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S R Smith

Publications and source records attributed to S R Smith.

At least 217 records · Page 12Linked to original sources
PubMed1992

Actions of a 5-lipoxygenase inhibitor, Sch 40120, on acute inflammatory responses.

Sch 40120 (10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b] [1,8]naphthyridin-5(7H)-one) is an inhibitor of the 5-lipoxygenase enzyme in rat neutrophils, human neutrophils and the the MC9 murine mast cell clone with IC50 values of 8, 4 and 7 microM, respectively. The drug was examined for its effects on acute inflammatory responses in the paw and pleural cavity of rats. The drug suppressed paw inflammation triggered by a reverse passive Arthus reaction or a subplantar injection of the polysaccharide carrageenan with p.o. ED50 values of 0.2 and 1.5 mg/kg, respectively. In reverse passive Arthus reaction and carrageenan pleurisy models, Sch 40120 was found to suppress both the cellular and fluid components of the acute inflammation. The p.o. ED50 values for inhibition of cells and fluid in pleurisy models were in the range of 0.1 to 0.7 mg/kg. When applied locally to the ears of mice, the drug blocked an arachidonic acid-induced and leukotriene-mediated ear inflammation with an ED50 of 0.072 mg/ear. These findings suggest that Sch 40120 is a potent anti-inflammatory agent that may be particularly useful in the treatment of inflammatory diseases such as psoriasis in which leukotrienes appear to be major mediators of the pathological symptoms that characterize the disease state.

Acute Disease↗
PubMed1992

Detection of in vivo-induced IL-1 mRNA in murine cells by flow cytometry (FC) and fluorescent in situ hybridization (FISH).

Flow cytometry (FC) and fluorescent in situ hybridization (FISH) were used to detect in vivo induced IL-1 alpha (a) messenger RNA. Spleen cells and thioglycollate-induced peritoneal exudate cells (PEC) were harvested from Balb/C mice three hours after intraperitoneal injection of 20 micrograms LPS. Cells from each population were phenotyped for MAC or IAd, fixed in 4% paraformaldehyde and then permeabilized with 70% ETOH. RNA-RNA FISH was performed by incubating suspended cells at 37 degrees C for 17 hours with biotinylated sense IL-1a, antisense IL-1a or antisense IL-2 probes in 50% formamide. Hybridized cells were washed in 2X SSC, treated with RNAse, stained with avidin conjugated to fluorescein (FITC) or allophycocyanin (APC) and analyzed immediately by FC. Initially, avidin-FITC was used to detect hybridized probe. Dual fluorescent FC analysis of IL-1a mRNA expression in LPS stimulated IAd+ cells showed an increase in mean fluorescent intensity (MFI) of 51 log channels (0.25 logs) when compared to unstimulated cells. Additionally, induction of specific IL-1a mRNA expression in cells from LPS treated animals was illustrated by increases in percent positive cells (24%) and in equivalent soluble fluorescein molecules (ESFM) bound (47%) when compared to cells from vehicle treated mice. Unhybridized cells and cells hybridized with control antisense IL-2 probe did not exhibit increases in MFI or ESFM. In subsequent experiments on MAC+ PEC, the use of avidin-APC to detect bound probe resulted in a greater separation between the FISH signals of antisense IL-1a and control sense probe (121 log channels, 0.6 logs) than that seen with FITC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Quantitative magnetic resonance studies of lumbar vertebral marrow in patients with refractory or relapsed Hodgkin's disease.

Lumbar vertebral (LV) bone marrow proton relaxation times were measured from midline sagittal magnetic resonance images of the lumbar spine of 20 patients with refractory or relapsed Hodgkin's disease (HD) referred for autologous bone marrow transplantation (ABMT) and 18 aged-matched normal volunteers. Two patients with positive bone marrow biopsies had markedly elevated mean LV marrow T1 and T1 variation. Elevated mean LV marrow T1 or T1 variation, consistent with bone marrow involvement with HD, was also seen in four other patients with negative bilateral posterior iliac crest bone marrow biopsies. Four patients with abnormal quantitative MR studies were examined serially following treatment. Mean LV marrow T1 and T1 variation normalised post ABMT, consistent with a good response to treatment. Quantitative MR studies of LV marrow may improve the detection of bone marrow involvement with lymphoma and be a complementary examination to bone marrow biopsy. Serial studies allow an objective and non-invasive assessment of treatment response.

Adult↗
PubMed1991

A study of cytokine production in acute graft-vs-host disease.

The role of cytokines in the development of acute graft-vs-host disease (GVHD) was investigated in B6AF1 mice that were injected with parental A/J lymphocytes. Splenocytes from GVH mice exhibited an increased capacity to produce interleukin (IL)-1, IL-6, and TNF-a when stimulated in culture with lipopolysaccharide (LPS). This enhanced capacity was diminished following in vivo treatment with immunosuppressive drugs. Concanavalin A-stimulated GVH spleen cells produced significantly lower levels of IL-2 but higher levels of interferon-gamma (IFN-gamma) than did syngeneic spleen cells. Immunosuppressive therapy in vivo increased the capacity of GVH spleen cells to produce IL-2. However, immunosuppressants differed in their effects on IFN-gamma production. Sch 24937 (6-bromo-5-chloro-2-[1-(methylsulfonyl)acetyl] 3-(2-pyridyl)indole) enhanced or had no effect while cyclosporin A consistently decreased the capacity of splenocytes to produce this lymphokine. These results indicate that the capacity of GVH splenocytes for cytokine production can be differentially affected by the actions of some pharmacological agents. The data also indicate that there may be differential regulation of the production of IL-2 and IFN-gamma by the Th1 subset in the GVH spleen.

Acute Disease↗
PubMed1991

Diethyldithiocarbamate suppresses the plant activation of aromatic amines into mutagens by inhibiting tobacco cell peroxidase.

Diethyldithiocarbamate is an antimutagen and repressed the activation of promutagens by plant systems. Earlier work implicated the involvement of tobacco cell (TX1) peroxidases in the plant cell activation of aromatic amines. We now present data that diethyldithiocarbamate represses the activation of 2-aminofluorene and m-phenylenediamine by inhibiting intracellular TX1 peroxidases under in vivo conditions. Concentrations of diethyldithiocarbamate that caused a 50% repression of TX1 cell activation of 2-aminofluorene and m-phenylenediamine also induced a 50% inhibition of TX1 cell peroxidase activity. Diethyldithiocarbamate in a concentration range between 25 and 500 microM directly inhibited peroxidase activity in TX1 cell homogenates in a concentration-dependent manner. Similar results were observed with purified horseradish peroxidase. The kinetics of peroxidase activity were studied in homogenates from control cells and cells treated with 750 microM and 25 mM diethyldithiocarbamate. There was no significant difference among the Km values among the three groups with a mean (+/- standard error) Km of 2.58 +/- 0.23 mM. However, the Vmax differed from 4.02 to 2.12 nmoles tetraguaiacol/min/micrograms protein, in the control and in the 25 mM diethyldithiocarbamate treatment group, respectively. These data indicate that diethyldithiocarbamate is a non-competitive inhibitor of TX1 cell peroxidase.

Biotransformation↗
PubMed1991

Racial differences in the incidence and progression of renal diseases.

There is an excess incidence of ESRD treatment among non-White North Americans that is not completely explained by the racial prevalences of the underlying diseases, including hypertension, which can potentially cause renal disease. The racial difference is particularly striking for presumed nephrosclerosis from hypertension and for nephropathy from Type II diabetes, but is not yet substantiated for ESRD attributed to polycystic kidney disease or Type I diabetes. The existing data are insufficient to support the notion that poorer blood pressure control alone is responsible for the racial differences in incident ESRD. Black race (and possibly Mexican or Native American heritage) may be a specific risk factor for ESRD, independent of hypertension and its treatment.

Black People↗
PubMed1991

Captopril renography in the diagnosis of renovascular disease.

Several investigators have reported methods for the use of renal scintigraphy in the diagnosis of renal artery stenosis. We report the experience of Duke University Medical Center, and offer some suggestions for standardizing and optimizing the use of this potential screening tool. We evaluated 140 clinically selected hypertensive adults with postcaptopril renal scintigraphy (renography), pre- and postcaptopril peripheral renin activity, and conventional renal arteriography. Postcaptopril renography (using 99mTc-diethylenetriaminepentaacetic acid (DTPA) to measure glomerular filtration and [131I]iodohippurate to measure renal plasma flow) was considered abnormal if one kidney contributed 47% or less of total activity. Postcaptopril renin was considered elevated if it was at least 4 ng/mL/h. Renovascular disease was defined as 50% or greater main renal artery stenosis. Of 140 subjects, 31 (22%) had significant renovascular disease. Captopril-stimulated DTPA renography suggested asymmetric function in 24 (74%) of these, but was also abnormal in 61 of 109 (56%) with normal renal arteries. Captopril-stimulated hippuran renography performed in a similar manner. Captopril-stimulated renin activity was elevated in only 58% of subjects with renal artery stenosis, and had a false positive rate of 24%. These data differ from reports from other centers, perhaps due to differences in renography methods, criteria for interpretation of renography, and/or patient selection criteria.

Adult↗
PubMed1991

A two-year experience with premedical postbaccalaureate students admitted to medical school.

To determine how well premedical postbaccalaureate students performed in and adjusted to medical school, the author examined the records for all 123 matriculants to the Brown University Program in Medicine in 1987-88 and 1988-89 and sent each student a questionnaire. More than one-third of the first-year students admitted to Brown were from premedical postbaccalaureate programs (that is, they had taken the traditional premedical course requirements after graduating from college). The postbaccalaureate students were older than the rest of their classmates, on average, and were more likely to have been non-science majors in college. Academic performances over the first two years were comparable in the two groups, and there was no significant difference between the groups in their self-reports of adequacy of preparation or involvement in extracurricular activities. The author concludes that, faced with a smaller applicant pool, medical schools may wish to consider premedical postbaccalaureate students as a valuable resource.

Adaptation, Psychological↗
PubMed1991

Medical school and residency performances of students admitted with and without an admission interview.

In 1982 the Brown University Program in Medicine eliminated the personal interview from its process of selecting applicants for admission to medical school. This study compares the 113 M.D.-program students admitted to the first three classes (entering between 1983 and 1985) without an interview with the 67 students in the previous three classes admitted with an interview. The students' characteristics were essentially the same with respect to the preadmission variables, the proportions of women and minority students, course performances, scores on Parts I and II of the National Board of Medical Examiners examinations, and evaluation scores from residency program directors. This study offers additional evidence that the selection interview, as practiced in most U.S. medical schools, does not contribute to the predictive validity of the admission process.

Educational Measurement↗
PubMed1991

Similar prevalence of renovascular hypertension in selected blacks and whites.

Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate, however, that in a clinically selected population, the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy, according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated, 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p = 0.27). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p = 0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking, but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension, but this and other potential screening tests require further evaluation.

Adolescent↗
PubMed1991

The quantitative study of lumbar vertebral bone marrow using T1 mapping and image analysis techniques: methodology and preliminary results.

A method of quantifying lumbar vertebral bone marrow using pixel by pixel T1 mapping of spin echo magnetic resonance images is described. The accuracy and precision of the relaxation time measurements is confirmed by studies with the EEC Concerted Research Project, test object no. 5. The T1 data from all the pixels sampled from lumbar vertebral marrow are displayed as a histogram. By "thresholding" relative to normal control data the spatial distribution of high or low T1 pixels can be demonstrated. The approach is superior to that of the conventional region of interest method for quantifying and analysing relaxation time data, and allows tissue heterogeneity to be studied. Studies in patients with aplastic anaemia and acute leukaemia have been performed.

Adult↗
PubMed1991

Tumour pH and response to chemotherapy: an in vivo 31P magnetic resonance spectroscopy study in non-Hodgkin's lymphoma.

Serial image-localized 31P magnetic resonance spectroscopy studies were performed in nine patients with newly diagnosed non-Hodgkin's lymphoma (NHL) during the early part of treatment with chemotherapy. The pre-treatment intracellular pH (pHi) of the tumours ranged from 6.97 to 7.61 for high-grade NHL (n = 3), and 7.16 to 7.39 for low-grade NHL (n = 5). A pH of 7.24 was recorded in a patient with intermediate-grade NHL. Slice-to-slice variation in tumour pHi in spectra obtained with a one-dimensional chemical shift imaging (1D-CSI) technique varied from zero to 0.5 pH units. The largest variation was seen in high-grade tumours. Slice-to-slice variation may reflect tumour heterogeneity. Alkaline shifts in tumour pHi of 0.14 to 0.45 pH units were seen in six patients following chemotherapy. Maximal change in tumour pH was related temporally to increases in the phosphodiester/beta-adenosine triphosphate ratio, and occurred before alterations in tumour size were documented. Cell death and necrosis may be associated with an alkaline shift in pHi due to cessation of H(+)-producing processes and release of basic components of proteins. An alkaline shift in tumour pHi may therefore be an early metabolic marker of response to chemotherapy.

Abdominal Neoplasms↗
PubMed1991

Cytokine inhibition by a novel steroid, mometasone furoate.

Mometasone furoate (9 alpha, 21 dichloro-11 beta, 17 alpha dihydroxy-16 alpha methyl-1,4 pregnadiene-3, 20 dione-17-[2'] furoate) was an unexpectedly potent inhibitor of the in vitro production of three inflammatory cytokines, IL-1(1), IL-6, and TNF-alpha. The potency of mometasone furoate in inhibiting cytokine production was compared to that of hydrocortisone, betamethasone, dexamethasone, and beclomethasone. IL-6 and TNF-alpha were both produced by WEHI-265.1 (murine myelomonocytic leukemia) cells following stimulation by lipopolysaccharide (LPS). Twenty-four hours after stimulation by LPS, the cell-free supernatant fluids were removed. Their cytokine content was analyzed using ELISAs specific for each cytokine. IL-1 synthesis was induced in the harvested peritoneal macrophages of BALB/c mice by incubation with LPS for twenty-four hours. The IL-1 content in the cell-free supernatant fluids was determined by the thymocyte-costimulator bioassay. Using these systems, mometasone furoate was found to be the most potent steroid tested for inhibiting the production of the three cytokines. The IC50's were 0.05 nM (IL-1), 0.15 nM (IL-6), and 0.25 nM (TNF-alpha). The inhibition of the production of proinflammatory mediators by extremely low concentrations of mometasone furoate suggests that this steroid should be highly effective in various disorders.

Administration, Topical↗
PubMed1991

Ankle arthrodesis in rheumatoid arthritis. 30 cases followed for 5 years.

We have reviewed the results of 30 ankle arthrodeses performed on 26 patients with rheumatoid arthritis. This procedure was associated with a high morbidity, with wound breakdown and infection occurring in 12 cases. Eighteen ankles had fused, six had pain-free fibrous union, and six required further surgery for nonunion. Clinical evaluation, at an average follow-up of 5 years, was based on a modified ankle-grading system with good or excellent results in 14, fair results in nine, and poor in two. Only 4 patients had some residual pain in the ankle, and so, despite the high complication rate, arthrodesis is an effective method of treating the painful, rheumatoid ankle.

Adult↗