Biomedical subjects
Publications and source records attributed to M Mark.
This paper highlights the diverse ways in which army mental health specialists can intervene as therapists, consultants and supervisors to the primary care physician and his team. Various consultation and collaboration approaches are described, as well as the need for army medical staff to participate in ongoing mental health training workshops.
A major challenge facing those caring for patients with ovarian carcinoma is inducing remission following the failure of first-line treatment. Toward this end, we have examined the efficacy of continuous infusion fluoropyrimidines. During a 2-year period, nine patients with recurrent ovarian carcinoma received treatment with continuous infusion 5-fluorouracil (5-FU) or 5-fluorouracil-deoxyribose as single agents or in combination with other drugs. Eight patients were evaluable, with responses obtained with each treatment regimen. Myelotoxicity was mild, with only 3 episodes of grade 4 toxicity out of 70 total cycles of chemotherapy. Mucositis was moderate to severe, tending to be the dose-limiting adverse effect. Continuous infusion 5-FU in these combinations appears to be active with very acceptable toxicity in heavily pretreated patients.
The effect of a single dose (60 mg p.o.) of the serotonin agonistic agent fenfluramine (FNF) on plasma cortisol, prolactin (PRL), growth hormone (GH), and immunoreactive beta-endorphin (ir-beta-EP) levels was assessed in eight major depressed patients and eight controls. The hormones were monitored at basal level (0') and hourly during 5 h following FNF administration. The pharmacological challenge caused an elevation of 80% in PRL secretion in the healthy controls and only 42% in the depressed patients. However, the actual prolactin response (delta max) failed to discriminate depressed patients from controls. A blunted response followed by a decrease (33%) in serum cortisol levels was observed in depressed patients 5 h after drug administration while an increase of 94% was obtained in controls after 3 h. FNF provocation did not affect GH and ir-beta-EP plasma levels. The blunted cortisol responsiveness to FNF administration in depressed patients may reflect functional hypoactivity of central serotonergic system at least during the acute phase of major depression. It is not clear why the cortisol hyporesponsivity in depressed patients is not accompanied by a similar reduced PRL response to FNF challenge.
Serotonin active transport by platelets of psychiatric patients was determined at 2 and at 8 a.m. Kinetic values, Vmax and Km, of serotonin uptake by platelets of bipolar depressive patients at 2 a.m. were higher than those at 8 a.m. Contrary to that, the kinetic values, Vmax and Km, for unipolar patients at 2 a.m. were rather lower than the values at 8 a.m. Serotonin uptake kinetics by platelets of schizophrenic patients at 2 a.m. were similar to those at 8 a.m. The curves of serotonin uptake kinetics by platelets of bipolar patients at 2 and at 8 a.m. were different from those observed for platelets of unipolar and schizophrenic patients. The variability of the kinetics of serotonin uptake by platelets of the three groups of psychiatric patients may offer a clue to the heterogenicity of these disorders.
Propylthiouracil and methylthiouracil have been shown to potentiate glucose-induced insulin secretion from rat pancreatic islets: the effect of methylthiouracil being less pronounced than that of propylthiouracil. In this study the effects of these substances on cAMP levels, 86Rb+ efflux, 45Ca2+ net uptake, and 45Ca2+ efflux were tested in isolated rat islets in order to obtain information on their possible mechanism of action. Propylthiouracil and to a lesser extent methylthiouracil increased islet cyclic AMP in a concentration-related manner. Maximum increases at the highest concentrations tested were 261% and 190% respectively. In the presence of 3 mM glucose propylthiouracil and methylthiouracil led to a decrease in the 86Rb efflux rate. With 5.6 mM glucose, both thiourea derivatives produced an increase in the 86Rb+ efflux rate which was independent of the presence or absence of calcium in the medium. Propylthiouracil and methylthiouracil augmented the 45Ca2+ efflux rate in the presence as well as in the absence of external calcium at various glucose concentrations. Propylthiouracil did not change, and methylthiouracil only slightly augmented, 45Ca2+ net uptake into the isolated islets. It is suggested that the synergistic effect of propylthiouracil and methylthiouracil on glucose-induced insulin release is at least in part due to an increase in islet cAMP levels. Whether the two substances have additional direct effects on ionic fluxes which contribute to their insulinotropic action or whether the observed changes in ion movements are secondary to the elevation of cAMP levels remains to be unclear and needs further investigation.
In rat pancreatic islets the effects of cholecystokinin-8 (CCK8) on glucose-mediated insulin release, 45Ca2+ net uptake, 45Ca2+ efflux, 86Rb+ efflux, cAMP- and cGMP levels were studied. In the presence of a substimulatory glucose concentration (3 mM) CCK8 concentrations of up to 1 microM had no effect on insulin release, but CCK8 at 10 nM potentiated the stimulatory effect of glucose (11.1 mM). 10 nM CCK8 enhanced glucose-stimulated 45Ca2+ net uptake but was ineffective at substimulatory glucose levels. CCK8 had no effect on cAMP and cGMP levels in the presence of 11.1 mM glucose, CCK8 increased 86Rb+ (a measure of K+) in the presence of both 3 and 11.1 mM glucose. This effect was abolished when Ca2+ was omitted from the perifusion medium. CCK8 did not alter glucose (11.1 mM)-stimulated 45Ca2+ efflux rate. These data indicate that (1) CCK8 potentiates glucose-stimulated insulin secretion possibly via an effect on Ca2+ uptake, 2) by affecting Ca2+ uptake, CCK8 enhances K+ efflux, and 3) CCK8 does not mediate its effect via cAMP or cGMP. With respect to 86Rb+ efflux the mechanism of CCK8 action appears to be different from that of glucose. When the mechanism of CCK action on islets is compared with that on exocrine pancreas (data from others) there are similarities (importance of Ca2+ uptake and non-importance of cAMP and cGMP).
1. The effect of glucose on 86Rb+ efflux, 45Ca2+ net uptake and insulin secretion of pancreatic islets from 3- and 24-month-old rats was studied. 2. Raising the glucose concentration from 3 to 5.6 and 16.7 mM had no effect on 86Rb+ efflux from islets of 24-month-old male rats whereas that from 24-month-old female rats was decreased. 3. At 16.7 mM-glucose, net uptake of 45Ca2+ was significantly diminished in islets of 24-month-old rats compared to islets of 3-month-old rats. 4. In the presence of 16.7 mM-glucose, islets of 24-month-old rats exhibited only 60-70% of the insulin release obtained with islets from 3-month-old rats. 5. Neither net uptake of 45Ca2+ nor insulin secretion appear to differ between the sexes. 6. These data suggest that the decreased insulin secretory response to glucose during old age is due, at least in part, to inadequate inhibition of K+ efflux and diminished net uptake of Ca2+.
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In pancreatic islets insulin secretion in response to a variety of stimulators is sensitive to the redox state of extracellular and intracellular thiols. In this connection variations of plasma glutathione (GSH) may also be of importance. In the process of stimulus-secretion coupling, membrane thiols play an important role. One major localization of critical thiols appears to be related to the influx of calcium through the voltage-dependent channel. Other transmembranal ion movements and the cAMP system seem to be less sensitive to thiol oxidation than calcium influx via voltage-dependent Ca channels.
It has been suggested that, during odontoblast differentiation, the extracellular matrix present at the epitheliomesenchymal junction modulates the activity of the cytoskeleton by means of membrane constituents (proteins, proteoglycans or gangliosides). To investigate this, we studied the interaction of iodinated fibronectin and type-I collagen with dissociated dental tissues and with membrane proteins prepared from these tissues. Isolated dental papillae and enamel organs were cultured for increasing periods of time in the presence of iodinated proteins. Fibronectin and type-I collagen were preferentially bound to dental papillae; however, after 6 h of incubation, fibronectin no longer interacted with the dental papillae, and the bound radioactivity was released. In the meantime, de novo synthesized fibronectin was deposited in the extracellular matrix of the dental papillae. Membrane proteins were prepared from isolated enamel organs and dental papillae. After sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis, these proteins were transferred to nitrocellulose by electroblotting and then incubated in the presence of either 125I-labelled fibronectin or 125I-labelled type-I collagen. Autoradiography confirmed the preferential interaction of fibronectin with the dental papilla. Fibronectin interacted with three high-molecular-weight proteins (Mr, 145,000, 154,000 and 185,000), which were not detected when membranes were prepared from enamel organs. Under the same conditions, type-I collagen did not interact with membrane proteins. The known interaction of type-I collagen with the plasma membrane of dental-papilla cells might be mediated either by another constituent of the extracellular matrix or by cell-surface-associated proteoglycans.
Ion movements and insulin secretion of pancreatic islets of adult and fetal rats have been studied at three glucose concentrations. In islets of adult rats, 86Rb efflux is maximally decreased by 5.6 mM-glucose. 16.7 mM-glucose caused a biphasic efflux pattern which may be due to glucose-stimulated Ca uptake. In islets of fetal rats elevation of the glucose concentration from 3 to 5.6 or 16.7 mM does not cause a change of 86Rb efflux, and the fractional efflux from fetal islets in the presence of 3 mM-glucose is similar to that from adult rat islets in the presence of 5.6 mM-glucose. Elevation of the glucose concentration from 3 to 16.7 mM is not associated with an increase in 45Ca uptake into fetal islets, although this change in glucose concentration doubles 45Ca uptake into adult islets. When challenged with 16.7 mM-glucose, fetal islets exhibit no insulin secretory response; however, they do respond to theophylline. It is concluded that the failure of fetal islets to exhibit an insulin-secretory response when challenged with glucose might be related to the inability of glucose to affect 86Rb efflux and Ca uptake. The present data are discussed in light of differences between pancreatic islets of fetal and adult rats with respect to the redox state of pyridine nucleotides, thiols and glucose metabolism.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
A new tricyclic agent with an allenyl side chain experimentally shows antidepressant activity similar to amitriptyline and imipramine but also exerts marked CNS depression. Such dual activity should be of clinical interest for treatment of mixed anxiety and depression.