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Biomedical subjects

R N Smith

Publications and source records attributed to R N Smith.

At least 19 recordsLinked to original sources
PubMed1992

Multiple pathways in the rejection of skin grafts.

We have analyzed the ability of CD4+ and CD8+ T cells to cause rejection of skin grafts in an Ir gene high responder strain. (DA.RT1u x DA.RT1c)F1 B rats (thymectomized, lethally irradiated, reconstituted with fetal liver cells) were grafted with ear skin of the recombinant strain, DA.RT1rl. The only allogeneic difference was a single class I MHC antigen. The B rats, which do not reject these grafts due to the absence of T cells, were reconstituted at various time intervals after skin grafting with either unsorted lymph node cells (LNCs), CD4+, CD8+ or CD4+ and CD8+ T cells. Unsorted LNCs given any time after graft placement always caused rejection (MST = 15d). CD4+ cells alone never caused rejection (MST greater than 60d, n = 8). CD8+ cells alone caused rejection if given within 3 weeks of graft placement. Thereafter, CD8+ cells alone lost their ability to cause rejection (MST greater than 60d, n = 6). B rats with grafts in place more than 3 weeks, when CD8+ cells alone were ineffective, rejected their skin grafts when given both CD8+ and CD4+ cells. These data suggest that there may be two T cell pathways in skin graft rejection. The first requires only CD8+ cells and causes rejection of a recently placed graft. The second pathway requires both CD4+ and CD8+ cells to reject long-standing grafts in which donor antigen-presenting cells have been putatively depleted and, therefore, may be dependent on host antigen-presenting cells.

Animals↗
PubMed1991

Separation of electronic and hydrophobic effects for the papain hydrolysis of substituted N-benzoylglycine esters.

The role of hydrophobic and electronic effects on the kinetic constants kcat and Km for the papain hydrolysis of a series of 22 substituted N-benzoylglycine pyridyl esters was investigated. The series studied comprises a wide variety of substituents on the N-benzoyl ring, with about a 300,000-fold range in their hydrophobicities, and 2.1-fold range in their electronic Hammet constants (sigma). It was found that the variation in the log kcat and log 1/Km constants could be explained by the following quantitative-structure activity relationships (QSAR): log 1/Km = 0.40 pi 4 + 4.40 and log 1/kcat = 0.45 sigma + 0.18. The substituent constant, pi 4, is the hydrophobic parameter for the 4-N-benzoyl substituents. QSAR analysis of two smaller sets of glycine phenyl and methyl esters produced similar results. A clear separation of the substituent effects indicates that in the case of these particular esters, acylation appears to be the rate limiting catalytic step.

Catalysis↗
PubMed1991

Inhibition of intergeneric coaggregation among oral bacteria by cetylpyridinium chloride, chlorhexidine digluconate and octenidine dihydrochloride.

The potential inhibitory effect of chlorhexidine digluconate on the intergeneric coaggregation of 11 pairs of Gram-positive organisms was compared to its ability to inhibit coaggregations of 14 pairs comprised of both a Gram-positive and a Gram-negative cell type. Dramatic differences in the inhibitory effectiveness of the antimicrobial compound on the two kinds of coaggregation pairs were found. Gram-positive pairs were not inhibited at a concentration of 0.25%, whereas the coaggregations involving a Gram-negative partner were usually completely blocked at concentrations as low as 0.01%. Similar effects to chlorhexidine digluconate were found with octenidine dihydrochloride and cetylpyridinium chloride, while sodium dodecylsulfate was inhibitory only at 10- to 50-fold higher concentrations. These results suggest that chlorhexidine digluconate, octenidine dihydrochloride, and cetylpyridinium chloride may be effective inhibitors of later microbial colonizers of dental plaque but may not disturb a normal healthy indigenous flora.

Actinomyces↗
PubMed1991

The safety and tolerability of sumatriptan: an overview.

Safety information was pooled from 4,859 patients, mainly treated in controlled clinical trials with a dispersible tablet of sumatriptan or by a subcutaneous injection, and from 1,164 patients who received placebo by these routes. Safety monitoring involved collection of all adverse events, regardless of their relationship to treatment, and included routine laboratory screening tests and some special investigations. Individuals experienced several groups of symptoms that might be considered to be features of migraine itself or of the post-migraine period or due to treatment. The commonest complaints were an unpleasant taste or pain on injection. After oral sumatriptan (100-300 mg), some events (nausea, malaise) were characteristic of migraine and others (fatigue, sedation, weakness) were characteristic of the recovery period. With subcutaneous sumatriptan (4-8 mg) similar events were observed, but certain distinctive symptoms variously described as heaviness, pressure sensation, tingling, feelings of heat or warmth, were more common and affected various parts of the body. Their early onset and transient nature suggests some pharmacological mechanism, as yet not identified. Despite the mixed picture of symptoms recorded after treatment, they were not serious, they were transient and they were accepted by patients. Close patient monitoring allowed detailed evaluation of any possible cardiovascular side-effects as seen with other anti-migraine agents, particularly ergotamine. The evidence is reassuring but, since experience in patients with symptomatic ischaemic heart disease is limited, it is recommended that they should initially be treated with sumatriptan under medical supervision for their first two or three attacks.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Evaluation of a commercial radioimmunoassay kit for the detection of lysergide (LSD) in serum, whole blood, urine and stomach contents.

The Diagnostic Products Corporation Coat-A-Count radioimmunoassay kit for LSD in urine has been evaluated for use in forensic toxicology with a variety of sample types. The cut-offs (defined as the mean response of blank samples plus three standard deviation) for LSD in serum, haemolysed whole blood, urine and stomach contents were 0.06, 0.050-0.055, 0.18 and 0.18 ng/ml, respectively. Preliminary extraction of LSD from the samples is not usually necessary. The precision of the analysis and the recoveries from spiked samples were satisfactory. The cross-reactivities of 2-oxo-LSD, lysergic acid methyl propylamide, lysergic acid monoethylamide and nor-LSD were estimated to be 11,6,2 and 1% respectively relative to LSD (100%).

Calibration↗
PubMed1990

Aberrant radioimmunoassay results for cannabinoids in urine.

False negative and false positive radioimmunoassay results for cannabinoids in urine are reported. Such results occur infrequently and appear to be due to non-specific binding of the radiolabel by interfering substances, possibly proteins, in the specimens. False negatives arise when these substances and the non-specifically bound radiolabel are precipitated by polyethylene glycol in the separation stage of the assay, increasing the radioactivity in the bound fraction and thus lowering the assay result. False positives occur when the interfering substances and non-specifically bound radiolabel remain in solution during the separation stage, increasing the radioactivity in the free fraction and giving an erroneously high result. False positives could also occur in assays involving solid-phase antibodies or second-antibody separations. Methanol treatment of the samples prior to analysis precipitates the interfering substances and eliminates the aberrant effect. The interfering substances have not been identified through common serum proteins and semen have been excluded. No common factor in the circumstances of the cases that can account for the results has been identified.

Adolescent↗
PubMed1990

Gas chromatographic-mass spectrometric confirmation of radioimmunoassay results for cannabinoids in blood and urine.

A simple gas chromatographic-mass spectrometric (GC-MS) method is described for the detection of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (delta 9-THC-COOH) in blood and urine samples found to be positive by two in-house cannabinoid radioimmunoassays (RIAs). The delta 9-THC-COOH in the samples, which is partly present as its glucuronide conjugate, is isolated by solvent extraction after hydrolysis of the glucuronide. It is converted to its trimethylsilyl derivative and analysed by capillary GC-MS in the electron impact mode with selected ion recording. All samples that were positive by both RIAs were also positive by GC-MS apart from four blood and two urine samples in which the GC-MS results were inconclusive owing to the presence of coextractives. No sample that was positive by both RIAs was found to be negative by GC-MS.

Cannabinoids↗
PubMed1990

Placental CSF-like activity.

We have examined amniotic fluid and cultured supernatants of a variety of placental cells for the presence of colony-stimulating factor (CSF) activity. The supernatants of cultured human choriocarcinoma cell lines, Jeg and Jar, contained CSF activity that induced the formation of granulocyte-macrophage colony-forming unit (CFU-GM) and multipotential colony-forming unit (CFU-GEMM) colonies. Cultured supernatants of nontransformed rat placental cells, chorionic villous cells, and amniotic fluid also induced CFU-GM colonies.

Amniotic Fluid↗
PubMed1989

Products of lipopolysaccharide-activated macrophages (tumor necrosis factor-alpha, transforming growth factor-beta) but not lipopolysaccharide modify DNA synthesis by rat trophoblast cells exhibiting the 80-kDa lipopolysaccharide-binding protein.

Pregnancy losses from gram negative bacterial infections could be caused by direct effects of LPS on placental cells, or indirectly via LPS activation of macrophages in the uteroplacental unit. To evaluate those alternatives, LPS, LPS-activated peritoneal cells, conditioned medium from LPS-activated peritoneal cells, and some purified and recombinant molecules known to be secreted by activated macrophages were tested for their abilities to modify DNA synthesis by rat trophoblast cells. Three trophoblast cell lines derived from midgestation placentas of outbred and inbred rats were used for the experiments. Although the 80-kDa LPS-binding protein was demonstrated on trophoblast cells, LPS alone had no effect on the ability of trophoblast cells to synthesize DNA. In cocultures, trophoblast cell DNA synthesis was slightly enhanced by low concentrations of both unstimulated and LPS-activated peritoneal cells. At higher concentrations, LPS-activated cells caused significant inhibition of DNA synthesis by trophoblast cells. Conditioned media from LPS-activated peritoneal cells were highly inhibitory to trophoblast cell DNA synthesis. When specific molecules likely to be components of those media were tested, IL-1 was found to have a modest but reproducible stimulatory effect and PGE2 did not change trophoblast cell incorporation of [3H]TdR. In contrast, trophoblast cell DNA synthesis was markedly inhibited in a dose-dependent manner by both TNF-alpha and TGF-beta 1. No differences in the sensitivity of trophoblast cells from outbred and inbred rats were observed. Given the limitations of the experimental model system, the results suggest that in cases of infection by gram-negative bacteria LPS may have an adverse effect on pregnancy by stimulating resident macrophages to generate and release molecules that are inhibitory to trophoblast cell DNA synthesis.

Animals↗
PubMed1989

Safety of ondansetron.

The safety of ondansetron has been reviewed based on experience in its use as an anti-emetic treatment in about 1,400 patients receiving cancer treatment and further experience in about 650 volunteers and patients with other medical conditions. Evidence from animal pharmacology and toxicology had indicated that ondansetron had a wide therapeutic index, no interaction with commonly co-prescribed drugs, and no dependence liability. No end-organ toxicity had been seen. Clinical experience showed that ondansetron is well tolerated; the principal side effects being constipation and headache, which in the context of cancer treatment were not troublesome. Increases in liver function tests were observed, undoubtedly due in many instances to the underlying cancer or metastases and to chemotherapy, and the incidence was similar on ondansetron and metoclopramide. No extrapyramidal side effects were reported.

Animals↗
PubMed1988

The alloantibody response in the allogeneically pregnant rat. VI. Detection in maternal serum of specific antigen-antibody complexes.

We have examined prepartum and postpartum sera from allogeneically pregnant rats for the presence of paternal antigen using a mAb sandwich assay. Paternal class I antigen, RT1Aa, was frequently detected in postpartum and prepartum rat sera. Postpartum sera from high responders also include anti-RT1Aa alloantibodies, some of which were complexed with the RT1Aa antigen. Although the concentration of antigen is low, the high uterine blood flow causes the amount of class I antigen entering the pregnant female to be in the low microgram per day range. Such an amount could have immunoregulatory significance.

Animals↗
PubMed1988

7-[125I]iodoclonazepam: purification by high-performance liquid chromatography for use in a very sensitive benzodiazepine radioimmunoassay of broad specificity.

The purification of 7-[125I]iodoclonazepam by high-performance liquid chromatography (HPLC) for use in a very sensitive benzodiazepine radioimmunoassay is described. A silica column is used with a non-aqueous eluent and sequential ultra-violet and gamma-ray detection. A commercially available antiserum is used at a dilution of 1:1000. Blood samples are diluted 10-fold with buffer before analysis and only 25 microliters of diluted sample are required per assay tube. Benzodiazepines, but not the radiolabel, appear to be bound by blood proteins in competition with the antiserum and so, if undiluted blood is assayed, erroneously low results are obtained. The minimal sample requirement and the high sensitivity of the assay described here largely avoid this problem while maintaining acceptable detection limits. For diazepam, the detection limit is 2.5 ng/ml in blood or urine (after correction for the initial 10-fold dilution) and therapeutic or sub-therapeutic levels of many other benzodiazepines can be detected. In practice, the assay is reliable, simple to perform and extremely economical.

Anti-Anxiety Agents↗
PubMed1987

The alloantibody response in the allogeneically pregnant rat. V. Absence of cell-mediated immunity in high responders.

Allogeneically pregnant rats have been examined postpartum to determine whether they are sensitized against paternal class I antigens for cell-mediated immunity. This study was undertaken as this point is ambiguous. Since the response of the female to paternal MHC antigens is genetically controlled it is possible that the inability of some investigations to detect cell-mediated immunity against the paternal strain was due to the use of non-responder strain combinations. Cell-mediated immunity was assayed in a strain combination that is an unambiguous high responder, in which 100% of the females respond to the paternal strain by making alloantibodies. Maternal cell-mediated responses to paternal antigens were measured by the assays of DTH and IL-2 secretion under limiting conditions. We were unable to detect any cell-mediated immunity to paternal class I antigens even though the female produced copious quantities of alloantibody.

Animals↗
PubMed1986

The alloantibody response in the allogeneically pregnant rat. IV. Analysis of the alloantibody specificities with monoclonal antibodies.

We have compared the serum alloantibody population from female rats immunized either by allogeneic pregnancies or by conventional immunizations. The only allogeneic difference in both types of immunization was class I of the MHC. Pregnancy-induced alloantibodies as compared with conventionally raised alloantibodies were more homogeneous with respect to isoelectric point, and were more homogeneous as defined by competition experiments with anti-class I monoclonal antibodies. The genetic control of the pregnancy-induced alloantibody response was also verified.

Animals↗