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Biomedical subjects

G N Smith

Publications and source records attributed to G N Smith.

At least 19 recordsLinked to original sources
PubMed1992

Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline.

OBJECTIVE: In vitro studies have indicated that levels of neutral metalloproteinases in osteoarthritic (OA) cartilage are elevated and that doxycycline (doxy) inhibits collagenolytic and gelatinolytic activity in extracts of OA cartilage. The purpose of the present study was to test the effect of oral doxy administration on the severity of cartilage degeneration in OA. METHODS: OA was induced in 12 adult mongrel dogs by transection of the anterior cruciate ligament (ACL) 2 weeks after dorsal root ganglionectomy. Six dogs received doxy orally from the day after ACL transection until they were killed 8 weeks later; the other 6 served as untreated OA controls. RESULTS: The unstable knee of each untreated dog exhibited extensive full-thickness cartilage ulceration of the medial femoral condyle. In sharp contrast, cartilage on the distal aspect of the femoral condyle of the unstable knee was grossly normal in 2 doxy-treated dogs, and exhibited only thinning and/or surface irregularity in the others. Degenerative cartilage lesions on the medial trochlear ridge, superficial fibrillation of the medial tibial plateau, and osteophytosis were, however, unaffected by doxy treatment. Collagenolytic activity and gelatinolytic activity in cartilage extracts from OA knees of untreated dogs were 5-fold and 4-fold greater, respectively, than in extracts from dogs given doxy. CONCLUSION: Prophylactic administration of doxy markedly reduced the severity of OA in weight-bearing regions of the medial femoral condyle. It remains to be determined whether administration of doxy after OA changes have developed is also effective.

Administration, Oral↗
PubMed1992

Effect of ethanol on the release of prostaglandins from ovine fetal brain stem during gestation.

Prostaglandins (PGs) have been implicated as mediators of the ethanol-induced suppression of ovine fetal breathing movements (FBM). The objectives of the present study were to determine the ontogeny of the in vitro efflux of PGE2 and 6-keto PGF1 alpha in ovine fetal brain stem during the second half of gestation and to determine the effect of in vitro ethanol exposure on the efflux of these PGs. Ovine fetal brain stem tissue was obtained at mean gestational ages of 80 days (n = 6), 105 days (n = 10), and 135 days (n = 16) by rapid excision following maternal euthanization. Tissue slices (400 microM thickness) were prepared from the lower pons-medulla region of the brain stem. After a 1-hr equilibration period in artificial cerebrospinal fluid, efflux of PGE2 and 6-keto PGF1 alpha in the brain stem was determined using the brain slice-superfusion method, and the PGE2 and 6-keto PGF1 alpha concentrations in the superfusate were determined by specific radioimmunoassay. The mean spontaneous efflux of PGE2 and 6-keto PGF1 alpha expressed as pmol PG/gram wet weight of tissue/5-min collection period was, respectively, 31.9 +/- 4.2 and 26.6 +/- 2.4 at 80 days, 38.3 +/- 5.2 and 29.6 +/- 2.2 at 105 days, and 57.4 +/- 3.1 and 27.1 +/- 1.1 at 135 days of gestation. In vitro exposure to 20, 40, and 80 mM ethanol did not affect PG efflux in the brain stem at 80 and 105 days of gestation. In vitro ethanol exposure decreased PGE2 and 6-keto PGF1 alpha efflux at 135 days of gestation to 36.8 +/- 5.3% and 41.6 +/- 4.3% of spontaneous efflux within 15 min, respectively; this effect of ethanol was not dose-dependent. The data do not support the hypothesis that ethanol increases PG efflux in the ovine fetal brain stem. In view of these findings and the data implicating PGs in the mechanism of ethanol-induced suppression of FBM, it is possible that ethanol acts at either central sites rostral to the brain stem (i.e., upstream CSF) or peripheral sites to increase the synthesis of PGs and their efflux into the systemic circulation, with subsequent transfer to the respiratory control region(s) of the brain stem.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Characterization of type V collagenase (gelatinase) in synovial fluid of patients with inflammatory arthritis.

Gelatin degrading matrix metalloproteinases in synovial fluid from 21 patients with inflammatory arthritis were shown to consist of two distinct gene products, 92 and 70 kDa gelatinases. The gelatinolytic activity of 92 kDa enzyme, which is released from stimulated neutrophils, was positively correlated to neutrophil count in the fluid. By contrast, 70 kDa molecule did not correlate with neutrophil cell count. Purification of these enzymes revealed they could degrade type XI collagen, a cartilage component resistant to interstitial collagenase. The elevated levels of 92 kDa gelatinase in rheumatoid arthritis samples compared to osteoarthritis suggest a role of this enzyme in cartilage destruction.

Adult↗
PubMed1992

Diagnostic confusion in treatment-refractory psychotic patients.

BACKGROUND: Two surveys of diagnostic practices in the United States suggest that many clinicians base their diagnoses on presenting symptoms and pay little attention to course and exclusionary criteria. Failure to correctly diagnose patients may result in inappropriate therapy and poor treatment response. The purpose of the present study was to investigate diagnostic practices. METHODS: We made detailed assessments of 50 consecutively admitted treatment-refractory psychotic patients and carefully applied DSM-III-R criteria. RESULTS: Referral diagnoses were changed in 23 of the 50 patients. Diagnoses of schizophrenia and schizoaffective disorder were made far less frequently and mood disorders (bipolar disorder and major depression) were diagnosed far more frequently by our group than by referring psychiatrists. Patients whose diagnosis was changed were more likely to be given mood-stabilizing medication and tended to show more improvement than patients whose diagnosis was not changed. CONCLUSIONS: These findings raise the possibility that patients may not respond to treatment because incorrect diagnoses result in inappropriate treatment.

Adolescent↗
PubMed1992

Hypothesis: can type IX collagen "glue" together intersecting type II fibers in articular cartilage matrix? A proposed mechanism.

Type IX collagen is crosslinked to the surface of type II collagen molecules, and has been proposed as the glue that binds the collagen network of cartilage matrix. However, there is as yet no evidence that the crosslinks that have been described to date provide interfibrillar connections, and the only mechanism proposed for such connections between intersecting fibers is unlikely on stereochemical grounds. We propose that both type IX collagen and an intermediary molecule are necessary for network stabilization and that proteoglycans are likely candidates for the role of intermediary.

Animals↗
PubMed1991

On the identification of a conjugated diene component of duodenal bile as 9Z,11E-octadecadienoic acid.

The lipid free radical marker, termed diene conjugation, in secretin-stimulated human bile obtained from the duodenum, was shown by high performance liquid chromatography and capillary gas chromatography-mass spectrometry, to be due mainly to 9Z,11E-octadecadienoic acid. The lack of evidence for possible conjugated diene isomers argues for an enzymatic origin of this product rather than being due to a random free radical mechanism, as is usually assumed.

Bile Acids and Salts↗
PubMed1991

Cleavage of type XI collagen fibers by gelatinase and by extracts of osteoarthritic canine cartilage.

Gelatinase (matrix metalloproteinase 2) purified from culture medium of MDCK cells by affinity chromatography on gelatin-sepharose was tested against type XI collagen. The purified enzyme-digested native type XI collagen in solution, and as reconstituted fibers, at 30, 34, and 37 degrees C. Both substrates yielded the same digestion products, as characterized by SDS-polyacrylamide gel electrophoresis, but the soluble collagen was cleaved at a higher rate. The first major product seen was an 87-kDa peptide, which was usually associated with one or two peptides migrating between it and alpha 3(XI). With time, a second group of 3 peptides appeared at 78, 75, and 73 kDa. After continued digestion, a third group of peptides was detected with prominent 69- and 67-kDa peptides and minor peptides at 71, 65, and 62 kDa. In overnight (20 hour) digestions, the 60-kDa digestion product accumulated and most of the larger digestion products could no longer be detected. Minor products at 71, 55, and 50 kDa were also noted in these limited digestions. Under the same conditions, denatured type XI was digested to fragments smaller than 13.5 kDa. The enzyme was inhibited by 1,10-phenanthroline or EDTA. Two purified components of cartilage matrix, type II collagen and proteoglycan subunit, as well as crude cartilage homogenates, were not effective inhibitors of the purified enzyme. Similar activity was extracted from canine articular cartilage, and the activity was much stronger in cartilage from osteoarthritic joints than from control joints.

Animals↗
PubMed1991

Effects of ethanol exposure on the embryo-fetus: experimental considerations, mechanisms, and the role of prostaglandins.

The purpose of this review is to critically examine the effects of ethanol on the embryo-fetus. There has been a tremendous amount of human epidemiological and experimental animal research on the characterization of the anomalies produced by chronic prenatal ethanol exposure and the identification of critical periods of vulnerability and critical amounts of ethanol necessary to produce fetal effects and (or) abnormal development. Few studies have examined the underlying mechanism(s) of the action of ethanol, and even fewer studies have examined the effects of single-dose ethanol exposure on the embryo-fetus. In this review, the current state of knowledge of the effects of chronic use of ethanol on the embryo-fetus is summarized. The primary focus of the review is on the embryonic-fetal effects of acute ethanol exposure, with particular emphasis on the ethanol-induced suppression of fetal breathing movements, as this effect appears to be a very sensitive index of acute exposure of the near-term fetus to ethanol. Factors to be considered in the selection of experimental animals to investigate the mechanism of action of ethanol and to study the acute effects of ethanol are discussed. Postulated mechanisms of action of ethanol on the embryo-fetus are evaluated with a focus on the role of prostaglandins. Finally, future directions in this field of research are proposed.

Animals↗
PubMed1991

Doxycycline inhibits type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelatinase.

Doxycycline was shown to inhibit digestion of exogenous type XI collagen by homogenates of human osteoarthritic cartilage in vitro. On SDS-PAGE, the cleavage products generated by cartilage extracts were larger and less abundant, indicating less complete cleavage, when doxycycline (10 or 30 microM) was added to the samples. The inhibitory effect was concentration dependent. Purified gelatinase from canine kidney epithelial cells, which also digests type XI collagen, was inhibited in a similar manner by doxycycline. If tetracyclines inhibit this metalloproteinase activity in articular cartilage in vivo, they could modify cartilage breakdown in osteoarthritis.

Animals↗
PubMed1991

The effects of indomethacin and prostaglandin E2 on the ethanol-induced suppression of ovine fetal breathing movements.

A study was performed to examine the role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of FBM, in which the objective was to test the hypothesis that fetal administration of PGE2 can suppress the incidence of FBM following reversal of ethanol-induced suppression of FBM by indomethacin, a fatty acid cyclooxygenase inhibitor. Instrumented near-term pregnant ewes received 1-h maternal infusion of ethanol (1 g/kg maternal body weight) followed 0.5 h later by a 3-h fetal infusion of indomethacin (1 mg/kg fetal body weight/h), and then a 2-h fetal infusion of PGE2 (400 ng/kg fetal body weight/min). Prior to drug administration, FBM occurred approximately 36.1 +/- 2.6% of the time. FBM were suppressed during the period of ethanol infusion (9.6 +/- 1.7%); the ethanol-induced suppression of FBM was reversed by fetal indomethacin treatment (77.5 +/- 14.1%); shortly after the onset of fetal PGE2 infusion, the incidence of FBM decreased to a 2-h mean incidence of 14.1 +/- 4.2%, which was similar in magnitude to that observed after maternal ethanol infusion. After the completion of PGE2 infusion, the incidence of FBM rapidly increased to a peak incidence of 83.4 +/- 19.2%, which was indicative of a prolonged effect of indomethacin on FBM. The data indicate that PGs mediate the ethanol-induced suppression of ovine FBM and that the action of indomethacin to antagonize ethanol-induced suppression of FBM is primarily due to its inhibition of PG synthesis.

Animals↗
PubMed1991

Effects of alcohol (ethanol) on the fetus.

Alcohol (ethanol) use during pregnancy can produce a wide spectrum of effects in the developing embryo/fetus that are dependent on the maternal drinking pattern. The effects of chronic ethanol exposure on the developing conceptus are reviewed with primary focus on ethanol teratogenesis, manifesting in the human as the fetal alcohol syndrome or fetal alcohol effects. The effects of acute ethanol exposure on the near-term fetus are described, including suppressed fetal breathing movements, electrocorticographic (ECoG) activity and electrooculographic (EOG) activity. The ethanol-induced suppression of fetal breathing movements is a very sensitive index of acute exposure of the near-term fetus to ethanol, and appears to involve a direct mechanism of action rather than an indirect mechanism involving suppression of electrocortical activity. The disposition of ethanol and its pharmacologically active proximate metabolite, acetaldehyde, and the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the near-term maternal-fetal unit are described, and a pharmacokinetic model is proposed. The effects of short-term ethanol exposure on the near-term fetus include the development of tolerance to the ethanol-induced suppression of fetal breathing movements, low-voltage ECoG activity and EOG activity. The development of tolerance occurs more rapidly to the latter two fetal biophysical activities. The mechanism of tolerance development appears to be pharmacodynamic (functional) in nature, as there is no increase in the rate of ethanol elimination from the maternal-fetal unit. The role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of fetal breathing movements is described. In the near-term fetus, there is a direct relationship between fetal blood ethanol concentration and fetal plasma PGE2 concentration, and an inverse relationship between the incidence of fetal breathing movements and each of fetal plasma and fetal cerebrospinal fluid (CSF) PGE2 concentrations. Indomethacin, a PG synthetase inhibitor, selectively blocks and reverses the ethanol-induced suppression of fetal breathing movements. These data support the postulates that the ethanol-induced suppression of fetal breathing movements is mediated by increased PGE2 concentration in the near-term fetus and that the ability of indomethacin to antagonize the ethanol-induced suppression of fetal breathing movements is due to its biochemical action to decrease fetal PGE2 concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Drinking↗
PubMed1991

Effect of ethanol on 15-hydroxyprostaglandin dehydrogenase activity in the brain stem of the near-term fetal sheep.

The effect of in vitro incubation with ethanol (10-80 mM) on 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) activity was determined in the brain stem (pons and medulla) of the fetal sheep at a mean gestational age of 126 days (term: about 147 days). Enzyme activity was determined by measuring the rate of oxidation of PGE2 to 15-keto-PGE2 using a radiometric assay. There was no statistically significant ethanol-induced inhibition of 15-OH-PGDH activity. The data apparently do not support the hypothesis that acute in vitro exposure to ethanol directly inhibits 15-OH-PGDH activity in the near-term fetal brain stem.

Animals↗
PubMed1990

Type XI collagen-degrading activity in human osteoarthritic cartilage.

Homogenates of 6 samples of human osteoarthritic cartilage were shown to degrade exogenous type XI collagen. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the cleavage products generated by each homogenate were similar, and they were identical to those obtained by cleavage of the substrate with purified gelatinase. Enzyme activity, which was inhibited by EDTA, was greater in extracts of fibrillated osteoarthritic cartilage than in extracts of grossly normal cartilage from the same joint or in extracts of cartilage from joints with osteonecrosis. Activation with APMA enhanced digestion, but breakdown was apparent in extracts of fibrillated osteoarthritic cartilage even without APMA. Enzymatic degradation of type XI collagen could play a significant role in the turnover of articular cartilage in health and disease states.

Adolescent↗
PubMed1990

Indomethacin reversal of ethanol-induced suppression of ovine fetal breathing movements and relationship to prostaglandin E2.

The effects of indomethacin on the ethanol-induced suppression of fetal breathing movements and fetal arterial plasma and cerebrospinal fluid (CSF) PGE2 concentrations and maternal arterial plasma PGE2 concentration were determined in the near-term fetal lamb. Eight conscious instrumented pregnant ewes (between 130 and 133 days of gestation; term, 147 days) received 1-h maternal intravenous infusion of 1 g ethanol/kg total body weight, and the fetus received 6-h intravenous infusion of indomethacin (1 mg/h per kg fetal body weight) commencing 30 min later. Serial fetal and maternal arterial blood samples (n = 8) and fetal CSF samples (n = 5) were collected at selected times throughout the 12-h study for the determination of PGE2 concentration. Fetal breathing movements were monitored continuously throughout the experimental period. Maternal ethanol infusion resulted in initial suppression (P less than 0.05) of fetal breathing movements for 2 h below pretreatment value, followed by a rapid increase in the incidence of fetal breathing movements after the onset of fetal indomethacin treatment. Fetal and maternal plasma PGE2 concentrations and fetal CSF PGE2 concentration were increased (P less than 0.05) above the pre-infusion value during the administration of ethanol and 1 h thereafter. Fetal indomethacin treatment suppressed (P less than 0.05) to undetectable levels fetal plasma and CSF PGE2 concentrations, which then became similar (P greater than 0.05) to pretreatment by 12 h. There was a positive correlation between fetal plasma and CSF PGE2 concentrations. There was an inverse correlation between the incidence of fetal breathing movements and fetal CSF PGE2 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of ethanol on ovine fetal and maternal plasma prostaglandin E2 concentrations and fetal breathing movements.

The effect of maternal administration of ethanol on fetal and maternal plasma prostaglandin E2 (PGE2) concentrations and fetal breathing movement was determined in the near-term pregnant ewe. Six conscious instrumented pregnant ewes (between 129 and 134 days of gestation; term, 147 days) were studied on two successive days (day 1 and day 2). On each of the two days of the experiment, there was a 1-h period of maternal infusion of ethanol (1 g ethanol/kg total body weight) or an equivalent volume of normal saline. Animals were assigned to two groups with one group (n = 3) receiving ethanol on day 1 and saline on day 2, and the other group (n = 3) receiving saline on day 1 and ethanol on day 2. Fetal and maternal blood samples were collected at selected times for blood ethanol determination (n = 2), and plasma was obtained for the determination of PGE2 concentration (n = 6). Fetal breathing movements were monitored continuously during the experimental periods. Maternal saline infusion had no effect (P greater than 0.05) on fetal breathing movement and fetal and maternal plasma PGE2 concentrations (187 +/- 25 (SEM) pg/ml and 196 +/- 32 pg/ml, respectively). Maternal ethanol infusion suppressed (P less than 0.05) fetal breathing movement below preinfusion levels for 8 h and increased (P less than 0.05) both fetal and maternal plasma PGE2 concentrations to 314 +/- 55 pg/ml and 306 +/- 25 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1989

Type XI collagen is associated with the chondrocyte surface in suspension culture.

Chondrocytes from bovine articular cartilage were stripped of matrix, then allowed to reconstitute their pericellular matrix in suspension culture. After incubation, the cells were centrifuged through a Percoll (TM) cushion and separated into a cell fraction, a medium fraction, and an interface fraction. The collagen in each fraction was analyzed by SDS-polyacrylamide gel electrophoresis and immunolocation with antisera against type XI and type II. Under these conditions, type XI collagen was recovered in the cell fraction, but was not detectable by immunolocation in the medium fraction or the interface fraction. In contrast, type II collagen was found in all three of these fractions. Insoluble type XI fibers subjected to the same fractionation scheme in the absence of cells were recovered in the medium and interface fractions, but not in the cell fraction. Incubation of intact cells with collagenase digested the cell-associated collagen, indicating that it was outside of the cells. The type XI collagen was removed from the cells by extraction with 4 M guanidinium chloride. These results indicate that type XI collagen is preferentially retained at the chondrocyte surface, and are consistent with our proposal that it is involved in organization of the pericellular matrix.

Animals↗