Biomedical subjects
Publications and source records attributed to A J Cooper.
This report describes the investigation of a spontaneous grand mal seizure in a 55-year old woman, being treated with drugs and ECT for depression. The spontaneous seizure was due to hyponatremia caused by self-induced water intoxication, although psychotrophic medication may have contributed by lowering the seizure threshold. The diagnosis of hyponatremia is discussed.
Fourteen males with major depressive illness (DSM-III) received a course of electroconvulsive therapy (ECT). Serum prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone (T), were measured 15 minutes before and 15 minutes after each treatment. The severity of depression was assessed with the Hamilton Rating Scale for Depression (HRSD) two to three days before the first and two to three days following the last treatment. Post-ECT levels of PRL and LH were significantly higher than pre-ECT levels across every treatment. Changes in FSH and testosterone were not significant. There were no relationships between hormone levels (first versus last ECT) and severity of depression, including sexual functioning. It is argued that the relatively greater increases of LH than FSH is due to an acute antidopaminergic action of ECT which acts selectively on the secretion of the former. The blunted testosterone response to the increase of gonadotropins may be due to ECT-induced hyperprolactinemia.
The cheese reaction following use of the irreversible monoamine oxidase inhibitors (MAOIs) began to be reported in the UK with increasing frequency from about 1961. By 1965, the underlying mechanism (tyramine-provoked hypertension) had been essentially elucidated. Thereafter, this potentially severe side-effect could have been largely avoided by the use of fairly simple dietary precautions. Unfortunately, suspicion and fear burgeoned, and both the seriousness and the frequency of risk were dramatically inflated. This was a major factor in the subsequent general disuse of the irreversible MAOIs. Second-generation MAOIs which are selective for monoamine oxidase-A and B are now being synthesised and may eliminate the eventuality of hypertension without special dietary precautions.
Tracer quantities (in 0.2 ml) of 13N-labeled glutamate, alanine, or glutamine(amide) were administered rapidly (less than or equal to 2 s) via the portal vein of anesthetized adult male rats. Liver content of tracer at 5 s was 57 +/- 6 (n = 6), 24 +/- 1 (n = 3), and 69 +/- 7 (n = 3)% of the injected dose, respectively. Portal-hepatic vein differences for the corresponding amino acids were 17 +/- 6, 26 +/- 8, and 19 +/- 9% (n = 4), respectively, suggesting some export of glutamate and glutamine, but not of alanine, to the hepatic vein. Following L-[13N]glutamate administration, label rapidly appeared in liver alanine and aspartate (within seconds). The data emphasize the rapidity of nitrogen exchange via linked transaminases. By 30 s following administration of either L-[13N]glutamate or L-[13N]alanine, label in liver glutamate was comparable; yet, by 1 min greater than or equal to 9 times as much label was present in liver glutamine(amine) following L-[13N]glutamate administration than following L-[13N]alanine administration. Conversely, label in liver urea at 1 min was more pronounced in the latter case despite: (a) comparable total pool sizes of glutamate and alanine in liver; and (b) label incorporation from alanine into urea must occur via prior transfer of alanine nitrogen to glutamate. The data provide evidence for zonal differences in uptake of alanine and glutamate from the portal vein in vivo. The rate of turnover of L-[amide-13N]glutamine was considerably slower than that of L-[13N]alanine or of L-[13N]glutamate, presumably due in part to the higher concentration of glutamine in that organ. Nevertheless, it was possible to show that despite occasional suggestions to the contrary, glutamine(amide) is a source of urea nitrogen in vivo. The present findings continue to emphasize the rapidity of nitrogen exchange reactions in vivo.
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Intracardiac injection, in hooded Lister rats, of syngeneic MC28 sarcoma cells never induced tumour growth in normal bowel. Tumour growth occurred at the site of a colonic anastomosis if surgery preceded tumour injection but not if it followed tumour injection, even by as little as 1 h. Maximum enhancement of tumour growth occurred when the healing process had progressed between 2 and 8 days, with a peak at 5 to 7 days. The enhancing effect was largely over by the time the healing had progressed 14 days. The syngeneic OES5 breast carcinoma also grew at colonic anastomoses when surgery preceded tumour injection by 5 days, but not in normal colon. The MC28 sarcoma also grew at ileal anastomoses but not in the normal ileum after intracardiac injection. By injecting radiolabelled sarcoma cells, an estimate of the probability of a single bloodborne tumour cell lodging at a colonic anastomosis and leading to a tumour deposit was calculated to be of the order of 1:43 whereas the probability of the cell lodging in normal colon and causing a deposit is less than 1:4 x 10(4).
Both ammonia and beta-methylene-DL-aspartate (beta-MA), an irreversible inhibitor of aspartate aminotransferase activity and thus of the malate-aspartate shuttle, were found previously to decrease oxidative metabolism in cerebral cortex slices. In the present work, the possibility that ammonia and beta-MA affect energy metabolism by a common mechanism (i.e., via inhibition of the malate-aspartate shuttle) was investigated using primary cultures of neurons and astrocytes. Incubation of astrocytes for 30 min with 5 mM beta-MA resulted in a decreased production of 14CO2 from [U-14C]glucose, but did not affect 14CO2 production from [2-14C]pyruvate. Conversely, incubation of astrocytes with 3 mM ammonium chloride resulted in decreased 14CO2 production from [2-14C]pyruvate, but 14CO2 production from [U-14C]glucose was not significantly affected. Ammonium chloride had no significant effect on 14CO2 production from either [U-14C]glucose or [2-14]pyruvate by neurons. However, incubation of neurons with beta-MA or beta-MA plus ammonium chloride resulted in a approximately 45% decrease of 14CO2 production from both [U-14C]glucose and [2-14C]pyruvate. A 2-h incubation of astrocytes with beta-MA resulted in no change in ATP levels, but a 35% decrease in phosphocreatine. Similar treatment of neurons resulted in greater than 50% decrease in ATP, but had little effect on phosphocreatine. beta-MA also caused a decrease in glutamate and aspartate content of neurons, but not of astrocytes. The different metabolic responses of neurons and astrocytes towards beta-MA were probably not due to a differential inhibition of aspartate aminotransferase which was inhibited by approximately 45% in astrocytes and by approximately 55% in neurons.
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A retrospective examination of all patients referred by the emergency department of a medium sized general hospital for a mandated Form I psychiatric assessment during a 12 month period was conducted. The principal aim was an analysis of the clinical phenomena and especially the antecedents and course of violent behaviour (following admission and throughout the hospital stay) which in the majority of cases was the reason for the referral. Thirty percent had behaved violently prior to admission but within 24 hours all had settled and during the remainder of their hospital stay were indistinguishable from the generality of the ward population (for example, non-violent). Two-thirds of the patients were non-psychotic; that is, not suffering from a major mental illness; nevertheless, they required a disproportionate amount of time and effort in initial management. A high proportion had several prior admissions to the psychiatric ward, particularly for alcohol misuse and/or a personality disorder.
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The short-term metabolic fate of [13N]ammonia in the livers of adult male, anesthetized rats was determined. Following a bolus injection of tracer quantities of [13N]ammonia into the portal vein, the single pass extraction was approximately 93%, in good agreement with the portal-hepatic vein difference of approximately 90%. High performance liquid chromatographic analysis of deproteinized liver samples indicated that labeled nitrogen is exchanged rapidly among components of: mitochondrial aspartate aminotransferase and glutamate dehydrogenase reactions and cytoplasmic aspartate aminotransferase and alanine aminotransferase reactions (t1/2 for the exchange of label toward equilibrium is on the order of seconds). Comparison of specific activities of glutamate and ammonia suggests that at 5 s most labeled glutamate was mitochondrial, whereas at 60 s approximately 93% was cytosolic; this change is presumably brought about by the combined action of the mitochondrial and cytosolic aspartate aminotransferases and the aspartate carrier of the malate-aspartate shuttle. Specific activity measurements of glutamate, alanine, and aspartate are in accord with the proposal by Williamson et al. (Williamson, D.H., Lopes-Vieira, O., and Walker, B. (1967) Biochem. J. 104, 497-502) that the components of the aspartate aminotransferase reaction are in thermodynamic equilibrium, whereas the components of the alanine aminotransferase reaction are in equilibrium but compartmented in the rat liver. Despite considerable label in citrulline at early time points, no radioactivity (less than or equal to 0.25% of the total) was detected in carbamyl phosphate, suggesting very efficient conversion to citrulline with little free carbamyl phosphate accumulating in the mitochondria. Our data also show that some portal vein-derived ammonia is metabolized to glutamine in the rat liver, but the amount is small (approximately 7% of that metabolized to urea) in part because liver glutamine synthetase is located in a small population of perivenous cells "downstream" from the urea cycle-containing periportal cells. Finally, no tracer evidence could be found for the participation of the purine nucleotide cycle in ammonia production from aspartate. The present work continues to emphasize the usefulness of [13N]ammonia for short-term metabolic studies under truly tracer conditions, particularly when turnover times are on the order of seconds.
Cells exfoliated from colorectal cancers may only be implicated in local recurrence if they are proven to be viable and capable of growth. Thirty patients with primary colorectal cancer were studied. Cells were obtained from primary tumour, uninvolved mucosa, mesorectum, lumen of the bowel, luminal mucus, serosal surface of the bowel and from washings of the tumour bed after dissection. Colonies grew in vitro in monolayer culture from 21/30 primary tumours; 11/41 mesorectum specimens; 11/27 luminal washings; 14/29 luminal mucus specimens; 1/27 serosal surface washings and 3/13 post-dissection washes. Colonies stained positively for the epithelial markers cytokeratin and desmosomes and also for carcinoembryonic antigen. Cells capable of in vitro growth are present in these various sites and, if spilled at operation, may well be implicated as one of the factors leading to local recurrence.
The radiation-sensitive rad mutants of the yeast Saccharomyces cerevisiae exhibit a complex pattern of sensitivity to simple monofunctional alkylating agents. The RAD1, RAD2, RAD4 and RAD14 genes of the RAD3 epistasis group are implicated in the repair of ethylations to DNA. The RAD3, RAD10 and RAD16 genes of this group are not involved. The RAD4 and RAD14 genes have a particular role in repair following exposure to those ethylating agents that preferentially alkylate oxygen, but not to those that preferentially ethylate nitrogen. The RAD1 and RAD2 genes are involved in the repair of damage induced by all the ethylating agents used except EMS. The mutants in this group that are sensitive to ENU were not sensitive to MNU, suggesting that nucleotide excision operates on ethylations but not on methylations. In the RAD6 group, the RAD6 and RAD18 genes are involved in DNA repair after exposure to all the alkylating agents tested, whereas RAD8 appears to have a role in the repair of O-alkylations but not N-alkylations. RAD9 operates in the repair of methylations and ethylations, but does not influence events after exposure to EMS. In the RAD52 group, the mutants tested were sensitive to ENU and DES. Thus some members of all three epistasis groups are involved in the repair of alkylations to DNA.
A method for the fluorometric determination of alpha-ketosuccinamic acid, the alpha-keto acid analog of asparagine, is described. The procedure involves the hydrolysis of alpha-ketosuccinamate to oxaloacetate by omega-amidase followed by NADH-dependent reduction of oxaloacetate to malate by malate dehydrogenase. A correction for endogenous oxaloacetate is made by using control samples lacking omega-amidase. Of the rat tissues investigated, liver contained the highest concentration, followed by kidney (53 +/- 6 (n = 11) and 18 +/- 3 (n = 3) mumol/kg wet wt, respectively). alpha-Ketosuccinamate was not detected in brain (less than 8 mumol/kg wet wt). Some chemical properties of alpha-ketosuccinamate were investigated. Concentrated solutions of sodium alpha-ketosuccinamate frozen for extended periods and the solid sodium salt of alpha-ketosuccinamate dimer heated to 130 degrees C are converted to at least 10 products by processes involving dimerization, dehydration, and decarboxylation. Isobutane chemical ionization mass spectral analysis (170-230 degrees C) of the free acid monomer yielded similar products. Many of the breakdown products were identified as di- and monoheterocyclic compounds, some of which are known to be of biological importance.
The VCD is a mechanical device that produces an erection by creating a vacuum of up to 250 mm Hg. Up to now, it has been used in patients with organic impotence (mainly diabetic) with a high level of success and minimal side effects. This study reports preliminary findings on the application of the VCD in both organic (e.g. diabetics) and psychogenic cases of impotence. All subjects were able to develop an adequate erection with the instrument making intercourse possible. However, the frequency of use dropped sharply as the study progressed and some subjects and their sexual partners expressed reservations about continuing with it. Mild numbness in the penis was experienced by several users.
In basic solutions, pyruvate enolizes and reacts (through its 3-carbon) with the 4-carbon of the nicotinamide ring of NAD+, yielding an NAD-pyruvate adduct in which the nicotinamide ring is in the reduced form. This adduct is a strong inhibitor of lactate dehydrogenase, presumably because it binds simultaneously to the NADH and pyruvate sites. The potency of the inhibition, however, is muted by the adduct's tendency to cyclize to a lactam. We prepared solutions of the pyruvate adduct of NAD+ and of NAD+ analogues in which the -C(O)NH2 of NAD+ was replaced with -C(S)NH2, -C(O)CH3, and -C(O)H. Of the four, only the last analogue, 3-[4-(reduced 3-pyridine aldehyde-adenine dinucleotide)]-pyruvate (RAP) cannot cyclize and it was found to be the most potent inhibitor of beef heart and rat brain lactate dehydrogenases. The inhibitor binds very tightly to the NADH site (Ki approximately 1 nM for the A form). Even at high concentrations (20 microM), RAP had little or no effect on rat brain glyceraldehyde-3-phosphate, pyruvate, alpha-ketoglutarate, isocitrate, soluble and mitochondrial malate, and glutamate dehydrogenases. The glycolytic enzymes, hexokinase and phosphofructokinase, were similarly unaffected. RAP strongly inhibited lactate production from glucose in rat brain extracts but was less effective in inhibiting lactate production from glucose in synaptosomes.
An alkaline, followed by an acid-going transient, characterizes acid-base changes in the interstitial space during spreading depression in a variety of brain structures. In rat, such changes are associated with a significant rise in brain lactate content. How brain proton buffers behave during spreading depression is unknown. Techniques to significantly improve the response time of gas permeable membrane semimicroelectrodes for carbon dioxide and ammonia are reported. Measurements with such electrodes, when coupled to measurements of hydrogen ion concentration (from microelectrodes), permit rapid changes to be determined in bicarbonate concentration or ammonia and ammonium ion concentration, respectively. Bicarbonate concentration fell from 30 +/- 1 (n = 16) to 14 +/- 1 mM (n = 16) during spreading depression. On the other hand, ammonia concentration rose from 2.3 +/- 0.1 to 4.4 +/- 0.3 microM (n = 17) while ammonium ion concentration rose from 116 +/- 11 (n = 17) to 382 +/- 30 microM (n = 17) during spreading depression. Bicarbonate changes probably reflect titration of brain bicarbonate stores by accumulated lactic acid. Similar physicochemical changes do not explain the rise in ammonia and ammonium ion concentrations. Instead, elevation of the latter can only result from an increase in ammonia content of the interstitial space.