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Biomedical subjects

M Wilkinson

Publications and source records attributed to M Wilkinson.

At least 181 records · Page 10Linked to original sources
PubMed1990

Osteoporosis and skeletal fractures in chronic liver disease.

In order to determine the prevalence and severity of hepatic osteodystrophy by non-invasive means we compared 115 consecutive ambulant patients with histologically proven chronic liver disease to 113 age and sex matched control subjects. Methods used included the assessment of fracture prevalence rates, spinal radiography, and measurements of bone mineral density in the spine and the forearm. Spinal and peripheral fractures were more prevalent in the patients than in the control subjects (p less than 0.03 and p less than 0.01 respectively). The type of the underlying liver disease did not significantly affect the fracture prevalence rates, but alcoholic patients sustained more peripheral fractures than patients with other hepatic disorders (p less than 0.05). The bone mineral densities of the spines and the forearms were significantly reduced in male patients of all age groups and in female patients aged 60 years or more (p less than 0.001 for men and p less than 0.01 for women for both measurements). The prevalence rates of spinal and forearm osteoporosis were twice as high among patients with liver disease than in control subjects regardless of the definitions used. The presence of cirrhosis and hypogonadism were major risk factors for development of both spinal (Beta coef = 0.190 and 0.176; SE = 0.079 and 0.086 respectively) and forearm osteoporosis (Beta coef = 0.20 and 0.29; SE = 0.073 and 0.80 respectively). Spinal bone density was the predominant determinant of spinal fractures (Beta coef = -0.007; SE = 0.001), while hypogonadism (Beta coef = 0.363; SE = 0.075) and cirrhosis (Beta coef = 0.185; SE = 0.068) were the major predictors of peripheral fractures. The concentrations of serum calcium and serum vitamin D metabolites and the use of corticosteroids were apparently without effect on the prevalence of skeletal fractures or bone density.

Adrenal Cortex Hormones↗
PubMed1990

Peripubertal treatment with N-methyl-D-aspartic acid or neonatally with monosodium glutamate accelerates sexual maturation in female rats, an effect reversed by MK-801.

Recent reports from several laboratories have implicated the excitatory neurotransmitter glutamate as a component in the neural regulation of sexual maturation. In the rat we have previously proposed that a hypothalamic opioid restraint mechanism may ultimately be overridden by maturation of an excitatory drive, culminating in first ovulation. We have now investigated whether glutamate may be the excitatory factor. Treatment of immature female rats with single, daily injections of two N-methyl-D-aspartate (NMDA) antagonists--dextrorphan (18 mg/kg) and MK-801 (0.1 mg/kg)--beginning on the 27th postnatal day, significantly delayed the timing of vaginal opening (VO). Interestingly, treated rats reached VO in spite of continued antagonist treatment. The antagonist effect was reversed by preinjection of NMDA, suggesting that endogenous glutamate exerts its effect via an NMDA-subtype glutamate receptor. Injection of NMDA alone (15 mg/kg; once daily) produced a striking synchronization of VO such that all treated rats showed VO over a 24-hour period compared to a normal distribution of several days for control rats. In a model of first ovulation, i.e., rats induced to ovulate by pregnant mare serum, MK-801 (1 mg/kg) arrested treated rats at proestrus. This was readily reversible after discontinuing injections. A lower dose of MK-801 (0.1 mg/kg/day) was ineffective in delaying ovulation. In a second series of experiments we studied the consequences of a neonatal hypothalamic lesion which destroys glutamate-sensitive neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Tsk mice with genetic emphysema. Right ventricular hypertrophy occurs without hypertrophy of muscular pulmonary arteries or muscularization of arterioles.

The causes for the development of right ventricular hypertrophy (RVH) in emphysema are not fully understood. In the 1960s, studies of RVH in association with emphysema found no correlation between the extent of tissue damage in the lung and the RV weight. This was thought to disprove the theory that the RVH was due to an increase in pulmonary vascular resistance secondary to capillary destruction. In the present study, the development of RVH was investigated in tight-skin (tsk) mice with genetic emphysema. RVH started to develop in mature to senescent animals between 8 and 16 months of age and progressed thereafter. At 24 months of age, RV weight and the ratios RV/body weight and RV/LV + S weight were, respectively, 52, 96, and 60% greater than in control (pa) mice. At this time blood gas analysis revealed hypoxemia in tsk but not in pa mice. The mean linear intercept of tsk mice was 83% larger and the surface area of the walls of distal air spaces per unit lung volume was 40% smaller than in pa mice. There was a strong correlation between the severity of emphysema, assessed by both techniques, and the RV/LV + S ratio (p less than 0.001 for both). No muscularized arterioles were seen in the tsk mice, and the medial thickness of muscular arteries was almost identical in the two groups. This demonstrates that in emphysema, RVH can develop in the absence of pulmonary vascular changes and is probably due to tissue (and thus capillary) destruction.

Animals↗
PubMed1990

Parathyroid hormone sensitivity in primary hyperparathyroidism and idiopathic hypercalciuria: effects on postadenylate cyclase parameters.

We performed 6-h human PTH-(1-34) infusions in 8 control subjects, 10 subjects with primary hyperparathyroidism, and 7 men with idiopathic hypercalciuria. We measured serum calcium, serum 1,25-dihydroxyvitamin D, urinary calcium, and fractional phosphate excretion. The PTH-induced rise in serum 1,25-dihydroxyvitamin-D was significantly smaller in the hyperparathyroid patients than in either the controls or the hypercalciuric patients. The rise in serum calcium was similar in all 3 groups. The hyperparathyroid subjects had higher basal fractional phosphate excretion than the other two groups. PTH failed to increase fractional phosphate excretion in the hyperparathyroid individuals, whereas there was a statistically significant increase in the other two groups. PTH was without significant effect on urinary calcium excretion in any of the three groups. There were no discernible differences between the responses of the hypercalciuric patients and those of the normal subjects. These findings suggest that while responses to PTH are normal in hypercalciuria, some hyperparathyroid patients are resistant to exogenous PTH. This resistance is limited to specific arms of the PTH response pathway and may not involve PTH receptors.

Adenylyl Cyclases↗
PubMed1990

Spontaneously occurring antibodies to parathyroid hormone.

A 76-yr-old female with acute pancreatitis and a normal/borderline elevated serum calcium level was found to have an elevated immunoreactive circulating PTH concentration using a C-terminal assay. This high PTH concentration misled the attending physicians and resulted, in retrospect, in an unnecessary neck exploration. When the patient's serum was examined it was found to contain a binding component that bound both C-terminal and PTH-(1-84). This binding component was not retained on a Sep-Pak column and was precipitated by antiserum directed against human immunoglobulin M. The presence of circulating anti-PTH immunoglobulin M explains the apparently high PTH concentrations measured by RIA. The antibodies occurred spontaneously. To the best of our knowledge, this phenomenon has not previously been described.

Acute Disease↗
PubMed1989

The use of PhastSystem crossed immunoelectrophoresis with immunoblotting to demonstrate a complex between glycoprotein Ib and the actin-binding protein (ABP) of human platelets.

The study shows how a technique described in an accompanying paper can be applied to solve a biological problem. The technique makes use of the observation that a monoclonal antibody that has been coprecipitated with its antigen during crossed immunoelectrophoresis can be transferred to a nitrocellulose membrane and visualized. Previous studies using crossed immunoelectrophoresis of Triton X-100 extracts of platelets have indicated that a particular immunoprecipitate (peak III) of the membrane receptor glycoprotein Ib (GP Ib) might contain a complex between the receptor and the actin-binding protein (filamin). When a monoclonal antibody (PM6/317) directed towards the actin-binding protein was added to a platelet extract prior to immunoelectrophoresis and blotting, this was visualized on the blot as a replica of the peak III immunoprecipitate. This demonstrates a colocalization of GP Ib and the actin-binding protein in the precipitate, and thus the existence of a complex between the membrane receptor and the cytoskeletal protein.

Antibodies, Monoclonal↗
PubMed1989

Ethanol reduces bone formation and may cause osteoporosis.

INTRODUCTION: The etiology of ethanol-associated osteopenia is not fully understood. In order to define the role of ethanol in the pathogenesis of hepatic osteodystrophy, we compared two groups of alcoholic patients with histologically established alcoholic liver disease. PATIENTS AND METHODS: Twenty-eight patients currently drinking ethanol ("drinkers") and 12 claiming not to have consumed any ethanol for at least six months ("abstainers") were enrolled in the study. In addition, 35 non-alcoholic control subjects without clinical or biochemical evidence of liver disease were also studied. Bone mineral density and various biochemical and hormonal values were measured in each subject; iliac crest biopsies were taken under local anesthesia in the patients and under general anesthesia in the control subjects. RESULTS: Forearm bone mineral densities, spinal bone mineral densities, and iliac crest cancellous bone areas were significantly lower in the alcoholic patients compared with control subjects (p less than 0.01 for all measurements), but these values did not differ between the drinkers and the abstainers. The drinkers, however, had significantly less osteoblastic activity than the abstainers, as assessed by dynamic bone histomorphometry (p less than 0.001). Serum bone Gla-protein concentrations were higher in the abstainers than in the drinkers (p less than 0.001). No differences were seen relating to histologic parameters of bone resorption, although the alcoholic patients who had lower serum free testosterone concentrations than the control subjects also had higher urinary hydroxyproline excretion rates. CONCLUSION: These data suggest that ethanol may be responsible for osteoblastic dysfunction resulting in diminished bone formation and reduced bone mineralization.

Alcoholism↗
PubMed1989

Myocardial slice: a physiological approach to beta-adrenergic ([3H] CGP-12177) receptor binding in hamster and guinea pig heart.

A new technique is described for the characterization and quantification of beta-adrenergic receptors in biologically viable slices of myocardium from the hamster right ventricle using the hydrophilic radioligand, [3H]CGP-12177 (CGP). Binding was stereospecific, saturable, of high affinity, reversible, displaceable by appropriate drugs, and highly positively correlated with increasing tissue concentrations. Bmax for CGP binding to myocardial slices from 50-day-old male Golden Syrian hamsters was 3.28 +/- 0.15 fmol/mg wet weight, while Kd was 0.21 +/- 0.02 nM. Freezing resulted in a close to 50% loss of receptor number with no apparent change in affinity. The slice preparation may be utilized to detect in vivo changes in myocardial cell surface receptors, as evidenced by the fact that the number of receptors in slices from ischemic guinea pigs was increased (Bmax = 15.5 +/- 1.25 fmol/mg wet wt) compared with sham-operated controls (Bmax = 10.4 +/- 0.38 fmol/mg wet wt). The minimal tissue disruption associated with this procedure, as well as its speed, simplicity, and relatively low cost, suggest that the myocardial slice preparation provides an important methodology for the study of beta-adrenergic receptor binding in the semiintact myocardium.

Adrenergic beta-Antagonists↗
PubMed1989

Characterization of muscarinic acetylcholine receptors in rat cerebral cortex slices with concomitant morphological and physiological assessment of tissue viability.

We have begun studies on regulatory mechanisms of muscarinic acetylcholine receptors (mAChRs) in slices of rat cerebral cortex. This paper, the first of two, deals with the viability of the cells in the slices (a prerequisite for studying receptor regulation) and provides a characterization of binding sites for [3H]N-methyl scopolamine ([3H]NMS) and [3H]quinuclidinyl benzylate ([3H]QNB) in this preparation. Trypan blue exclusion tests in 400-microns-thick cortical slices showed a number of dead cells in a 100 microns zone from each cut edge, for a total of about 15-30% of all cells in the slice. In agreement with previous reports, electron microscopy revealed healthy tissue in the middle of the slice, but after incubation for several hours, swollen cells and dendrites were seen without cytoplasmic organelles. Axon terminals, however, were still seen to synapse upon these processes. Electrophysiological single unit recordings showed spontaneous action potentials in the slices. For receptor binding experiments, slices were incubated with either [3H]NMS, a hydrophilic mAChR ligand which does not penetrate the cell membrane, or the lipophilic ligand [3H]QNB which readily enters cells. For both ligands, equilibrium binding was reached after 8 h at 4 degrees C, and after 3 h at 30 degrees C. Binding of both ligands could be displaced by unlabelled atropine sulphate, NMS or QNB. Saturation binding curves yielded a Bmax of 2187 fmol/mg protein for [3H]QNB (reflecting all mAChRs) and 1335 fmol/mg protein for [3H]NMS (only mAChRs on the cell surface) at 30 degrees C. Kd values were 8.2 and 5.2 nM for [3H]QNB and [3H]NMS, respectively. These values are high compared with values obtained from homogenates, frozen sections or dissociated cells, and presumably reflect the use of intact, living tissue. These data are probably a better reflection of the actual, in vivo mAChR number and affinity than those obtained from dead tissue. This slice preparation suggests itself as a simple but effective method with which to study the regulation of mAChRs in living brain tissue.

Animals↗
PubMed1989

A role for potassium channels in the regulation of cortical muscarinic acetylcholine receptors in an in vitro slice preparation.

The rules underlying muscarinic acetylcholine receptor (mAChR) regulation in an in vitro cortical slice preparation of adult rats were examined following various alterations of bioelectric activity and following agonist stimulation. Muscarinic ACh antagonists [3H]N-methyl scopolamine ([3H]NMS) or [3H]quinuclidinyl benzylate ([3H]QNB) were used to label cell surface vs total (i.e. surface and internal) receptors, respectively. Depolarization of neural membranes for 4 h at 22-37 degrees C using veratridine or high external potassium (K+) led to a temperature-dependent down-regulation of surface mAChR of 26.2% and 11.3%. Total mAChRs decreased by 37.6% and 8.1%. Addition of picrotoxin and glutamic acid also led to decreases in mAChRs. Increases in inward chloride ion current induced by gamma-aminobutyric acid (GABA) or gold chloride had no significant effect on mAChRs. Blockade of calcium channels and synaptic transmission by magnesium or cobalt and postsynaptic calcium channels with nifedipine showed a significant effect on mAChRs only in the latter case. In contrast, agonist stimulation using carbachol led to a large down-regulation for both [3H]NMS and [3H]QNB (26.1%, 35.9%). ACh decreased [3H]QNB binding by 33.9%, but had little effect on [3H]NMS binding (6.3%). For [3H]QNB binding sites the effects of carbachol appeared to summate with those of veratridine. Down-regulation of [3H]NMS labelled mAChRs by carbachol and veratridine had an estimated half-time of 30 min and 2 h, respectively. Neither the effects of veratridine nor carbachol could be antagonized by tetrodotoxin (TTX), showing that the effects were not due to an increase in sodium ion currents. However, a common thread linking the various agents which induce mAChR down-regulation appears to involve changes in potassium (K+) current. Potassium channel blockers tetraethylammonium chloride (TEA), 4-aminopyridine (4-AP) and apamin had little independent effect on mAChR number, but prevented veratridine-induced down-regulation, presumably through a blockade of K+- and Ca2+-dependent K+-channels. Only TEA and 4-AP diminished carbachol-induced down-regulation suggesting that this effect involves only the non Ca2+-dependent K+-channels. It thus appears that mAChR regulation in the rat cerebral cortex is linked to changes in active K+-channel currents: activation of the K+-channel by depolarization-induced changes in K+ current or by agonist stimulation leading to changes in the selective K+ currents stimulate mAChR down-regulation; blockage of the K+-channels prevents this down-regulation.

4-Aminopyridine↗
PubMed1989

Use of the lithotripter in the burned patient as an aid to mobilization.

A young lady with extensive burns and multiple fractures developed renal calculi, and repeated attacks of colic, accompanied by nausea and vomiting which delayed her hyperalimentation and mobilization. The insertion of J stents stopped these episodes of colic and the stones were eliminated by extracorporeal lithotripsy before the burn wounds were healed. Urinary infections cleared and rehabilitation thereafter was uncomplicated.

Adult↗
PubMed1989

Haemostasis in migraine.

There has been much discussion about the role of platelets in the pathogenesis of migraine. A new in vitro technique using a custom built device called the Haemostatometer measures haemostasis, thrombolysis, and coagulation from non-anticoagulated, undiluted (native) blood. Using this device, data were analysed from blood samples taken from 10 migraineurs between attacks and 10 control subjects. Results showed no difference in haemostasis, spontaneous thrombolysis or coagulation between migraineurs and control subjects.

Adolescent↗
PubMed1989

Response of tumors to therapy studied by 31P magnetic resonance spectroscopy.

Magnetic resonance (MR) methods have been used to study the metabolic and vascular response of model tumors to tumor necrosis factor (TNF). Magnetic resonance measurements demonstrated acute reductions in tumor blood flow, measured from tumor uptake of D2O, and in tumor adenosine triphosphate (ATP), measured by 31P magnetic resonance spectroscopy (MRS) following administration of TNF. The decrease in ATP generally followed reduction in tumor blood flow, and therefore was probably due to ischemia caused by damage to tumor vasculature. Superficial human tumors have been studied by MRS to characterize their 31P spectra, and to measure metabolic changes during therapy. The ratio of the intensities of the phosphomonoester (PME) and ATP resonances (PME/ATP) was much higher in tumors than in the normal tissue displaced by the tumors. During therapy, decreases in PME/ATP were detected that paralleled, but did not anticipate, decreases in tumor size. In some cases, a transient increase in PME/ATP was detected during therapy, which did not correlate with changes in tumor size, and which may reflect stimulation of cell growth in some tumor zones.

Adenosine Triphosphate↗
PubMed1989

Familial hypoparathyroidism due to an abnormal parathyroid hormone molecule.

The case of a 53-year-old man with familial hypoparathyroidism in the presence of circulating immunoreactive PTH is discussed. The patient responded to exogenous PTH by an increase in urinary cAMP excretion and by several post cyclase parameters including an increase in serum calcium and 1,25-dihydroxyvitamin D, an increase in urinary phosphate excretion and a decrease in urinary calcium. Immunoreactive PTH was detected in this patient's serum by three separate anti-PTH antisera. This immunoreactive PTH behaved aberrantly with these antisera. Nonparallelism to the standard curve was seen in two radioimmunoassays and the material was detected by an antiserum which preferentially binds bovine PTH. No circulating PTH binding activity was detectable. Family studies confirmed the genetic nature of the abnormality. HPLC studies revealed the presence of an abnormally hydrophobic fraction containing immunoreactive PTH. We believe these findings constitute strong evidence for the presence of an abnormal PTH molecule with reduced biological activity resulting in hypoparathyroidism.

Adult↗
PubMed1989

Seizure-induced delay of puberty in female rats: effects of age, stress and opioid antagonists.

We have shown that pre- and post-pubertal female rats are sensitive to seizures. For example, daily convulsions commencing at 24 days of age delay puberty. Here we examine the effect of seizures at various ages. In addition, because opioid peptides are implicated in regulating the onset of puberty and are activated by convulsions, we also investigate the effect of opioid antagonists in the seizure-induced delay of puberty. A single daily electroconvulsive shock (ECS) was given for 10 days to neonatal (days 2-11), infantile (days 15-24) and juvenile (days 22-31) rats. The treatment delayed vaginal opening (VO) in juvenile rats. Neonatal and infantile rats were unaffected. VO was also delayed by daily ECS for only 5 days in the late juvenile (days 27-31) period. The opioid receptor antagonists naloxone, naltrexone and nalmefene injected before and after single daily ECS were unable to block this effect of ECS on VO. To examine whether the effect of ECS is related to stress, we examined several stressors known to induce opioid-mediated alterations in gonadotrophin secretion. Footshock, immobilization and ether stress administered in the juvenile period (days 27-31) did not affect the timing of VO. In addition, rats anaesthetized with halothane, and then given ECS, still showed a delay of VO. These data demonstrate that rats in the late juvenile stage of development are most sensitive to convulsions. We also suggest that opioids are not critical to the mechanism by which the ECS disturbs puberty, and that ECS elicits its effect seemingly independently of the convulsive stress.

Aging↗
PubMed1989

Postnatal beta-adrenergic receptor [(3H] CGP-12177) binding in myocardial slices of cardiomyopathic hamsters.

A muscle slice technique was used to compare the development changes in binding of the beta-adrenergic antagonist, [3H]CGP-12177 (CGP), in right ventricles of male Canadian Hybrid Farms CHF 147 cardiomyopathic hamsters and two strains of control healthy animals, golden Syrian (GH) and CHF 148 albino noncardiomyopathic (AH) hamsters. CGP binding to myocardial slices was saturable, reversible, stereospecific, proportional to slice number and of high affinity. Bmax in GH and AH myocardium was not altered with age although there was a tendency to decrease between 16 and 30 days of age in both strains. In the cardiomyopathic ventricles, receptor number decreased between 30 (7.07 +/- 0.74 fmol/mg wet weight) and 60 days of age (4.58 +/- 0.52) (P less than 0.05) and remained at the lower level thereafter. Bmax in cardiomyopathics was slightly higher than that of either GH (5.01 +/- 0.88) or AH (5.05 +/- 0.82) at 30 days of age (P less than 0.05) but was not different at the other ages tested. Kd was decreased in GH at 30 days of age but was unaltered during postnatal development in either the AH or cardiomyopathic hearts. The elevated level of cell surface beta-adrenergic receptors in the cardiomyopathic ventricle at a time when necrotic lesions are developing may be important with respect to the pathogenesis of cardiomyopathy in these animals.

Age Factors↗
PubMed1989

Depth perception after prolonged usage of night vision goggles.

The present study was initiated following a report that a few helicopter pilots had failed a test of stereoscopic depth perception after a prolonged training flight employing night vision goggles (NVGs). In order to determine the cause of the loss, 12 helicopter pilots/copilots were assessed for depth perception, lateral and vertical phoria, and contrast sensitivity before and after training flights requiring the pilots to wear night vision goggles for the duration of the flight. Pilots flew one to three missions while wearing either PVS-5A or AN/AVS-6 goggles. Mission duration ranged from 1 to 4 h. The results indicate that contrast sensitivity and depth perception when monocular cues are present did not degrade over the course of the mission. Lateral phoria, however, did demonstrate an average exophoric shift of 1.5 prism diopters for 12 out of the 24 missions. The results indicate that the original report of a loss of depth perception based on a test of depth requiring stereopsis might have been caused by a shift in lateral phoria. It would be expected that as additional fusional effort is required, the minimum resolvable disparity degrades due to the increase in accommodation brought about through vergence accommodation. Possible causes for the phoria shift and future testing are discussed.

Accommodation, Ocular↗