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Biomedical subjects

S A Smith

Publications and source records attributed to S A Smith.

At least 91 records · Page 5Linked to original sources
PubMed2000

Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic findings.

Propofol, a central-acting sedative agent, has been implicated in the development of rhabdomyolysis in children. We describe two adults who developed rhabdomyolysis after receiving high rates of propofol infusion. Rhabdomyolysis of both skeletal and cardiac muscle was suggested in both patients by marked increases of creatine kinase (>170 000 U/L) and cardiac troponin I (11 and 46 microg/L in patients one and two, respectively). Creatine kinase and cardiac troponin I values were highly correlated in each patent (r = 0.786 and 0.988 in patients one and two, respectively). Autopsy of one patient confirmed the diagnosis of skeletal and cardiac rhabdomyolysis.

Adult↗
PubMed2000

Anti-beta2-glycoprotein I autoantibodies, in vitro thrombin generation, and the antiphospholipid syndrome.

OBJECTIVE: Thrombin plays a pivotal role in the regulation of hemostasis. We examined the effect of antiphospholipid (aPL) antibodies, in particular those with specificity for beta2-glycoprotein I (beta2-GPI), on in vitro thrombin generation, and examined the association with clinical manifestations of the antiphospholipid syndrome (APS). METHODS: We studied plasma samples from 59 patients with aPL antibodies determined by the presence of either elevated anticardiolipin (aCL) antibodies or lupus anticoagulant (LAC). Direct antibody binding of IgG, IgM, and IgA to beta2-GPI and prothrombin (PT) was determined by ELISA. Affinity purification of total IgG and IgG anti-B2-GPI antibodies was performed using staphylococcal protein A and phospholipid liposomes. A chromogenic assay was used to determine the effect of plasma samples and purified autoantibodies on in vitro thrombin generation. RESULTS: Thirty-three of 59 (56%) plasma samples inhibited in vitro generation of thrombin and 7/59 (12%) accelerated thrombin formation. There was a strong negative correlation between thrombin generation and IgG aCL (r = -0.72, p < 0.001) and IgG anti-beta2-GPI (r = -0.71, p < 0.001) antibody levels, and a weaker correlation with LAC (r = -0.46, p = 0.001). This association was not found with anti-PT antibodies and could not be attributed to concurrent therapy with warfarin. Additional experiments with affinity purified IgG antibodies indicated a dose dependent inhibition of thrombin generation, which was restricted to anti-beta2-GPI antibodies. Patients with a history of core clinical manifestations of the APS [venous and arterial thrombosis, recurrent (> or = 2) fetal loss] had significantly greater inhibition of in vitro thrombin generation (mean +/- SEM Z score: -3.38 +/- 0.51 vs -1.42 +/- 0.56; p = 0.01) and higher levels of IgG aCL (mean +/- SEM Z score: 8.39 +/- 1.12 vs 5.39 +/- 0.88; p = 0.04) and IgG anti-beta2-GPI antibodies (mean +/- SEM Z score: 4.49 +/- 0.69 vs 2.26 +/- 0.54; p = 0.01). Odds ratios for these variables and clinical manifestations of the APS were 5.43, 4.17, and 3.28, respectively. CONCLUSION: aPL antibodies may accelerate or inhibit the rate of in vitro thrombin formation. The predominant effect is inhibition that is restricted to IgG anti-beta2-GPI antibodies and it is strongly associated with clinical manifestations of the APS.

Antiphospholipid Syndrome↗
PubMed2000

Artificial nutrition and hydration at the end of life.

Patients who are terminally ill do not respond to administration of artificial nutrition and hydration in the same way as patients who have potential for recovery. Knowledge of end-stage disease and ethical and legal parameters are necessary for health care team members to make clinically and morally sound therapeutic decisions in conjunction with the patient and family.

Decision Making↗
PubMed1999

Comparative severity of experimentally induced mycobacteriosis in striped bass Morone saxatilis and hybrid tilapia Oreochromis spp.

Twenty striped bass Morone saxatilis and 20 hybrid tilapia Oreochromis niloticus x O. mossambicus x O. aureus each received a single intramuscular injection of 1.6 x 10(6) colony forming units per gram body weight of Mycobacterium marinum. Striped bass manifested significantly greater clinical and microscopic disease compared to tilapia. Whereas all the striped bass had died or were clinically ill by Day 8 post-infection, there was no apparent disruption of normal behaviour, physical appearance, or growth in any of the sacrificed or surviving tilapia. Histologically, granulomas in striped bass were generally larger and less discrete, with a higher proportion of heavily vacuolated macrophages, and large cores of necrotic cells. Visceral granulomas in tilapia were smaller, with a higher proportion of epithelioid macrophages, more pigment-containing cells, more peripheral lymphocytes, and virtually no central necrosis. Visceral granulomas were 18-fold more numerous in striped bass than in tilapia. Based upon histomorphometric data, mean proportions of acid-fast bacteria within pronephros granulomas were 4-fold greater in striped bass than tilapia, and striped bass granulomas averaged more than twice as large as tilapia granulomas. In the anterior kidney of striped bass, a positive correlation existed between mean mycobacterial proportions and mean necrosis scores. In tilapia, mean mycobacterial proportions correlated negatively with mean granuloma numbers, whereas there was no correlation between these parameters in striped bass. Results suggest that intrinsic functional differences in the immunologic systems of striped bass and hybrid tilapia may contribute to inter-species variation in mycobacteriosis susceptibility.

Animals↗
PubMed1999

PPARalpha activation by Wy 14643 induces transactivation of the rat UCP-1 promoter without increasing UCP-1 mRNA levels and attenuates PPARgamma-mediated increases in UCP-1 mRNA levels induced by rosiglitazone in fetal rat brown adipocytes.

Rodent brown adipocytes express peroxisome proliferator activated receptor-alpha (PPARalpha) and PPARgamma and while the rodent uncoupling protein-1 (UCP-1) gene contains a putative peroxisome proliferator response element (PPRE), only PPARgamma activation by thiazolidinediones increase UCP-1 mRNA levels. We have investigated this phenomenon in foetal rat brown adipocytes (FBA) and show that although transactivation occurs in FBA containing a plasmid encoding 4.5kb of the 5'-flanking region of the rat UCP-1 promoter ((-4551)-UCP-1-CAT) treated with either the selective PPARgamma agonist rosiglitazone (1.0 microM) or the selective PPARalpha agonist Wy 14643 (10.0 microM), only rosiglitazone induced transcription of UCP-1 mRNA. Furthermore, Wy 14643 (10 and 100.0 microM) abolished rosiglitazone-induced UCP-1 mRNA induction in spite of a transactivation event occurring with the combination treatment. Thus in FBA PPARalpha-activation with Wy 14643 elicits a "blind" transactivation of the UCP-1 promoter which can prevent PPARgamma-mediated UCP-1 mRNA transcription either by competition for the PPRE or by an unidentified post-transcriptional event.

Adipose Tissue, Brown↗
PubMed1999

Efficacy of various chemotherapeutic agents on the growth of Spironucleus vortens, an intestinal parasite of the freshwater angelfish.

Seven chemotherapeutic agents (dimetridazole, metronidazole, pyrimethamine, albendazole, fenbendazole, mebendazole and magnesium sulfate) were examined for growth inhibition on the cultivation of Spironucleus vortens. Dimetridazole and metronidazole were effective in inhibiting the parasite's growth. At concentrations of 1 microgram ml-1 or higher, both dramatically decreased numbers of parasites. At 24 h exposure, 33% of parasites were inhibited when exposed to dimetridazole or metronidazole at concentrations of 2 and 4 micrograms ml-1, respectively. Dimetridazole at 4 micrograms ml-1 or higher concentrations decreased the number of organisms to 50% or less after 48 h exposure. During the same period of time, the numbers of parasites decreased to 50% or less when exposed to metronidazole at 6 micrograms ml-1 or higher. Pyrimethamine at concentrations of 1 to 10 micrograms ml-1 was not effective in inhibiting the parasite's growth. Albendazole and fenbendazole at concentrations of 0.1 and 0.5 microgram ml-1 were similar in inhibiting the growth of the organism. Both compounds suppressed parasite growth at concentrations of 1.0 microgram ml-1 or higher after 24 h exposure. Mebendazole inhibited the parasite's growth at concentrations of 0.5 microgram ml-1 or higher. At 72 h exposure, 45 to 50% of the parasites were inhibited when exposed to mebendazole at concentrations higher than 0.5 microgram ml-1. Magnesium sulfate at concentrations of 70 mg ml-1 or higher also suppressed the growth of parasites after 24 h exposure. These results indicate that dimetridazole, metronidazole and mebendazole are the most effective chemotherapeutic agents in vitro at inhibiting the growth of S. vortens.

Albendazole↗
PubMed1999

Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor.

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.

Animals↗
PubMed1999

BRCA1-related and sporadic ovarian cancer in the same family: implications for genetic testing.

OBJECTIVE: The aim of this study was to present a family with both BRCA1-related and sporadic ovarian cancer and address current difficulties in genetic testing. METHODS: BRCA1 mutation detection was performed on a family having four confirmed cases of ovarian cancer, two cases of breast cancer, and one case each of colon, stomach, and prostate cancer. The incidence and types of cancer were consistent with a BRCA1 mutation although previous linkage analysis had excluded this family as being due to BRCA1. RESULTS: A protein-truncating mutation in BRCA1, denoted 2799delAA, was identified in the germline DNA of each of the women affected with breast and ovarian cancer in this family except the proband, who was diagnosed with ovarian cancer at age 65. CONCLUSIONS: In an earlier study, which sought to determine the proportion of site-specific ovarian cancer due to BRCA1, the family described in this report was wrongly identified as not being due to BRCA1 when, in fact, all but one of the breast and ovarian cancer cases carry a deleterious BRCA1 mutation. Our analysis suggests that the proband, who was the first of the women in this family to seek genetic counseling, developed ovarian cancer by chance and not as the result of an inherited mutation. We describe the results of our analysis in light of current issues that face clinicians who may be involved in genetic testing for breast and ovarian cancer predisposition.

BRCA2 Protein↗
PubMed1999

Relaxation effects in a system of a spin-1/2 nucleus coupled to a quadrupolar spin subjected to RF irradiation: evaluation of broadband decoupling schemes.

We have investigated the suitability and performance of various decoupling methods on systems in which an observed spin-1/2 nucleus I (13C or 15N) is scalar-coupled to a quadrupolar spin S (2H). Simulations and experiments have been conducted by varying the strength of the irradiating radiofrequency (RF) field, RF offset, relaxation times, and decoupling schemes applied in the vicinity of the S-spin resonance. The T1 relaxation of the quadrupolar spin has previously been shown to influence the efficiency of continuous wave (CW) decoupling applied on resonance in such spin systems. Similarly, the performance of broadband decoupling sequences should also be affected by relaxation. However, virtually all of the more commonly used broadband decoupling schemes have been developed without consideration of relaxation effects. As a consequence, it is not obvious how one selects a suitable sequence for decoupling quadrupolar nuclei with exotic relaxation behavior. Herein we demonstrate that, despite its simplicity, WALTZ-16 decoupling is relatively robust under a wide range of conditions. In these systems it performs as well as the more recently developed decoupling schemes for wide bandwidth applications such as GARP-1 and CHIRP-95. It is suggested that in macromolecular motional regimes, broadband deuterium decoupling can be achieved with relatively low RF amplitudes (500-700 Hz) using WALTZ-16 multiple pulse decoupling.

Computer Simulation↗
PubMed1999

Morphine regulation of a novel uridine diphosphate glucuronosyl-transferase in guinea pig pups following in utero exposure.

The uridine diphosphate glucuronosyltransferases (UGTs) catalyze conjugation reactions between various substrates and glucuronic acid, UDPGA (uridine diphosphate glucuronic acid), within the endoplasmic reticulum. Conjugation with UDPGA (glucuronidation) is an important pathway in the elimination, detoxification, and activation of compounds including steroid hormones, xenobiotics, and quaternary ammonium substrates. The guinea pig, which has a placental structure and a glucuronidation profile for morphine that are similar to the human, serves as a good small animal model to study the ontogeny of UGTs and the effect of in utero exposure to morphine on UGTs. We examined type 2 UGTs expressed in the guinea pig using amplification and cloning of partial cDNAs from liver RNA. Sequence analysis revealed a novel UGT2 (subsequently named UGT2A3),(2) that has a 64% amino acid sequence similarity to a known UGT2.(3) Full-length cDNAs were isolated from a guinea pig liver cDNA library. Tissue distribution of UGT2A3 using Northern blot analysis showed expression of three distinct size UGT2A3 mRNAs with unique expression in liver and small intestine. UGT2A3 mRNA is expressed at high levels in liver and lower levels in kidney and small intestine. In utero exposure to chronic intermittent morphine resulted in the up regulation of mRNA in 7-day-old female pups' liver and kidney as determined by quantitative RT-PCR analysis. The conjugation profile for UGT2A3 using stable expression in CHO cells and thin-layer chromatography demonstrated active conjugation of phenolic substrates. Regulation of UGTs by in utero morphine exposure may play an important role in fetal development.

Amino Acid Sequence↗
PubMed1999

Tilapia (Oreochromis niloticus) dosed with azathioprine display immune effects similar to those seen in mammals, including apoptosis.

Azathioprine, an anti-neoplastic drug and therapeutic immunosuppressant, was administered intraperitoneally at 10.0 and 50.0 mg/kg to 3-6-month-old tilapia (Oreochromis niloticus). Consistent alterations in immune cellular parameters of the blood, pronephros (hematopoietic kidney) and spleen were observed. Peripheral blood total cellularity decreased as the azathioprine dose increased, to approximately half that of the control. Differential analysis of white blood cells indicated a decline in lymphocyte number, in particular, with increased dosage of azathioprine. Pronephric total cellularity was depressed in fish receiving the 10.0 or 50.0 mg/kg dose. In contrast, both splenic weight and splenic total cellularity increased proportionately with the increase in the drug dosage. Histopathologic examination of the spleens showed normal patterns for both control and 10.0 mg/kg dose groups. At 50.0 mg/kg, spleens were characterized by marked expansion of the white pulp, although lymphocytes were rare. Melanomacrophage centers at the higher dose were also larger and more numerous than in the control group. Evaluation of splenic and pronephric leukocytes with apoptotic markers showed an increase in apoptotic cells in the pronephros with increasing drug dose. These changes in fish are consistent with those seen in humans and laboratory rodents dosed with azathioprine, suggesting that fish may be potentially useful as preliminary models for detecting immunosuppressive compounds.

Animals↗
PubMed1999

Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids.

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

Animals↗
PubMed1999

Production and specificity of polyclonal antibodies to hexanal-lysine adducts.

Hexanal content is a widely used index of lipid oxidation in foods. The objectives of this study were to develop antibodies to hexanal-lysine adducts, devise an ELISA, and characterize antibody specificity. Hexanal was made immunogenic by covalent attachment to lysine side chains of bovine serum albumin via reductive alkylation. Polyclonal antibodies had antiserum titers as high as 6.15 x 10(5). A competitive indirect ELISA was developed with a detection limit of 0.7 ng of hexanal/mL. Antibodies were carrier-independent, reacting with hexanal conjugates of several proteins but not with the corresponding native proteins. Cross-reactivities with chicken serum albumin conjugates of n-heptanal, n-pentanal, and n-octanal were 86. 3, 11.8, and 2.2%, respectively. Antibodies reacted strongly with hexanal-modified lysine and hexanal-modified epsilon-aminocaproic acid but did not recognize free amino acids or free hexanal. It may be feasible to use this ELISA to monitor lipid oxidation in food provided hexanal is alkylated to a carrier protein prior to analysis.

Aldehydes↗
PubMed1999

Multiple effector pathways regulate the insulin secretory response to the imidazoline RX871024 in isolated rat pancreatic islets.

When isolated rat islets were cultured for 18 h prior to use, the putative imidazoline binding site ligand, RX871024 caused a dose-dependent increase in insulin secretion at both 6 mM and 20 mM glucose. By contrast, a second ligand, efaroxan, was ineffective at 20 mM glucose whereas it did stimulate insulin secretion in response to 6 mM glucose. Exposure of islets to RX871024 (50 microM) for 18 h, resulted in loss of responsiveness to this reagent upon subsequent re-exposure. However, islets that were unresponsive to RX871024 still responded normally to efaroxan. The imidazoline antagonist, KU14R, blocked the insulin secretory response to efaroxan, but failed to prevent the stimulatory response to RX871024. By contrast with its effects in cultured islets, RX871024 inhibited glucose-induced insulin release from freshly isolated islets. Efaroxan did not inhibit insulin secretion under any conditions studied. In freshly isolated islets, the effects of RX871024 on insulin secretion could be converted from inhibitory to stimulatory, by starvation of the animals. Inhibition of insulin secretion by RX871024 in freshly isolated islets was prevented by the cyclo-oxygenase inhibitors indomethacin or flurbiprofen. Consistent with this, RX871024 caused a marked increase in islet PGE2 formation. Efaroxan did not alter islet PGE2 levels. The results suggest that RX871024 exerts multiple effects in the pancreatic beta-cell and that its effects on insulin secretion cannot be ascribed only to interaction with a putative imidazoline binding site.

Animals↗
PubMed1999

Ultrastructural morphology of the gill of the hybrid striped bass (Morone saxatilis x M. chrysops).

The fine structure of the principal cell types found in the gill filaments and secondary, respiratory lamellae of the hybrid striped bass (Morone saxatilis x M. chrysops) was studied by transmission electron microscopy. Most of the cell types generally resembled those observed at this level of resolution in other euryhyaline, teleostean species, and the mucus cells, epithelial cells, and cartilage cells were non-distinctive. Pillar cells were atypically flattened within the lamellae. The extensive cytoplasmic tubular system of the chloride cells was more densely distributed and was less branched than reported for many other teleosts. The vascular endothelial cells of the marginal, lamellar blood vessels were particularly striking because of their prominent, electron-dense cytoplasmic granules. Although the physiological function and chemical composition of these granules remain obscure, their presence suggests an important role of secretion into the vascular lumen. These gill data from normal specimens of this sport and commercial, hybrid species constitute a useful basis for interpreting gill changes in diseased striped bass.

Animals↗
PubMed1999

Systemic zygomycosis in farmed tilapia fish.

Decreased feed intake and persistent low-level mortality in a production tank of hybrid tilapia (Oreochromis niloticus x Oreochromis mossambicus x Oreochromis aureus) prompted the submission of three affected fish for diagnosis. Consistent macrosopical findings included multifocal dermal haemorrhage, excess abdominal fluid and an enlarged friable liver. On microscopical examination, broad non-septate fungal hyphae and chlamydospores were identified within numerous internal organs, often within and adjacent to blood vessels. The fungal hyphae were readily seen by silver staining (GMS) and the chlamydospores were stained deep magenta by the periodic acid-Schiff reaction. In addition to several species of Gram-negative bacteria, moderate growths of woolly white fungal colonies were obtained from the posterior part of the kidney in two of the three tilapia. These colonies were identified as a Rhizomucor sp. on the basis of the morphological characteristics of the sporulating fungi in culture. This represents the first reported episode of zygomycosis in fish.

Animals↗