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Biomedical subjects

J A Watt

Publications and source records attributed to J A Watt.

At least 19 recordsLinked to original sources
PubMed1995

Distribution of growth-associated class I alpha-tubulin and class II beta-tubulin mRNAs in adult rat brain.

A comprehensive survey of class I alpha-tubulin (alpha 1) and class II beta-tubulin (beta II) mRNAs was performed using in situ hybridization in order to determine the extent of continued expression of these immature tubulin isotype mRNAs in the adult rat brain. Qualitatively similar distributions of the two isotype mRNAs were observed, with marked variations in hybridization intensity of both probes apparent across different brain regions. Neurons in a wide variety of structures throughout the brain exhibited intense hybridization signals. While the presence of large numbers of neurons with a moderate hybridization intensity could account for the relatively high level of total binding in some regions such as the cerebellar and dentate granule layers, in most cases higher regional mRNA levels reflected greater hybridization intensity per neuron. Little variability in hybridization intensity was typically seen between individual cells within specific nuclei throughout the brain. The presence of occasional intensely labeled neurons scattered throughout the basal ganglia provided the most striking exception to this pattern. While no qualitative differences between the distributions of alpha 1-tubulin and beta II-tubulin mRNAs were observed, consistent differences in the relative intensity of hybridization for alpha 1-tubulin versus beta II-tubulin mRNA were apparent in a few brain regions. Expression by glia did not appear to contribute significantly to detectable levels of either alpha 1-tubulin or beta II-tubulin mRNA. These findings suggest that continued expression of growth-associated tubulin isotype mRNAs may have functional significance in specific neuronal populations of the adult brain. Partial overlap between the distributions of alpha 1- and beta II-tubulin mRNAs and that of GAP-43 mRNA is discussed, as are potential roles for growth-associated tubulin gene expression in supporting cytoskeletal turnover, reactive axonal growth, and dendritic remodeling in the adult brain.

Animals↗
PubMed1995

Coordinated upregulation of alpha 1- and beta II-tubulin mRNAs during collateral axonal sprouting of central peptidergic neurons.

An in situ hybridization study was performed to determine the relationship between levels of mRNAs for the axonal growth-associated alpha 1-tubulin and beta II-tubulin isotypes and the process of collateral axonal sprouting by identified central nervous system (CNS) neurons. A unilateral hypothalamic knife-cut was used to hemisect the hypothalamoneurohypophysial tract, which results in a robust collateral sprouting response by the uninjured neurons of the contralateral supraoptic nucleus (SON) (Watt and Paden: Exp Neurol 111:9-24, 1991). At 10 and 30-35 days after the lesion, cryosections of the SON were obtained and hybridized with 35S-labeled cDNA probes specific to alpha 1- and beta II-tubulin mRNAs. Quantitative evaluation of the resulting autoradiographs revealed that alpha 1-tubulin mRNA levels were significantly increased by 10 days in SON neurons that were undergoing collateral sprouting compared to controls and that this increase was sustained at 30-35 days post-lesion. Less marked increases in hybridization intensity of the beta II-tubulin probe were also apparent in sprouting neurons at both 10 and 30-35 days after the lesion, but were statistically significant only at 10 days. The measured increases in intensity of hybridization of alpha 1- and beta II-tubulin probes are likely to be conservative estimates of the underlying increase in alpha 1- and beta II-tubulin mRNA levels because sprouting SON neurons undergo significant hypertrophy. High levels of both alpha 1- and beta II-tubulin mRNAs were also seen in surviving axotomized SON neurons ipsilateral to the hypothalamic lesion. We conclude that the pattern of regulation of alpha 1- and beta II-tubulin mRNAs in CNS neurons which are capable of supporting new axonal growth includes three elements: maintenance of significant basal alpha 1- and beta II-tubulin mRNA pools in mature neurons, rapid increases in the pool size of the mRNAs following stimulation of collateral sprouting, and sustained elevation of mRNA levels during the period of axonal sprouting.

Animals↗
PubMed1995

A detailed analysis of hydrogen peroxide-induced cell death in primary neuronal culture.

A variety of neurodegenerative disease states have been associated with oxidative damage or stress. Such stress is thought to be mediated by excessive exposure of cells to reactive oxygen species such as free radicals, which can be generated following cell lysis, oxidative burst (as part of the immune response) or by the presence of an excess of free transition metals. Since the neuronal death observed in neurodegenerative diseases may be related to free radical damage, we were interested in developing a model system to investigate the mechanisms by which reactive oxygen species may damage or kill neurons. To this end, we have recently reported that brief exposure of cultured cortical neurons to H2O2 can induce neuronal death that proceeds via an apoptotic cell suicide pathway. The studies reported here investigate H2O2-induced cell death in more detail. Our data suggest that exposure of cultured cortical neurons to H2O2 can induce apoptotic cell death within 3 h, as assessed by cell viability, morphological and ultrastructural measures. In addition, experiments presented show that exposure to high concentrations of H2O2 (100 microM) causes increases in intracellular free calcium within 3 h, suggesting that increased intracellular calcium may be associated with some aspects of H2O2-induced cell death. However, at intermediate concentrations of H2O2 (30 microM), intracellular calcium remained stable during a 3 h exposure, during which time membrane blebbing was observed in ultrastructural studies. This suggests that some aspects of apoptotic cell death induced by H2O2 may not be associated with increased intracellular free calcium. Thus, this model appears valuable for studies of the mechanism(s) by which oxidative injury may induce apoptotic cell death and damage to neurons in the CNS.

Animals↗
PubMed1994

Ultrastructural analysis of beta-amyloid-induced apoptosis in cultured hippocampal neurons.

Following treatment with the beta-amyloid (A beta) 25-35 analog, scanning and transmission electron microscopy were used to investigate the morphological changes in cultured hippocampal neurons during the course of degeneration. Ultrastructural analysis revealed focal cell surface blebbing and rapid condensation of nuclear chromatin. Changes in cytoplasmic morphology included prominent vacuole formation, dispersal of polyribosome rosettes and the disappearance of the golgi complex, smooth endoplasmic reticulum and microtubules with increased cytoplasmic electron density. Mitochondria and limited rough endoplasmic reticulum remained intact throughout the process of cell death. These results provide additional evidence suggesting A beta-induced cell death in vitro occurs via an apoptotic mechanism.

Amyloid beta-Peptides↗
PubMed1994

Quantitation of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in plasma and cerebrospinal fluid using solid-phase extraction and high-performance liquid chromatography with electrochemical detection.

An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard. Solid-phase extraction was used to separate morphine and its glucuronide metabolites from plasma constituents. Extraction efficiencies of morphine, M3G, and M6G from human plasma samples (0.5 ml) were 84, 87, and 88%, respectively. Extraction efficiencies of morphine, M3G, and M6G did not differ significantly (p > 0.05) between human plasma and CSF or rat plasma. Morphine, M3G, M6G, and hydromorphone were separated on a 10 mu C8 Resolve radially compressed cartridge using a mobile phase comprising methanol:acetonitrile:phosphate buffer, (0.0125M pH 7.5; 10:10:80), in which 11 mg/L of cetyltrimethylammonium bromide (cetrimide) was dissolved. Quantitation was achieved using a single electrochemical detector at ambient temperature (23 degrees C). Standard curves were linear over the ranges 0.020-2.190, 0.027-2.709, and 0.027-0.542 microM for morphine, M3G, and M6G, respectively. Lower limits of detection for morphine, M3G, and M6G in human plasma and CSF samples (0.5 ml) were 0.020, 0.027, and 0.027 microM, respectively. Corresponding lower limits of detection in rat plasma (0.1 ml) were 0.102, 0.135, and 0.135 microM, respectively. Intraassay precision for low and high concentrations of morphine, M3G, and M6G were < 23 and < 8% respectively. Similarly, interassay accuracy for low and medium concentrations of morphine, M3G, and M6G were < 17% and were < 9% for high concentrations.

Animals↗
PubMed1992

Comparative oxycodone pharmacokinetics in humans after intravenous, oral, and rectal administration.

The pharmacokinetics of oxycodone have been determined after single-dose administration by the intravenous (4.6-7.3 mg), oral (tablets, 9.1 mg and syrup, 9.1 mg), and rectal (30 mg) routes, in 48 patients undergoing minor surgery. There were no significant differences in the mean elimination half-lives between the intravenous (5.45 +/- 1.43 h), oral tablets (5.65 +/- 1.13 h), oral syrup (4.80 +/- 1.13 h), and rectal suppository (5.40 +/- 1.19 h) formulations of oxycodone. After intravenous administration, the mean plasma clearance of oxycodone was 25.5 +/- 10.1 L/h and the mean volume of distribution at steady state was 2.5 +/- 0.8 L/kg. The mean normalized area under the curve (AUC/D) obtained after intravenous dosing (48.2 +/- 30.2 micrograms.h/L/mg) was more than twice the AUC/D values obtained after the administration of oxycodone tablets (19.8 +/- 3.5 micrograms.h/L/mg), oxycodone syrup (17.5 +/- 5.3 micrograms.h/L/mg), and rectal suppository (20.3 +/- 5.1 micrograms.h/L/mg), indicating that the amount of oxycodone reaching the systemic circulation after the extravascular routes of administration was < 50% of that obtained after intravenous dosing. The mean absorption lag times after oxycodone tablets (0.52 +/- 0.33 h), oxycodone syrup (0.48 +/- 0.40 h), and rectal suppository (0.76 +/- 0.47 h) were consistent with the onset of pharmacological effects reported by the patients.

Administration, Oral↗
PubMed1992

Bibliotherapy: the use of books in psychiatric treatment.

The guided use of selected books as an adjunct to treatment is applicable to patients in all stages of life and with a variety of problems. This paper describes the authors' experience using books as an adjunct to therapy with psychiatric patients. The authors define the term, review the literature, and set out the objectives of bibliotherapy. The paper presents some principles to follow when assigning books, and examples of books used for common problems. Finally, examples are given of bibliotherapy in action at two Ontario hospitals, and some future directions are suggested.

Bibliotherapy↗
PubMed1991

Compensatory sprouting of uninjured magnocellular neurosecretory axons in the rat neural lobe following unilateral hypothalamic lesion.

Axonal sprouting of intact neurons of the magnocellular neurosecretory system was investigated using a unilateral hypothalamic knife cut of the hypothalamoneurohypophysial tract to partially denervate the rat neural lobe (NL). Densitometric, morphometric, ultrastructural, and metabolic measures were utilized to demonstrate the compensatory response to denervation in this system. Densitometric analysis revealed a transient reduction in the intensity of vasopressin staining in the NL at 10 days postsurgery (PS) with a subsequent recovery by 20 days PS. There was a comparable initial reduction in the cross-sectional area of the NL followed by a more gradual recovery to normal by 90 days PS. Ultrastructural investigation revealed a reduction in total axon number in the NL at 10 days PS similar to the declines in vasopressin immunoreactivity and size of the NL. A subsequent partial recovery of axon number occurred, paralleling the return to normal NL size between 30 and 90 days PS. Hypertrophy of both somata and cell nuclei of magnocellular neurons in the supraoptic and paraventricular hypothalamic nuclei contralateral to the lesion was also apparent during this period. Daily measurements of urine osmolality revealed an initial transient hypoosmolality followed by a chronic hyperosmolality which persisted throughout the 90 day postsurgical period. There was a concomitant chronic decrease in both daily drinking and urine excretion volumes which began immediately following surgery. These results suggest that intact, contralateral magnocellular vasopressinergic efferents undergo compensatory sprouting as a result of partial denervation of the NL in the absence of a functional deficit in vasopressin.

Animals↗
PubMed1991

Quantitation of oxycodone in human plasma using high-performance liquid chromatography with electrochemical detection.

An original, highly sensitive and specific high-performance liquid chromatographic (HPLC) assay has been developed for the measurement of oxycodone in human plasma with a detection limit of 10 ng/ml using a 1.0-ml plasma sample. Plasma samples were initially acid-washed and then extracted twice at pH 10 with butyl chloride. Oxycodone and codeine (internal standard) were eluted with a mixture of methanol, acetonitrile, and 0.01 M pH 7 phosphate buffer to which 40 mg/l of cetyltrimethylammonium bromide (cetavlon) was added at ambient temperature and detected with electrochemical detection. The addition of cetavlon to the mobile phase markedly reduced the interaction between oxycodone and Si-OH groups on the stationary phase of the HPLC column, so that the organic content of the mobile phase could be reduced from 80 to 25%. Quantitation was achieved using the peak height ratio of oxycodone to codeine. The assay is currently being used for the study of oxycodone pharmacokinetics after single oral doses of 10 and 20 mg and single rectal doses of 30 mg.

Administration, Oral↗
PubMed1991

Contrasting systemic stabilities of the acyl and phenolic glucuronides of diflunisal in the rat.

1. Diflunisal (DF) is metabolized in humans and rats primarily to its acyl glucuronide, phenolic glucuronide and sulphate conjugates. 2. After i.v. administration of DF acyl glucuronide to pentobarbitone-anaesthetized rats, DF and its phenolic glucuronide and sulphate conjugates appeared rapidly in plasma, indicating ready systemic hydrolysis of the acyl glucuronide and subsequent biotransformation of liberated DF. 3. Approximately 72% of the acyl glucuronide dose was recovered in bile and urine over 6 h: 52% as acyl glucuronide, 6% as phenolic glucuronide, 5% as sulphate, and 8% as isomers of the acyl glucuronide arising from intramolecular acyl migration. 4. Blockage of excretion routes by ligation of the ureters, bile duct, and both ureters and bile duct, decreased plasma clearance of the acyl glucuronide from 7.8 ml/min per kg to 6.0, 3.2 and 2.2 ml/min per kg respectively, and increased the apparent terminal plasma half-life of DF from 2.1 h to 2.6, 3.4 and 6.3 h, respectively. 5. By contrast, DF phenolic glucuronide was quite stable after i.v. administration at the same dose. 6. This study shows that systemic cycling between DF and its acyl glucuronide exists in the rat in vivo, with portions of each cycle of unstable acyl glucuronide through DF yielding stable phenolic glucuronide and (presumptively stable) sulphate conjugate.

Adult↗
PubMed1990

Reactivity of diflunisal acyl glucuronide in human and rat plasma and albumin solutions.

Diflunisal acyl glucuronide (DAG) is a major metabolite of diflunisal (DF) in rats and humans. We have investigated the reactivity of DAG, in purified albumin solutions and plasma from both rat and human sources, along three interrelated pathways: rearrangement via acyl migration to yield positional isomers of DAG, hydrolysis of DAG and/or its isomers to liberate DF, and formation of covalent adducts of DF (via DAG and/or its isomers) with plasma protein. Two initial concentrations of DAG (ca. 50 and 10 micrograms DF equivalents/mL) were used throughout. In all incubations, the order of quantitative importance of the reactions was: rearrangement greater than hydrolysis greater than covalent binding. At pH 7.4 and 37 degrees, degradation of DAG in albumin solutions (e.g. half-life ca. 95 min in fatty acid-free human serum albumin) was retarded in comparison to that found in buffer alone (half-life ca. 35 min). Degradation in unbuffered rat and human plasma containing heparin was comparable to that found in buffer. Maximal covalent binding to protein was achieved after 4-8 hr incubation, and was greatest for fatty acid-free human serum albumin (165 ng DF/mg albumin). Thereafter, slow degradation of the adducts was observed. Formation of DF-plasma protein adducts in vivo was also found in rats and humans dosed with DF.

Adult↗
PubMed1990

Morphine-3-glucuronide--a potent antagonist of morphine analgesia.

In this study, morphine-3-glucuronide (M3G), the major plasma and urinary metabolite of morphine, was shown to be a potent antagonist of morphine analgesia when administered to rats by the intra-cerebroventricular (i.c.v.) route. The antagonism of morphine analgesia was observed irrespective of whether i.c.v. M3G (2.5 or 3.0 micrograms) was administered 15 mins prior to or 15 mins after i.c.v. morphine (20 micrograms). When M3G (10mg) was administered intraperitoneally (i.p.) to rats 30-40 mins prior to morphine (1.5mg i.p.), the analgesic response was significantly reduced compared to administration of morphine (1.5mg i.p.) alone. It was further demonstrated that i.c.v. M3G (2.0 micrograms) antagonized the analgesic effects of subsequently administered i.c.v. morphine-6-glucuronide (0.25 micrograms).

Analgesia↗
PubMed1990

A double-blind comparative study of remoxipride and thioridazine in the acute phase of schizophrenia.

Sixty-one patients with acute schizophrenia received either remoxipride (75-375 mg daily) or thioridazine (150-750 mg daily) for 6 weeks. There was no statistically significant between-drug difference in improvement in mental state, as measured by the Brief Psychiatric Rating Scale, although the trend favoured thioridazine; global assessment of illness severity at the last rating also favoured thioridazine. Sedation, anticholinergic effects, autonomic dysfunction, and weight gain were significantly more common in patients receiving thioridazine. Both drugs produced few extrapyramidal effects, but both were associated with cardiovascular changes in two patients; neither drug produced significant abnormalities in laboratory tests.

Acute Disease↗
PubMed1990

The effect of diethyl ether, pentobarbitone and urethane anaesthesia on diflunisal conjugation and disposition in rats.

1. The disposition of diflunisal (DF) at 10 mg/kg i.v. was investigated over 4 h in bile-exteriorized male rats continuously anaesthetized with (a) diethyl ether inhalation (as required), (b) pentobarbitone sodium i.p. (55 mg/kg initially), (c) urethane i.p. (1500 mg/kg initially) or (d) urethane i.v. (750 mg/kg initially), and compared to that obtained in conscious rats. 2. Diethyl ether decreased the plasma clearance of DF to about 30% of control values, by inhibition of both glucuronidation and sulphation of DF. 3. Pentobarbitone anaesthesia caused only modest inhibition of DF elimination, with plasma clearance decreased to about 80% of control values. 4. Plasma profiles and biliary recovery of DF and its conjugates were little altered by urethane i.p. anaesthesia, but urinary recovery was low and variable because of the nearanuria produced by urethane via this administration route. 5. Urinary recovery of DF and its conjugates was satisfactory in rats given urethane i.v., but tissue distribution of DF was substantially decreased. 6. Pentobarbitone was considered to interfere least with DF disposition at the 10 mg/kg dose, and was selected as the most suitable anaesthetic agent for ongoing studies of disposition of DF and its conjugates in anaesthetized rats.

Anesthetics↗
PubMed1990

Effects of blockage of urine and/or bile flow on diflunisal conjugation and disposition in rats.

1. The effects of surgical blockage of either or both of the urinary and biliary excretion routes on the elimination of diflunisal (DF) and its conjugates were investigated in pentobarbitone-anaesthetized rats given DF at 10 mg/kg i.v. 2. In control animals the acyl glucuronide and phenolic glucuronide conjugates were excreted predominantly in bile, whereas the sulphate conjugate was eliminated almost exclusively in urine. 3. Bilateral ureter ligation had little effect on DF elimination, except for accumulation of the sulphate conjugate in plasma. Compensatory biliary excretion did not occur. 4. Total plasma clearance of DF decreased from 1.01 to 0.68 ml/min per kg following bile duct ligation. Plasma concentrations and urinary excretion of the glucuronides were elevated. 5. In rats with blockage of both urinary and biliary excretion routes, total plasma clearance of DF decreased to 0.59 ml/min per kg. Both the sulphate and phenolic glucuronide conjugates accumulated in plasma, whereas the acyl glucuronide peaked at 30 min and then declined in parallel with DF. The latter result indicates systemic instability of DF acyl glucuronide with hydrolytic regeneration of DF as the likely major consequence.

Animals↗
PubMed1989

The Scottish first episode schizophrenia study. VII. Two-year follow-up. Scottish Schizophrenia Research Group.

Of 49 schizophrenic patients followed up 2 years after their first admission to hospital, 37% were well, 47% had been readmitted to hospital at some time over the 2 years, and 38% showed schizophrenic symptoms at follow-up. A poor outcome at 2 years was associated with male sex, poor outcome after the first 5 weeks of the first admission, negative schizophrenic symptoms on first admission, and a diagnosis of definite or probable schizophrenia using the Feighner criteria. Only 23% were in employment. A small double-blind discontinuation study of maintenance antipsychotic medication during the second year found more relapses in those switched to placebo medication. Repeat psychometric assessment at 2 years confirmed modest improvements found at 12 months; that is, there was no evidence of intellectual decline. Relatives showed no more psychosocial distress than that found in a normal community sample; what distress there was correlated with patients' schizophrenic symptoms.

Clinical Trials as Topic↗