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Biomedical subjects

R McCauley

Publications and source records attributed to R McCauley.

At least 19 recordsLinked to original sources
PubMed2000

Branched-chain amino acids.

The branched-chain amino acids (BCAA), isoleucine, leucine and valine, are unique in that they are principally metabolized extrahepatically in the skeletal muscle. This observation led to the investigation of these nutrients in a number of clinical scenarios. By far the most intensively studied applications for BCAA have been in patients with liver failure and/or patients in catabolic disease states. However, the resulting studies have not demonstrated a clear clinical benefit for BCAA nutritional supplements. In patients with liver failure, the BCAA did improve nitrogen retention and protein synthesis, but their effect on patient outcome was less clear. Similarly, in critically ill septic patients, BCAA did not improve either survival or morbidity. The BCAA are important nutrients, and it seems that any specific benefits associated with their use will be based upon a greater understanding of the underlying cellular biology. Potential areas of further research may include the combination of BCAA supplements with other anabolic factors (e.g. growth hormone) in managing patients with catabolic disease states.

Amino Acids, Branched-Chain↗
PubMed1999

Mutations in the voltage-dependent anion channel of the mitochondrial outer membrane cause a dominant nonlethal growth impairment.

Point mutations at K234 and K236 in the yeast voltage-dependent anion channel 1 (VDAC1) of the mitochondrial outer membrane have been shown to markedly impair the membrane insertion of this protein (Smith et al., 1995; Angeles et al., 1998). Mutants of this type were expressed in vivo in a strain of yeast with a disruption in the VDAC1 gene. Expression of the various VDAC1 forms was under the control of a Gall promoter. Wild-type VDAC1 expression fully complemented the slow growth phenotype caused by the disruption. VDAC1 mutants in which K234 and K236 were replaced by arginine, glutamate, or glutamine caused a more severe negative effect on growth. This effect appeared to be dominant since the mutant VDAC1 forms suppressed growth in a yeast strain that retained its VDAC1 gene. This apparent dominant negative effect on growth did not seem to be specific for any stage of the cell cycle. However, the growth defect was not lethal as the affected cells still could accumulate the vital stain, FUN1. Expression of a mutant in which K234 had been replaced by glutamate had more serious negative growth effects than did a similar mutation at K236. Expression of delta71-116 VDAC1 complemented the VDAC1 disruption; however, expression of the same deletion mutant in which the lysines corresponding to K234 and K236 were mutated to glutamate severely impaired growth. These results have shown that a deficiency of lysine at positions 234 and 236 in VDAC I causes a nonlethal growth defect that is more severe than deletion of 45 amino acids from VDACI or disruption of the VDAC1 gene. They also indicate that there is a hierarchy in the importance of these lysines with mutations at K234 being the more serious.

Gene Expression Regulation, Fungal↗
PubMed1999

Mutation of K234 and K236 in the voltage-dependent anion channel 1 impairs its insertion into the mitochondrial outer membrane.

Previous in vitro studies indicated that mutation of both K234 and K236 to arginine, glutamine, or glutamic acid impaired the ability of the voltage-dependent anion channel (VDAC1) to insert into the outer membrane of the mitochondria (Smith et al. 1995). These same mutants were expressed in a strain of Saccharomyces cerevisiae with a disruption in the VDAC1 gene. The mutant VDAC1 forms were found in the mitochondria suggesting that they were correctly sorted to the outer membrane. However, only very small amounts of the mutants were inserted into the mitochondrial membranes. Mitochondria isolated from the strains expressing the mutants were capable of catalyzing the translocation of both wild-type VDAC1 and pre-alcohol dehydrogenase III indicating that the translocation apparatus was functional. These results confirm the previously drawn conclusion that K234 and K236 are part of a membrane insertion motif. The failure of the mutant VDAC1 forms to insert did not cause VDAC1 precursors to accumulate in the soluble cell cytoplasm or in the microsomal fraction. The apparent lack of a "precursor pool" suggested that a post-transcriptional control mechanism might limit the amounts of VDAC1 precursors in the cell. Such a control mechanism is consistent with the observation that the amount of VDAC1 was very similar after epichromosomal (gene in a 2u plasmid controlled by a Gal1 promoter) and chromosomal expression (endogenous gene controlled by the endogenous promoter).

Amino Acid Substitution↗
PubMed1998

The role of enterocytes in gut dysfunction.

Stem cells in the intestinal epithelium give rise to enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Each of these cell lines plays a role in cytoprotection of the intestinal mucosa. In particular, it has been demonstrated that mature enterocytes can act as antigen presenting cells. Parenteral and enteral nutrition are used to nourish critically ill patients. However, these regimens are unfortunately associated with gut atrophy. Glutamine, the preferred intestinal nutrient, reverses this gut atrophy and plays a key role in maintaining the barrier function of the gut. Specific nutrients (putrescine, spermidine, spermine) have been used to modulate intestinal adaption. In addition, ornithine has been shown to act as a regulator of intestinal adaption. In this review, we discuss the relationship between the biology of enterocytes and failure of the gut barrier.

Animals↗
PubMed1998

Influence of ischaemia-reperfusion injury on CD44 expression in rat small intestine.

BACKGROUND: CD44 is an adhesion molecule expressed by neutrophils and lymphocytes which is involved in cell-cell and cell-matrix binding. In this study, the effect of ischaemia-reperfusion injury on CD44 messenger RNA (mRNA) and cell surface immunohistochemical expression of CD44 in the rat small intestine was evaluated. METHODS: Wistar rats (n=16) were randomized to either serve as controls (sham surgery) or to be subjected to a standardized ischaemia-reperfusion injury (suprarenal aorta occluded for 1 h followed by 1 h of reperfusion). Standardized segments of jejunum were harvested after ischaemia-reperfusion injury (ischaemic and reperfused samples) to measure the mucosal protein and DNA content, mRNA expression of CD44 and the immunohistochemical expression of CD44. RESULTS: Reperfusion significantly damaged the jejunal mucosa, e.g. mucosal protein content was lower after reperfusion compared with that in the control group (z=-2.31, P=0.02) and the ischaemic samples (z=-2.52, P=001). The expression of cell surface CD44 protein was also significantly decreased after ischaemic injury (z=-1.99, P=0.04); this coincided with a decrease in the amount of cytoplasmic CD44 mRNA within isolated enterocytes (z=-2.31, P=0.02). CONCLUSION: Ischaemia-reperfusion injury decreases the expression of CD44 within the jejunal mucosa. This may contribute to the failure of the gut barrier after such injury.

Animals↗
PubMed1998

The influence of ischemia/reperfusion injury on the jejunum.

Ischemia/reperfusion injury (IRI) after free tissue transfer of the small intestine results in transmural tissue damage. This study examined the effects of IRI on the jejunum. Wistar rats served either as controls (N=10) or underwent clamping of the infrarenal aorta for 1 hour followed by 1 hour of reperfusion (N=10). Both ischemia and reperfusion reduced the protein and deoxyribonucleic acid content of the jejunal mucosa (p < 0.05). Myeloperoxidase activity in the jejunal mucosa remained relatively low. The expression of leukocyte function-associated antigen 1 and intercellular adhesion molecule 1 (ICAM-1) on the surface of mucosal cells was not altered significantly by the ischemic insult, but was reduced after the period of reperfusion (p < 0.05). This coincided with an increase in messenger ribonucleic acid (mRNA) for ICAM-1 within isolated mucosal cells (p < 0.05). The specific activity of glutaminase in isolated jejunal mucosal cells was diminished after ischemia and reperfusion (p < 0.05), and this was not associated with an appreciable change in glutaminase mRNA expression. These results have identified some molecular mechanisms underlying IRI of the small intestine that are possible candidates for therapeutic intervention.

Animals↗
PubMed1996

Glutamine.

Glutamine is the most abundant free amino acid in the circulation. It is a primary fuel for rapidly dividing cells and plays a key role in the transport of nitrogen between organs. Although glutamine is absent from conventional regimens aimed at nutritional support, glutamine deficiency can occur during periods of metabolic stress; this has led to the reclassification of glutamine as a conditionally essential amino acid. Experiments with various animal models have demonstrated that the provision of glutamine can result in better nitrogen homoeostasis, with conservation of skeletal muscle. There is also considerable evidence that glutamine can enhance the barrier function of the gut. This review concludes by discussing the clinical evidence that supports the inclusion of stable forms of glutamine in solutions of nutrients.

Enteral Nutrition↗
PubMed1996

The effect of branched-chain amino acid-enriched parenteral nutrition on gut permeability.

In situations of catabolic stress, the gut becomes atrophic and has a diminished barrier function as evidenced by an increased permeability to a variety of molecules. It is known that the parenteral administration of branched-chain amino acids (BCAA) reduce gut atrophy. The aim of this study was to examine the effect of BCAA-enriched solutions of parenteral nutrients on gut permeability. A secondary aim was to observe the association between gut permeability and variables that have been used to assess jejunal atrophy. Central venous lines were inserted into 30 rats before randomization to receive nutritional support with: (1) a conventional parenteral solution (CPN), (2) A 2.0% BCAA-enriched solution (BCAA), or (3) rat food ad lib (Rat Food). The rats were assessed after 7 d for nutritional status, gut morphology, and gut permeability ratio (ratio of the permeability to 14C raffinose and 3H mannitol). We found that rats in the Rat Food Group lost the least amount of weight, had the least amount of jejunal atrophy, and had better preservation of barrier function as determined by gut permeability. When compared with the CPN Group, the BCAA Group had better preservation of jejunal morphology and protein content (p < 0.05), but a similar gut permeability. A cross-correlation matrix demonstrated a significant negative correlation between permeability to mannitol and mucosal weight, mucosal protein content and mucosal DNA content. Branched-chain amino acid-enriched parenteral nutrition reduced gut atrophy but not the gut permeability associated with parenteral nutrition. In the parenterally nourished rat model, atrophy of the jejunum is associated with increased permeability to small molecules.

Amino Acids, Branched-Chain↗
PubMed1995

Adenosine-induced apoptosis in chick embryonic sympathetic neurons: a new physiological role for adenosine.

1. A newly found action of adenosine in neurons, which may have an important physiological function in the growth and development of the sympathetic nervous system, is described. Adenosine (1-100 microM) inhibited neurite outgrowth within the first 24 h and killed about 80% of sympathetic neurons supported by nerve growth factor over the next 2 days in culture. Neurons supported by excess KCl, forskolin or phorbol 12,13-dibutyrate were equally susceptible to the toxic actions of adenosine. Inosine, guanosine or hypoxanthine (all 100-300 microM) were without effect on neuronal growth and survival. 2. Specific agonists of adenosine A1 and A2 receptors were not neurotoxic, and toxic effects of adenosine were not antagonized by aminophylline. These results rule out involvement of adenosine receptors and the adenylyl cyclase-cAMP signalling system in neurotoxic actions of adenosine. 3. Adenosine toxicity was prevented by inhibitors of the adenosine membrane transporter, suggesting an intracellular site of action of adenosine. 4. Inhibitors of adenosine deaminase dramatically facilitated the toxic action so that physiologically relevant concentrations of adenosine were neurotoxic. 5. Adenosine kinase activity of sympathetic neurons was dose-dependently inhibited by 5'-iodotubercidin (3-100 nM). 5'-Iodotubercidin (100 nM) completely protected neurons against toxicity of adenosine plus adenosine deaminase inhibitors. These results provide convincing evidence that phosphorylation of the nucleoside is an essential requirement for initiation of adenosine toxicity. 6. Sympathetic neurons were successfully rescued from the lethal effects of adenosine deaminase inhibitor plus adenosine by uridine or 2-deoxycytidine, but not by nicotinamide or 2-deoxyguanosine, suggesting that depletion of pyrimidine nucleotides by phosphorylated adenosine compounds and consequent inhibition of DNA synthesis produces neuronal death. 7. DNA fragmentation, assessed by the fluorescent dye bisbenzimide and by the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labelling) method, indicated that neuronal death induced by adenosine was apoptotic. 8. We conclude that adenosine deaminase and adenosine kinase play an important role in the metabolism of intracellular concentrations of adenosine and thereby regulate the growth and development of sympathetic neurons. Our study highlights, for the first time, the importance of adenosine as a mediator of programmed cell death of neurons supported by nerve growth factor.

Adenosine↗
PubMed1995

Repeated measures of vocal fundamental frequency perturbation obtained using the Visi-Pitch.

This article reports on a study of intrasubject variability for a measure of vocal fundamental frequency perturbation in a group of young, normal speakers. Measurements of relative average perturbation (RAP) obtained using a Visi-Pitch were examined for the vowels /a/, /i/, and /u/ produced by 25 women and 24 men on two occasions, approximately 1 week apart. Important findings consisted of higher levels of RAP for women than men and greater variability of RAP over the time period studied for women than men. Conclusions include the need for additional normative data regarding the use of the Visi-Pitch for the purpose of examining jitter.

Adolescent↗
PubMed1994

Rupture of the mitochondrial outer membrane impairs porin assembly.

Outer membranes isolated from yeast mitochondria were capable mediating the in vitro insertion of porin. As with the outer membrane of intact mitochondria, the insertion was ATP-dependent, and the inserted porin was resistant to trypsin treatment after detergent solubilization. However, the extent of porin insertion into isolated outer membranes was much less per mg of outer membrane protein than with intact mitochondria. The greater efficiency of intact mitochondria was not due to contact site-mediated translocation as isolated contact sites were less able to insert porin than isolated outer membranes, and blockade of the contact site channel in intact mitochondria did not affect porin insertion. However, mitochondria that had been subjected to osmotic shock sufficient to rupture the outer membrane and deplete the contents of the intermembrane space (i.e. mitoplasts) lost most of their ability to insert porin. Since outer membranes are isolated from mitoplasts, the low insertion activity of mitoplasts explains the low efficiency of insertion into isolated outer membranes. These results also indicate that, unlike proteins that are imported to the inner membrane and matrix of the mitochondria, porin's assembly is severely reduced by breaching the outer membrane and depletion of the intermembrane space contents.

Adenosine Triphosphate↗
PubMed1994

The malpractice crisis and the rate of actual malpractice.

In summary, the major concern of healthcare providers regarding malpractice should be its impact on patient welfare and its reduction to an irreducible minimum, rather than concern for physicians' insurance, etc. Medicine, rather than acting defensively, should provide leadership in reducing the malpractice toll on patients. Primary remedial steps should involve the prevention of patient injury and/or death. Actual malpractice is an enormous public health problem with a yearly morbidity of approximately 350,000 patients, and a yearly mortality of approximately 50,000 patients. Effective measures would not only save lives and improve patient welfare but would eliminate enormous healthcare expenditures. The way to reduce malpractice costs, direct and indirect, is to reduce malpractice.

Data Collection↗
PubMed1991

The influence of branched chain amino acids on colonic atrophy and anastomotic strength in the rat.

Conventional solutions of parenteral nutrients fail to reverse the colonic atrophy caused by starvation. This may be due to the absence from these solutions of the amino acid glutamine--a fuel for rapidly dividing cells such as colonocytes and fibroblasts. Although glutamine is unstable in solution, the infusion of branched chain amino acids (BCAA) increases the rate of synthesis and release of glutamine from skeletal muscle. We evaluated the hypothesis that the infusion of BCAA into undernourished rats would reduce the extent of mucosal atrophy and enhance the healing of anastomoses in the colon. Undernourished rats were randomized to receive 6 days of either a normal diet (Chow), conventional parenteral nutrition (CPN), or CPN supplemented with 1.8% BCAA (BCAA). The BCAA group had a higher plasma glutamine concentration than the Chow group (P less than 0.05). Compared with the CPN group, the BCAA group had the greater colonic mucosal weight (P less than 0.05) and colonic mucosal protein content (P less than 0.05), but there were no significant differences between groups in the bursting wall tension of the colon or the hydroxyproline content of the anastomoses. Although the infusion of BCAA has a beneficial effect on colonic atrophy, this did not result in the more secure healing of colonic anastomoses in this experimental model.

Amino Acids↗
PubMed1990

Influence of branched chain amino acid infusions on wound healing.

Branched chain amino acids (BCAA) may serve as a major oxidative fuel for skeletal muscle during periods of starvation. This study compared the ability of protein-undernourished rats to heal musculo-aponeurotic wounds of the abdominal wall when they were infused with solutions containing 45% BCAA or 8% BCAA (conventional TPN). Although the provision of 45% BCAA tended to result in better nourished animals and significantly increased plasma glutamine concentrations, this was not associated with improved healing.

Amino Acids, Branched-Chain↗
PubMed1989

Ubiquitin is involved in the in vitro insertion of monoamine oxidase B into mitochondrial outer membranes.

Monoamine oxidase B that has been synthesized by a reticulocyte lysate charged with bovine liver RNA will insert in a proteinase K-resistant form into isolated outer membranes from rat liver mitochondria. It appears that ubiquitin, a 76-amino acid polypeptide which is enzymatically conjugated to proteins, may be involved in the insertion process. Depletion of endogenous ubiquitin from the reticulocyte lysate with purified antibodies against this polypeptide inhibits the insertion of monoamine oxidase B, and this inhibition is relieved if ubiquitin is restored. On the other hand, a mutant form of ubiquitin which is unable to conjugate with proteins will not support insertion. Conjugation with ubiquitin is an ATP-dependent process. Not only does enzymatic depletion of ATP from the lysate prevent the insertion of monoamine oxidase, but ubiquitin will not restore insertion unless ATP is also present. These data indicate that the formation of a ubiquitin conjugate is involved in the insertion of newly synthesized monoamine oxidase B into the outer membranes.

Adenosine Triphosphate↗