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Biomedical subjects

A Frazer

Publications and source records attributed to A Frazer.

At least 19 recordsLinked to original sources
PubMed2006

A case of chondromatosis indicates a synovial stem cell aetiology.

OBJECTIVE: To evaluate cell cultures derived from intrasynovial nodules from a patient with primary synovial chondromatosis (PSC) for aberrant numbers/differentiation of osteochondroprogenitor cells. METHODS: Cell cultures were established from PSC synovial nodules, or normal bovine or human osteoarthritis (OA) synovia (for comparison). Multi-lineage potential was determined using well-characterized in vitro culture systems to assess osteogenic, chondrogenic and adipogenic capability. RESULTS: Primary PSC cell cultures were typically fibroblastic but contained islands of dense cell clusters/nodules, some of which were isolated and cultured separately [putative osteochondroprogenitris (pOCP) cultures]. OA synovial cultures had barely detectable levels of alkaline phosphatase (AP) that increased (0.006+/-0.008 to 0.141+/-0.000 nmol p-nitrophenol/min/cm(2)) with dexamethasone treatment. AP activity was higher in primary PSC cell cultures and further enhanced by dexamethasone (from 0.076+/-0.022 to 5.735+/-0.000 nmol p-nitrophenol/min/cm(2)). Histochemically, AP was localized as discreet areas within PSC cultures. No AP activity was detected histochemically in OA or normal bovine synovial cultures. The pOCP cultures had high basal AP (5.036+/-0.439 nmol p-nitrophenol/min/cm(2)) and spontaneously formed mineralized nodules, which increased in number under standard osteogenic conditions. Under chondrogenic conditions, micromass or pellet-cultured pOCP cells spontaneously synthesized a matrix containing glycosaminoglycans and collagen II. In adipogenic medium, the number of lipid-containing cells was increased. CONCLUSIONS: Compared with cultures established from OA or normal synovia, cell cultures established from PSC synovial nodules were enriched in osteochondroprogenitors, which, unlike normal mesenchymal cells, differentiated along chondrogenic and osteogenic lineages in the absence of dexamethasone.

Adult↗
PubMed2002

Delayed pharmacological effects of antidepressants.

Although antidepressants may not be primary mood stabilizers, they are efficacious in the prophylaxis of recurrent depressive illnesses, as well as in the treatment of acute episodes. Pharmacological effects that may contribute to the prophylactic effects of these drugs are not understood. Studies have been carried out in which antidepressants have been given to laboratory animals, such as rats, for periods of up to 3-4 weeks. Data obtained in such studies are thought to be important for their beneficial effects in depressive episodes, but also may be relevant to their prophylactic effects. Results are presented showing that when selective inhibitors of serotonin or norepinephrine uptake are given for such time periods, they still produce selective effects on serotonergic or noradrenergic parameters. For example, long-term administration of selective norepinephrine reuptake inhibitors causes a down-regulation of beta(1) adrenoceptors. Selective serotonin reuptake inhibitors do not produce this effect. Long-term administration of selective serotonin reuptake inhibitors causes down-regulation of the serotonin transporter, but not the norepinephrine transporter. In contrast, selective norepinephrine reuptake inhibitors down-regulate the norepinephrine transporter but not the serotonin transporter. Substantial loss of serotonin transporter binding sites takes 15 days to occur and is accompanied by a marked reduction of serotonin transporter function in vivo.

Affect↗
PubMed2001

Same-day X-ray reporting is not needed in well-supervised emergency departments.

OBJECTIVE: To evaluate the efficacy of a missed radiological abnormality follow-up system in a teaching hospital emergency department. METHODS: Prospective audit of all reported radiological abnormalities missed by Fremantle Hospital Emergency Department medical staff from 1 January 1997 to 31 December 1998. RESULTS: Of 29,724 radiological examination series, 459 abnormalities (1.5%) were not clearly documented as being identified in the medical record. The commonest missed abnormalities were incidental chest findings, distal wrist fractures with minimal or no displacement, radial head fractures and tibial plateau fractures. The most senior doctor undertaking initial film review was a junior medical officer in 242 cases (53%), a registrar in 96 cases (21%), and a consultant in 42 cases (9%). The most senior staff member was unknown in 79 cases (17%). One hundred and twenty-four missed abnormalities required a change in patient management (0.41% of total examinations, CI 0.34-0.48%). Ninety patients (73%) were referred to the patient's general practitioner for management. Seventeen patients (14%) returned to the emergency department for management. Thirteen patients (10%) were referred to a specialist clinic and in four cases (3%) the management of the patient was not recorded. No patient required re-admission to hospital. CONCLUSIONS: Missed radiological abnormalities in an emergency department with extended-hours emergency physician supervision can be managed non-urgently on an outpatient basis. Same-day reporting of radiographs is not required if adequate follow-up mechanisms for missed abnormalities exist.

Diagnostic Errors↗
PubMed2001

Serotonergic and noradrenergic reuptake inhibitors: prediction of clinical effects from in vitro potencies.

This article reviews the pharmacology of antidepressants, particularly focusing on those that act acutely by blocking the reuptake of norepinephrine (NE) and/or serotonin (5-HT). Such drugs have a very wide range of potencies, measured in vitro, to inhibit the reuptake of these biogenic amines. As a group, the selective serotonin reuptake inhibitors (SSRIs) are the most potent at inhibiting the reuptake of 5-HT. Some tricyclic antidepressants (TCAs), such as desipramine and nortriptyline, are much more potent at blocking NE reuptake than 5-HT reuptake, as is the new non-TCA drug reboxetine. Among SSRIs, paroxetine is most potent at blocking the reuptake of NE. When considering whether such potencies measured in vitro translate into pharmacologic effects clinically, it is necessary to know how much drug gets to its site of therapeutic action, presumably the brain. Most, but not all, antidepressants are extensively bound to plasma proteins, and this binding limits considerably the penetration of these drugs across the blood-brain barrier. The amount of drug present in the extracellular fluid (ECF) of brain approximates the non-protein-bound drug concentration in plasma. Comparison of the concentration of antidepressants in ECF with their potencies to inhibit the reuptake of 5-HT and/or NE reveals why some drugs block the reuptake of these biogenic amines in either a selective or nonselective manner. This analysis reveals that venlafaxine may be unique among antidepressants in having a dose-dependent nonselectivity; at low doses it acts primarily as an SSRI, but at higher doses it inhibits the reuptake of NE as well.

Adrenergic Uptake Inhibitors↗
PubMed2000

5-HT(1B) receptor-mediated regulation of serotonin clearance in rat hippocampus in vivo.

The 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5-HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT(1B) antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT(1B) antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT(1A) antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5-HT(1A) receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT(1B) autoreceptors increases 5-HTT activity.

Animals↗
PubMed2000

Norepinephrine involvement in antidepressant action.

Because of the introduction and popularity of the selective serotonin reuptake inhibitor (SSRI) antidepressants, much attention was centered on the indolealkylamine 5-hydroxytryptamine, or serotonin. To some extent, this focus on serotonin occurred at the expense of the catecholamine neurotransmitter norepinephrine. Nevertheless, it has been apparent for almost 40 years that selective blockers of norepinephrine reuptake may be antidepressants (e.g., desipramine). This brief review covers the acute pharmacologic effects that may be responsible for the efficacy of currently marketed antidepressants as well as that of reboxetine, a newly developed selective norepinephrine reuptake inhibitor. Also discussed is the fact that the acute pharmacologic profile of selective reuptake inhibitors often predicts effects they produce when given long term. For example, the long-term administration of SSRIs produces certain effects on serotonergic systems, but not noradrenergic ones. By contrast, selective norepinephrine reuptake inhibitors, when given long term, modify certain noradrenergic parameters, but not serotonergic indices. Finally, it is speculated how drugs that enhance central noradrenergic transmission might ameliorate the symptoms of depression.

Adrenergic Uptake Inhibitors↗
PubMed1999

Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.

To investigate functional changes in the brain serotonin transporter (SERT) after chronic antidepressant treatment, several techniques were used to assess SERT activity, density, or its mRNA content. Rats were treated by osmotic minipump for 21 d with the selective serotonin reuptake inhibitors (SSRIs) paroxetine or sertraline, the selective norepinephrine reuptake inhibitor desipramine (DMI), or the monoamine oxidase inhibitor phenelzine. High-speed in vivo electrochemical recordings were used to assess the ability of the SSRI fluvoxamine to modulate the clearance of locally applied serotonin in the CA3 region of hippocampus in drug- or vehicle-treated rats. Fluvoxamine decreased the clearance of serotonin in rats treated with vehicle, DMI, or phenelzine but had no effect on the clearance of serotonin in SSRI-treated rats. SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated rats but not in those treated with phenelzine or DMI. The serotonin content of the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants; furthermore, the downregulation is not caused by decreases in SERT gene expression.

Adrenergic Uptake Inhibitors↗
PubMed1999

5-HT1B antagonists modulate clearance of extracellular serotonin in rat hippocampus.

In vivo chronoamperometry was used to determine the effects of locally applied antagonists of the serotonin-1B (5-HT1B) receptor (cyanopindolol, 5-HT-moduline and methiothepin) on the clearance of 5-HT in the CA3 region of the dorsal hippocampus and the corpus callosum (a brain region devoid of serotonin transporters and 5-HT1B receptors) of the rat. When 5-HT was pressure ejected into these regions, reproducible signals were detected. In the CA3 region, local application of 5-HT1B antagonists decreased the rate of clearance of the serotonin signal comparably to the selective 5-HT uptake inhibitor (SSRI), fluvoxamine. By contrast, in the corpus callosum, none of the drugs altered the 5-HT signal. One interpretation of these data is that 5-HT1B receptors can modulate the activity of the 5-HT transporter.

Analysis of Variance↗
PubMed1998

Serotonin transporter function in vivo: assessment by chronoamperometry.

Local application of selective serotonin reuptake inhibitors, fluvoxamine and citalopram, prolonged the clearance of exogenously administered serotonin (5-HT) in both the dentate gyrus and CA3 region of the dorsal hippocampus, as measured using in vivo chronoamperometry. These effects were abolished in rats pretreated with 5,7-dihydroxytryptamine. The NE uptake inhibitors, desipramine and protriptyline, did not alter the 5-HT signal in the CA3 region, but prolonged the clearance of 5-HT in the dentate gyrus; this effect was absent in rats pretreated with 6-hydroxydopamine. From these data, it is inferred that both the SERT and NET contribute to the active clearance of exogenously applied 5-HT in the dentate gyrus. In another experiment, cyanopindolol, an antagonist of the serotonin terminal autoreceptor, also prolonged the clearance of 5-HT from the CA3 region. These and other data have generated a working hypothesis that activation of the terminal serotonin autoreceptor enhances the kinetics of 5-HT uptake through an effect on the serotonin transporter.

Animals↗
PubMed1998

Cellular cholesterol synthesis--the relationship to post-prandial glucose and insulin following weight loss.

Hyperinsulinaemia is a risk factor for atherosclerosis. We have previously demonstrated a relationship between hyperinsulinaemia and cellular cholesterol synthesis. In this paper we examine the separate relationship of glucose and insulin to cholesterol synthesis in three groups of obese patients. The first group was a group of non-insulin-dependent diabetic patients with a low post-prandial insulin response (n=8). The second group had non-insulin-dependent diabetes and a high insulin response (n=9). The third group were non-diabetic patients with a high post-prandial insulin (n=12). Six diabetic and seven non-diabetic patients who were hyperinsulinaemic on initial analysis, were re-examined following an 8% body weight reduction. Insulin resistance was defined as the ratio of area under curve for insulin/area under curve for glucose. Cellular cholesterol synthesis was measured in freshly isolated mononuclear leucocytes. Fasting cholesterol synthesis was similar in the three groups. In both diabetic and non-diabetic high insulin subjects cholesterol synthesis rose significantly after the meal (p < 0.05). Both hyperinsulinaemic groups showed a significantly greater change from baseline than did the non-hyperinsulinaemic group. There was a positive correlation between post-prandial cellular cholesterol synthesis and insulin resistance (p < 0.05). Following weight reduction patients were divided into two groups, those who did reduce insulin resistance (group 1) and those who did not reduce insulin resistance (group 2). The significant post-prandial increase in cholesterol synthesis was no longer seen in group 1 after weight loss whereas in group 2 after a similar weight loss the post-prandial cholesterol synthesis remained elevated. These results demonstrate that post-prandial hyperinsulinaemia is associated with increased cellular cholesterol synthesis. This increase in cholesterol synthesis is no longer seen in those patients in whom insulin resistance improved with weight reduction. This study suggests a mechanism for the association between insulin resistance and atherosclerosis.

Blood Glucose↗
PubMed1998

Effects of antidepressant treatment on inhibitory avoidance behavior and amygdaloid beta-adrenoceptors in rats.

Chronic treatment of rats with a variety of antidepressants results in the down-regulation of beta-1-adrenoceptors in the amygdaloid nuclei. The present study sought to determine if this specific neurochemical effect caused an alteration in inhibitory avoidance conditioning, a behavior considered to be mediated by beta-adrenoceptors in the amygdala. Rats treated chronically with either desipramine (DMI) or phenelzine (PHEN), which down-regulate beta-1-adrenoceptors in the amygdala, or fluoxetine (FLUOX), which does not do this, did not exhibit a deficit in the retention of the inhibitory avoidance task. However, when scopolamine was given prior to acquisition of the task in a dose that, by itself, did not affect retention, DMI- and PHEN-treated rats showed a marked deficit in retention. This effect was also observed after acute administration of these drugs, although they did not down-regulate amygdaloid beta-1-adrenoceptors at this time. It seems that the ability of these antidepressants to potentiate the amnesic effect of scopolamine is unrelated to their effect on beta-1-adrenoceptor number in the amygdala and that the extent of the antidepressant-induced amygdaloid beta-1-adrenoceptor down-regulation is not sufficient, by itself, to cause a deficit in an inhibitory avoidance task.

Adrenergic beta-Antagonists↗
PubMed1998

Expression of type X collagen and matrix calcification in three-dimensional cultures of immortalized temperature-sensitive chondrocytes derived from adult human articular cartilage.

Chondrocytes isolated from normal adult human articular cartilage were infected with a retroviral vector encoding a temperature-sensitive mutant of the simian virus 40 large tumor antigen and a linked geneticin (G418)-resistance marker. G418-resistant colonies were then isolated, ring-cloned, and expanded in serum-containing media. Several immortalized chondrocyte cell lines were established from the clones that survived, some of which have been maintained in continuous culture for over 2 years. Despite serial subcultures and maintenance as monolayers, these cells retain expression of markers specific for cells of the lineage, namely type II collagen and aggrecan, detected immunocytochemically. We also examined the phenotype of three of these immortalized cell lines (designated HAC [human articular chondrocyte]) using a pellet culture system, and in this report, we present evidence that a prototype of these lines (HAC-F cells) expresses markers normally associated with hypertrophic chondrocytes. When HAC-F cells were cultivated in centrifuge tubes, for periods of up to 63 days, at 39 degrees C with mild and intermittent centrifugation they continued to express both lineage markers; total type II collagen/pellet remained stable, whereas there was a temporal decrease in cartilage-specific glycosaminoglycans content. In addition, in the presence of ascorbate but in the absence of a phosphate donor or inorganic phosphate supplement, the cells also begin to express a hypertrophic phenotype characterized by type X collagen synthesis and extensive mineralization of the extracellular matrix in late stage cultures. The mRNA encoding type X collagen was detected in the cell pellets by reverse transcriptase polymerase chain reaction as early as day 2, and anti-type X collagen immunoreactivity was subsequently localized in the matrix. The mineral was characterized by energy-dispersive X-ray microanalysis as containing calcium (Ca) and phosphorus (P) with a Ca:P peak height ratio close to that of mineralized bone tissue. The unexpected phenotype of this human chondrocyte cell line provides an interesting opportunity for studying chondrocyte maturation in vitro.

Adult↗
PubMed1998

In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters.

The effects of blockade of serotonin (5-HT) and norepinephrine (NE) transporters (SERT and NET, respectively) on the removal of locally applied 5-HT from extracellular fluid (ECF) were examined using in vivo chronoamperometry. Male Sprague-Dawley rats were anesthetized with chloralose/urethane, and a Nafion-coated, carbon fiber electrode attached to a multibarrel micropipette was positioned into either the dentate gyrus or CA3 region of the dorsal hippocampus. Pressure ejection of 5-HT elicited reproducible electrochemical signals of similar peak amplitude and time course in both structures. Local application of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram prolonged the clearance of 5-HT in both brain regions and also increased signal amplitude in the CA3 region. These effects were abolished in rats pretreated with 5, 7-dihydroxytryptamine (5,7-DHT), a selective 5-HT neurotoxin. The NE uptake inhibitors desipramine (DMI) and protriptyline did not alter the 5-HT signal in the CA3 region but prolonged the clearance of 5-HT in the dentate gyrus; this effect was absent in rats pretreated with 6-hydroxydopamine (6-OHDA), a selective catecholamine neurotoxin. The prolongation of the removal of 5-HT from the ECF in the dentate gyrus caused by fluvoxamine or desipramine was of comparable magnitude and was dose dependent. Furthermore, per picomole of 5-HT applied, the signal amplitude and clearance time were significantly increased in the dentate gyrus of rats lesioned with either 5,7-DHT or 6-OHDA. Only 5,7-DHT treatment caused this effect in the CA3 region. From these data, it is inferred that in certain regions of brain (dentate gyrus), both the SERT and NET contribute to the active clearance of exogenously applied 5-HT.

5,7-Dihydroxytryptamine↗
PubMed1997

In vivo chronoamperometric measurements of the clearance of exogenously applied serotonin in the rat dentate gyrus.

The present study evaluated high-speed chronoamperometry as a method for measuring the clearance of serotonin (5-HT) from extracellular space in vivo. Male Sprague-Dawley rats were anaesthetized and a Nafion-coated, carbon fiber electrode, attached to a multibarrel pipette, was lowered into the subgranular layer of the dentate gyrus, a region which receives dense serotonergic innervation, or the corpus callosum, a fiber tract relatively devoid of the 5-HT transporter (SERT). Serotonin, pressure ejected into these regions, produced replicable electrochemical signals. The amplitude and time course of the signals were significantly prolonged in the corpus callosum compared to the dentate gyrus. Similarly, signals produced by locally applied 5-HT in the dentate gyrus of rats following destruction of hippocampal serotonergic innervation with 5,7-dihydroxytryptamine (5,7-DHT), were significantly enhanced compared to those observed in control animals. The time course of the 5-HT signal was significantly prolonged by local application of the selective 5-HT reuptake inhibitor, fluvoxamine, into the dentate gyrus. By contrast, fluvoxamine did not modify the clearance of 5-HT when locally applied into the dentate gyrus of 5,7-DHT lesioned rats or into the corpus callosum of intact rats. Taken together, these data demonstrate that in intact rats, the SERT contributes to the clearance of exogenously applied 5-HT from the extracellular space. Under the experimental conditions used in this study, high-speed chronoamperometry proved to be a reliable method for directly measuring extracellular 5-HT and appears to be a valuable tool for the study of 5-HT clearance by the SERT in vivo.

5,7-Dihydroxytryptamine↗
PubMed1997

Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence.

We investigated specific subjective effects of naltrexone pretreatment or placebo during various intervals on the breath alcohol level (BAL) curve in nonalcoholic volunteers. Fifteen high-risk (social drinkers with an alcoholic father) and 14 low-risk (no alcoholic relatives in at least two generations) subjects were tested in a double-blind placebo-controlled study of the effects of 50 mg oral naltrexone on response to a moderate dose of alcohol. Dependent measures included subjective stimulation and sedation subscales from the Biphasic Alcohol Effects Scale (BAES) and mood subscales from the Profile of Mood States (POMS). At rising BALs, high-risk subjects showed a naltrexone-related attenuation of BAES stimulation. This effect was not evident in low-risk subjects, who directionally showed the opposite effect, although nonsignificant. For both groups, there were no significant naltrexone-related effects for BAES sedation; however, naltrexone did affect several POMS scales on alcohol response, such as decreased vigor, and increased fatigue, tension, and confusion. Confusion was significantly elevated for the high-risk group during rising BALs of the naltrexone session. The results suggest a differential response to naltrexone, based on paternal history of alcoholism and level of stimulation experienced during alcohol drinking.

Adult↗
PubMed1997

Effects of transforming growth factor beta on the production of prostaglandin E and caseinase activity of unstimulated and interleukin 1-stimulated human articular chondrocytes in culture.

Transforming growth factor beta (TGF beta) has previously been shown to have actions on chondrocytes and cartilage both in vitro and in vivo which suggest a role in connective tissue repair. In particular, some of its actions have been shown to be antagonistic to those of interleukin 1 (IL-1). In this study, the effects of TGF beta on prostaglandin E (PGE) production and caseinase activity, in the presence and absence of IL-1, in human articular chondrocytes were investigated. TGF beta 1 and TGF beta 2 were shown to modulate IL-1 beta-stimulated PGE production and caseinase activity. Both TGF beta 1 and beta 2 inhibited IL-1 beta-stimulated PGE production in the absence of serum and augmented it in the presence of serum. TGF beta 1 and TGF beta 2 inhibited IL-1-stimulated caseinase activity with and without serum. In general, the TGF beta s had little or no effect on basal PGE or caseinase levels. TGF beta s may be important modulators of chondrocyte metabolism, their effects on PGE production may depend on cytokine interactions; furthermore, their effects on caseinase activity may help prevent cartilage breakdown.

Aged↗