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Biomedical subjects

A J Cooper

Publications and source records attributed to A J Cooper.

At least 127 records · Page 7Linked to original sources
PubMed1992

The long-term use of cyproterone acetate in pedophilia: a case study.

This investigation reports the long-term use of the antiandrogen cyproterone acetate (CPA) in a pedophile, who was studied continuously over 38 months. Measures of sexual arousal, serum testosterone, and gonadotropin levels were significantly reduced by the drug as compared with placebo and no treatment; prolactin levels were significantly elevated. Some workers have observed that long-term administration of CPA (more than one year, which was then discontinued) produced enduring (in some cases apparently permanent) anti-libidinal effects; however, in the case described, within three weeks of stopping the drug, all measures had returned to pretrial levels. The importance of continuous long-term monitoring in sex offenders receiving an antiandrogen is discussed.

Adult↗
PubMed1992

Stable and specific association between the yeast recombination and DNA repair proteins RAD1 and RAD10 in vitro.

The RAD1 and RAD10 genes of Saccharomyces cerevisiae are two of at least seven genes which are known to be required for damage-specific recognition and/or damage-specific incision of DNA during nucleotide excision repair. RAD1 and RAD10 are also involved in a specialized mitotic recombination pathway. We have previously reported the purification of the RAD10 protein to homogeneity (L. Bardwell, H. Burtscher, W. A. Weiss, C. M. Nicolet, and E. C. Friedberg, Biochemistry 29:3119-3126, 1990). In the present studies we show that the RAD1 protein, produced by in vitro transcription and translation of the cloned gene, specifically coimmunoprecipitates with the RAD10 protein translated in vitro or purified from yeast. Conversely, in vitro-translated RAD10 protein specifically coimmunoprecipitates with the RAD1 protein. The sites of this stable and specific interaction have been mapped to the C-terminal regions of both polypeptides. This portion of RAD10 protein is evolutionarily conserved. These results are the first biochemical evidence of a specific association between any eukaryotic proteins genetically identified as belonging to a recombination or DNA repair pathway and suggest that the RAD1 and RAD10 proteins act at the same or consecutive biochemical steps in both nucleotide excision repair and mitotic recombination.

Base Sequence↗
PubMed1992

The effects of cyproterone acetate on sleeping and waking penile erections in pedophiles: possible implications for treatment.

This study reports the short term effects in five pedophiles of the antiandrogenic drug cyproterone acetate (CPA) on nocturnal penile tumescence (NPT); penile responses to erotic stimuli in the laboratory; and sex hormones (testosterone, LH, FSH and prolactin). During the administration of CPA, NPT, laboratory arousal and hormone measures (except prolactin) all decreased. Waking laboratory measures were influenced less and were more variable (one subject showed greater arousal) than NPT measures. The changes in NPT closely paralleled the reduction in testosterone. The results are discussed with reference to the known psycho-neuroendocrinology of sleeping and waking erections.

Cyproterone↗
PubMed1992

A double-blind placebo controlled trial of medroxyprogesterone acetate and cyproterone acetate with seven pedophiles.

Seven of ten pedophiles in hospital completed a double-blind, placebo-controlled two-dose comparison of medroxyprogesterone acetate and cyproterone acetate. Sequential measures during the 28 week study were: patient self-reports, nurses' observations, phallometry, hormone levels and side-effects. The drugs, which performed equivalently, reduced sexual thoughts and fantasies, the frequency of early morning erections on awakening, the frequency and pleasure of masturbation, and level of sexual frustration. Penile responses were also reduced but to a lesser degree and were more variable. Serum testosterone FSH and LH all declined during drug administration, but by the end of the final placebo phase had essentially returned to (or exceeded) pre-drug values. Our experience suggests that only a minority of pedophiles are likely to accept libido-reducing drugs.

Adult↗
PubMed1992

Thiamin and Alzheimer's disease.

Because of clinical and neuropathological overlap between the characteristics of dementia of the Alzheimer type (DAT) and of a human thiamin deficiency syndrome (Wernicke-Korsakoff syndrome), thiamin pyrophosphate (TPP) dependent processes have been studied in DAT brain and other tissues. The activities of 3 TPP-dependent enzymes are reduced in DAT brain: transketolase (TK), the pyruvate dehydrogenase complex (PDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC). Quantitatively, the most marked reductions are in KGDHC (to less than 20% of normal). In cultured skin fibroblasts, KGDHC activity is reduced to 50-60% of normal, TK activity to 80-90% of normal, and PDHC is normal. Structural and molecular studies of the DAT and non-DAT enzymes are in process. A lesion of KGDHC may be related to the pathogenesis of DAT. Treatment with large doses of thiamin has not been beneficial, but the data are not totally negative. Further studies of thiamin-dependent mechanisms in DAT seem justified.

Alzheimer Disease↗
PubMed1991

Glutamine transaminase K and cysteine S-conjugate beta-lyase activity stains.

An activity stain to detect glutamine transaminase K subjected to nondenaturing polyacrylamide gel electrophoresis (ND-PAGE) was developed. The gel is incubated with a reaction mixture containing L-phenyl-alanine, alpha-keto-gamma-methiolbutyrate (alpha KMB), glutamate dehydrogenase, phenazine methosulfate (PMS) and nitroblue tetrazolium (NBT). Glutamine transaminase K catalyzes a transamination reaction between phenylalanine and alpha KMB. The resultant methionine is a substrate of glutamate dehydrogenase. The NADH formed in the oxidative deamination of methionine reacts with PMS and NBT to form a blue band on the surface of the gel coincident with glutamine transaminase K activity. Cysteine S-conjugate beta-lyase activity is detected in the gel by incubating the gel with a reaction mixture containing alpha KMB (to ensure maintenance of the enzyme in the pyridoxal 5'-phosphate form), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), PMS, and NBT. The products of the lyase reaction interact with PMS and NBT to form a blue dye coincident with the lyase activity. In addition, a new assay procedure for measuring cysteine S-conjugate beta-lyase activity was devised. This procedure couples pyruvate formation from DCVC to the alanine dehydrogenase reaction. Preparations of purified rat kidney glutamine transaminase K yield a single protein band on ND-PAGE (apparent Mr approximately 95,000). This band coincides with both the cysteine S-conjugate beta-lyase and glutamine transaminase K activities. Activity staining showed that homogenates of rat kidney, liver, skeletal muscle, and heart possess a glutamine transaminase K/cysteine S-conjugate beta-lyase activity with an Rf value on ND-PAGE identical to that of purified rat kidney glutamine transaminase K.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Importance of the omentum in the development of intra-abdominal metastases.

Areas of trauma are preferred sites for metastatic tumour growth. In extensive intra-abdominal tumour recurrence the omentum is invariably involved. The importance of the omentum in the development of tumours at sites of intra-abdominal trauma has been investigated. Colonic anastomoses were performed in Hooded-Lister rats with and without omentectomy. Animals received intraluminal or intraperitoneal injections of a syngeneic tumour. With intraluminal injection, tumour occurred at the anastomosis and in the omentum in 38 and 43 per cent of animals respectively but following omentectomy the values were 14 and 9 per cent (omental remnant). With intraperitoneal administration tumour occurred in 53 per cent at the anastomosis and in 79 per cent in the omentum compared with 16 and 29 per cent (in omental remnant) following omentectomy. In this model a reduced ability of an anastomosis to support 'seeded' tumour following removal of the omentum is demonstrated and the development of local recurrence from spilled tumour cells during operation may be enhanced by, or be dependent on, the proximity of the omentum.

Anastomosis, Surgical↗
PubMed1991

Neurotoxicity of ammonia and fatty acids: differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme A derivatives.

In several metabolic encephalopathies, hyperammonemia and organic acidemia are consistently found. Ammonia and fatty acids (FAs) are neurotoxic: previous workers have shown that ammonia and FAs can act singly, in combination, or synergistically, in inducing coma in experimental animals. However, the biochemical mechanisms underlying the neurotoxicity of ammonia and FAs have not been fully elucidated. FAs are normally converted to their corresponding CoA derivatives (CoAs) once they enter cells and it is known that these fatty acyl CoAs can alter intermediary metabolism. The present study was initiated to determine the effects of ammonia and fatty acyl CoAs on brain mitochondrial dehydrogenases. At a pathophysiological level (2 mM), ammonia is a potent inhibitor of brain mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC). Only at toxicological levels (10-20 mM) does ammonia inhibit brain mitochondrial NAD(+)- and NADP(+)- linked isocitrate dehydrogenase (NAD-ICDH, NADP-ICDH), and NAD(+)-linked malate dehydrogenase (MDH) and liver mitochondrial NAD-ICDH. Butyryl- (BCoA), octanoyl- (OCoA), and palmitoyl (PCoA) CoA were potent inhibitors of brain mitochondrial KGDHC, with IC50 values of 11, 20, and 25 microM, respectively; moreover, the inhibitory effect of fatty acyl CoAs and ammonia were additive. At levels of 250 microM or higher, both OCoA (IC50 = 1.15 mM) and PCoA (IC50 = 470 microM) inhibit brain mitochondrial NADP-ICDH; only at higher levels (0.5-1 mM) does BCoA inhibit this enzyme (by 30-45%). Much less sensitive than KGDHC and NADP-ICDH, brain mitochondrial NAD-ICDH is only inhibited by 1 mM BCoA, OCoA, and PCoA by 22%, 35%, and 44%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl Coenzyme A↗
PubMed1991

A prospective study of patient assaults on nurses in a provincial psychiatric hospital in Canada.

A 27-month prospective study was conducted of patient assaults on nurses in a Canadian psychiatric hospital. Rates were low (4% of the patients committing an assault) and the injuries mostly trivial. Schizophrenics accounted for 43% of attacks, but when allowance was made for the disproportionate number of patients in the hospital with this diagnosis, individuals with mental retardation or dementia were approximately twice as likely to be assaultive as schizophrenics. Repeat assaulters (greater than 4 attacks) were more likely to be suffering from paranoid schizophrenia.

Adolescent↗
PubMed1991

Evaluation of I-C papaverine in patients with psychogenic and organic impotence.

Forty men with organic or psychogenic impotence, who were highly motivated for treatment, were offered instruction in the intracavernosal (I-C) self-injection of papaverine and regular ongoing supervision by the investigator. Twenty declined immediately, citing a number of reasons, notably qualms about pain of the injection, side-effects and the unnaturalness of the method. Eleven patients discontinued the drug within 11 months; nine used it for at least one year, and all were continuing with it albeit less frequently at the time of assessment. Those who discontinued treatment differed significantly from those who did not; the latter initially used the drug less frequently (less than once per month), did not have a regular sexual partner or had a poor relationship with their sexual partner, and reported a decline in libido during use of the drug. The findings suggest that I-C papaverine, although effective in treating impotence, is not a panacea, and a large percentage of users (55% in our study) are likely to discontinue the drug within a relatively short period of time.

Adult↗
PubMed1991

Monocyte-derived giant cell formation in patients with breast cancer.

Recent reports of monocyte-derived giant cell formation in breast cancer and associated retroviral findings have attracted much interest in the scientific literature and with the media, revitalising hypotheses of a viral role in the aetiology of the disease. We describe an assay developed to investigate further the giant cell forming phenomenon and report results which conflict with earlier work. We observed a smaller proportion of patients with breast cancer forming giant cells than in previous reports. Conversely, a much larger proportion of controls formed giant cells. Using our assay to calculate a fusion index the formation of giant cells, as defined in earlier work, was found to be a poor indicator of the degree of cell fusion in our samples. We discuss our experiences with the assay and suggest the calculation of a fusion index as a more comparable and quantitative measurement of cell fusion.

Adolescent↗
PubMed1990

Short-term metabolic fate of L-[13N]glutamate in the Walker 256 carcinosarcoma in vivo.

In vivo studies with L-[13N]glutamate in the Walker 256 carcinosarcoma implanted under the renal capsule of female Sprague-Dawley rats demonstrate that uptake of glutamate and the rate of incorporation of the nitrogen label from this amino acid into metabolites is slower in the tumor than in nontumorous kidney tissue. Glutamate dehydrogenase, glutaminase, and alanine aminotransferase activities are significantly lower within the tumor than within the adjoining kidney. However, the tumor expresses high levels of aspartate aminotransferase, attesting to the importance of this enzyme in the metabolism of glutamate. Indeed, high performance liquid chromatographic analysis showed that the principal metabolic fate of label derived from L-[13N]glutamate in the tumor is incorporation into aspartate. Measurement of specific activity ratios of glutamate to aspartate shows that the transfer of nitrogen from glutamate to aspartate is rapid and that equilibration of label among components of the aspartate aminotransferase reaction is attained within minutes after tumor uptake. Analyses of the nontumorous portion of the implanted kidney also showed that aspartate is the major recipient of glutamate nitrogen. However, high performance liquid chromatographic analyses of deproteinized tissue revealed that glutamine and ammonia are also significant 13N-labeled metabolites formed from L-[13N]glutamate within the kidney. Proportionately lower amounts of these labeled metabolites were found in the tumor.

Animals↗
PubMed1990

Inhibition of the bovine branched-chain 2-oxo acid dehydrogenase complex and its kinase by arylidenepyruvates.

A novel class of inhibitors for the branched-chain 2-oxo acid dehydrogenase (BCOAD) complex has been synthesized and studied. The sodium salts of arylidenepyruvates: e.g., furfurylidenepyruvate (compound I), 4-(3-thienyl)-2-oxo-3-butenoate (compound II), cinnamalpyruvate (compound III) and 4-(2-thienyl)-2-oxo-3-butenoate (compound IV) inhibit the overall and kinase reactions of the BCOAD complex from bovine liver. Inhibitions of the overall reaction occur at the decarboxylase (E1) step as determined by a spectrophotometric assay with 2,6-dichlorophenolindophenol as an electron acceptor. Inhibition of the E1 reaction by compound I (Ki = 0.5 microM) is competitive, whereas inhibitions by compounds II (Ki = 150 microM) and III (Ki = 500 microM) are non-competitive with respect to the substrate 2-oxoisovalerate. The Km value for 2-oxoisovalerate is 6.7 microM as measured by the E1 assay. Inhibition of the E1 step by compounds I, II and III are reversible at low inhibitor concentrations based on the Michaelis-Menten kinetics observed. By comparison, compound I does not significantly inhibit pyruvate and 2-oxoglutarate dehydrogenase complexes. The arylidenepyruvates (compounds I, II and IV) inhibit the BCOAD kinase reaction in a manner similar to the substrate 2-oxo acids. The inhibition of the kinase reaction by compound I is non-competitive with respect to ATP, with an apparent Ki value of 4.5 mM. The results suggest that arylidenepyruvates may be useful probes for elucidating the reaction mechanisms of the BCOAD complex and its kinase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1990

Blood transfusion and recurrence of colorectal cancer: the role of platelet derived growth factors.

Efforts to explain the possible effects of blood transfusion on the recurrence of colorectal cancer have been based entirely on the immunosuppressive effects of blood transfusion. However, the relationship between solid tumour development and the immune system is inconclusive. We have investigated an alternative mechanism involving the potential role of growth factors in this phenomenon. Using a human fibroblast: [125I]deoxyuridine uptake mitogenesis assay, the relative amounts of growth factor in the plasma of stored blood were measured. There was a progressive increase in mitogenesis from day 0 (n = 6) to day 28 (n = 6; P less than 0.001, Mann-Whitney U test). The effect of growth factors on the development of liver and intraperitoneal metastases was studied in Hooded Lister rats. Following an intraportal injection of 10(5) MC28 tumour cells, the experimental group (n = 25) received 2 ml of syngeneic serum intravenously for 4 days. Likewise, colonic anastomoses were performed on omentectomized rats and the peritoneal cavity seeded with 10(3) cells. The experimental groups (n = 20) received either 2 ml serum intravenously repeatedly or 3 ml serum intraperitoneally (n = 19). There was no significant increase in liver metastases or peritoneal disease following intravenous infusion of serum but serum delivered intraperitoneally resulted in a significant increase in tumour from 22 per cent in the controls to 89 per cent in the study group (P less than 0.01). Growth factors released from platelets following blood loss into the peritoneal cavity may be important in enhancing local recurrence of colorectal cancer.

Anastomosis, Surgical↗
PubMed1990

Ammonia metabolism in normal and portacaval-shunted rats.

Ammonia is generated from a large number of metabolically important reactions. Despite its central importance in whole body nitrogen homeostasis excess ammonia is neurotoxic and its concentration must be kept low. Ammonia generated in most extrahepatic tissues is detoxified by incorporation into glutamine (amide). This glutamine may be used in a number of biosynthetic reactions (e.g. in pyrimidine synthesis). Alternatively, as a means of maintaining nitrogen balance, glutamine may be released to the blood. Resting skeletal muscle is particularly important 1) as a "sink" for removal of blood ammonia, and 2) as a major source of circulating glutamine. However, during vigorous exercise skeletal muscle may become a net contributor of ammonia to the blood. A few tissues and cell types (e.g. lymphocytes, macrophages, enterocytes, colonocytes, thymocytes, fibroblasts, bone) and tumors exhibit marked rates of glutamine utilization. In the kidney, glutamine is an important source of urinary ammonia. Ammonia generated from 1) the breakdown of nitrogenous substances in the gut, and 2) from the use of glutamine as a metabolic fuel in the small intestine, is taken up by the liver wherein it is detoxified by conversion to urea and to a lesser extent, glutamine. Some portal vein glutamine acts as a source of urea nitrogen. Ultimately, however, most excess ammonia nitrogen is detoxified indirectly (via glutamine (blood)----glutamine (small intestine)----ammonia (portal vein) or directly in the liver as urea. Portal-systemic shunting of blood, as occurs in chronic cirrhosis of the liver or following the surgical construction of a portacaval shunt results in portal blood bypassing the normal ammonia detoxification machinery of the liver. Under this condition blood ammonia levels rise markedly, increasing the burden on extrahepatic tissues, such as skeletal muscle, brain, and kidney, in maintaining ammonia homeostasis. The most commonly employed animal model of human liver disease is the rat in which an end-to-side portacaval shunt (PCS) has been surgically constructed. Brain glutamine synthetase activity is not increased in PCS rats and in some areas of the brain there may even be a decrease in activity. The brain glutamine synthetase appears to be working at near maximal capacity. Thus, the PCS rats exhibit profound neurological dysfunction when administered ammonium salts in amounts easily tolerated by normal animals. Because of the limited capacity of brain to remove excess ammonia, a rational approach to the treatment of patients with liver disease should include a regimen directed toward lowering the associated hyperammonemia.

Ammonia↗
PubMed1990

Medroxyprogesterone acetate, nocturnal penile tumescence, laboratory arousal, and sexual acting out in a male with schizophrenia.

This study reports the effects of the antilibidinal drug, medroxyprogesterone acetate (MPA) on nocturnal penile tumescence (NPT) during sleep, tumescence responses to provocative audiotapes during wakefulness in the laboratory, and sexual behaviors in the hospital environment, in a conduct-disordered sexually aggressive male, who had not responded to previous treatment. NPT, laboratory tumescence, and sexual behaviors in the hospital environment were all decreased. Testosterone levels declined by 73% within 2 weeks of starting the drug and prolactin levels increased by 300% across the treatment period. The effects on NPT and laboratory arousal were still partially in evidence 2 months after the drug had been stopped, although testosterone levels had returned to predrug levels. Some differences between the NPT and daytime test data are discussed in terms of the probable importance of testosterone to erotic fantasy. NPT may be a useful addition to present methods for examining the effects of drugs used to suppress socially unacceptable sexual behaviors.

Adult↗
PubMed1990

Methods for the enzymatic synthesis of tyrosine and phenylalanine labeled with nitrogen-13.

L-[13N]Tyrosine and L-[13N]phenylalanine were synthesized using immobilized enzymes by two methods. In method 1, [13N]ammonia is converted to L-[13N]glutamate; transamination with p-hydroxyphenylpyruvate yields L-[13N]tyrosine. [13N]Tyrosine is separated from other labeled intermediates on a Poropak Q column. In method 2, phenylalanine dehydrogenase catalyzes the reversible reductive [13N]amination of either phenylpyruvate or p-hydroxyphenylpyruvate to form L-[13N]phenylalanine or L-[13N]tyrosine, respectively. The feasibility of labeling DOPA and tryptophan with 13N was also demonstrated.

Enzymes, Immobilized↗