobacterium terrae tenosynovitis of the hand].
This article presents the seventh case of human infection due to Mycobacterium terrae. This report of typical tenosynovitis clearly illustrates well all of the standard problems raised by this kind of atypical acid-fast mycobacterial infection: delayed and difficult diagnosis, danger of steroid infiltrations, frequency of recurrence. Nevertheless, M. terrae has certain specific features: it is probably less pathogenic than other atypical acid-fast such as marinum. Some authors propose surgical treatment alone, but this case suggests the need for surgery combined with antituberculous therapy.
Adult↗
Salvage trial of trimetrexate-leucovorin for the treatment of cerebral toxoplasmosis in patients with AIDS.
The clinical efficacy of trimetrexate, a dihydrofolate reductase inhibitor with potent in vitro antitoxoplasma activity, was assessed in 9 sulfonamide-intolerant patients with AIDS and biopsy-proven cerebral toxoplasmosis. The 9 patients were treated for 28-149 days with trimetrexate (30-280 mg/m2/day) plus leucovorin (20-90 mg/m2 every 6 h). Radiographic responses were documented in 8 patients, and clinical responses in 5 patients. Despite continued therapy, all patients deteriorated clinically and radiographically within 13-109 days of their initial improvement. Trimetrexate at very high doses for extended periods was not associated with serious toxicity. Trimetrexate alone had dramatic but transient activity in sulfonamide-intolerant patients and thus is not adequate as single-agent therapy for AIDS-associated toxoplasmosis.
Acquired Immunodeficiency Syndrome↗
How well do prediction equations predict? Using receiver operating characteristic curves and accuracy curves to compare validity and generalizability.
Although morbidity and mortality prediction equations are widely used in planning, clinical practice, and health risk appraisal, their validity and generalizability have been tested only in a limited way. Previous attempts lacked an absolute standard of performance and looked only at the equations' ability to predict who would become ill (sensitivity), not the equally important ability to predict who would remain healthy (specificity). We compared six all-cause mortality prediction equations using receiver operating characteristic curves and accuracy curves, which overcome the limitations of earlier methods and provide a concise visual representation of the results. We used equations from five prospective studies conducted in the United States (Tecumseh at 8 and 12 years of follow-up, Framingham, Chicago Gas, Chicago Western Electric, and Albany), each of which included cholesterol, smoking, and blood pressure as independent variables, to predict 12-year mortality in Tecumseh males age 40-54 years. Previous studies suggested that these equations predict equally well. Our analysis found that, although all predict better than chance, Albany, Chicago Western Electric, and Tecumseh at 8 years underestimate mortality. Receiver operating characteristic and accuracy curves are a promising technique for assessment of prediction equations.
Cholesterol↗
Comparison of dimethyl dioctadecyl ammonium bromide, Freund's complete adjuvant and mineral oil for induction of humoral antibodies, cellular immunity and resistance to Newcastle disease virus in chickens.
Dimethyl dioctadecyl ammonium bromide (DDA), a lipophilic quaternary amine, was evaluated in adult chickens for potentiation of immunological responses to subcutaneously administered inactivated Newcastle disease virus (NDV) vaccines. DDA enhanced humoral and cell-mediated immune (CMI) responses to levels which were significantly higher than those induced by the vaccine alone The haemagglutination inhibition antibody titers induced by DDA were slightly lower than those induced by mineral oil although neutralizing antibody titers seemed to be higher. DDA induced strong CMI (DTH and lymphocyte proliferation) responses, more than those induced by Freund's complete adjuvant and mineral oil. Both DDA and mineral oil induced comparable high levels of protection to challenge doses of 200,000 LD50 per chicken. No toxic effects or local tissue damage were observed in any of the inoculated chickens.
Adjuvants, Immunologic↗
Community boards increase hospitals' responsiveness.
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Community Participation↗