Discharge guidelines for children with acute asthma: a consensus statement.
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Acute Disease↗
Biomedical subjects
A Cahill
Publications and source records attributed to A Cahill.
Effects of chronic ethanol feeding on the protein composition of mitochondrial ribosomes.
Chronic ethanol feeding has been shown to decrease the number of functionally active mitochondrial ribosomes by 55%. In this work, 55S mitochondrial ribosomes were isolated from rat liver and their constitutive proteins characterized by two-dimensional polyacrylamide gel electrophoresis and quantified by densitometry. A total of 86 proteins were found to be associated with the mitochondrial ribosome. This compares with 70 isolated from cytoplasmic ribosomes. In addition, mitochondrial ribosomal proteins were found to be significantly less basic than their cytoplasmic counterparts. Chronic ethanol feeding was found to significantly decrease the levels of a number of constitutive proteins of the mitochondrial ribosome when compared to those isolated from pair-fed controls. Sucrose density gradient analyses revealed a significant decrease in the number of intact 55S ribosomes. It is suggested that ethanol-elicited alterations in specific constitutive proteins of the mitochondrial ribosome may lead to impaired assembly of the monosome and that this may result in lower levels of those displaying functional activity.
Electrophoresis, Gel, Two-Dimensional↗
Still hungry in hospital: identifying malnutrition in acute hospital admissions.
We assessed the prevalence, methods for recognition and clinical management of malnutrition in acute admissions in a large academic inner-city hospital. Of a total of 337 patients, it was possible to measure both height and weight in 219 patients (65% of admissions). As an alternative for bed-bound patients, mid-upper arm circumference was not very reliable in predicting BMI (sensitivity 98%; specificity 65%), and waist circumference even less so. Of these, 13% were malnourished (body mass index BMI <18.5 kg/m(2) or BMI 18.5-20 kg/m(2) with reported weight loss >3 kg in the last 3 months). Six patients (31% of those with BMI <18.5 kg/m(2)) and one with BMI 18.5-20 kg/m(2) were recognized as suffering from malnutrition and referred to the dietitian. Review of case records could not establish if the diagnosis was missed in the remainder, or if a conscious decision was taken not to manage malnutrition actively. Malnutrition in acute hospital admissions goes apparently unrecognized and unmanaged in 70% of cases. Since there are serious consequences, and effective simple treatment is readily available, increased awareness is required, with routine assessment of nutritional status in all patients.
Adolescent↗
Perfusion method for thoracoabdominal aneurysm repair using the open distal technique.
Challenges related to perfusion support of thoracoabdominal aneurysm repair include maintenance of distal aortic perfusion, rapidity of fluid resuscitation, and avoidance of both hypothermia and excessive hemodilution. Using available technology, we have devised a circuit and protocol that addresses these issues. To accomplish such support a bypass circuit consisting of 3/8 inch tubing connected to a centrifugal pump and low-prime heat exchanger was constructed. The circuit was primed via 1/4 inch spiked connectors attached to a 3-liter bag of normal saline. After initial de-airing, the solution was recirculated through this bag. Patients were anticoagulated with 1 mg/kg of heparin prior to initiation of support. Left atrial-descending aorta bypass was used primarily. A cell salvage device was used for autotransfusion. All blood products were delivered via a rapid infusion device. During partial exsanguination, shed blood was not processed, but directed to the rapid infusor for immediate retransfusion. Any packed cells given were washed prior to transfusion. Citrate dextrose solution was used as an anticoagulant for the cell scavenger. This configuration was used successfully in 50 procedures during an 18-month period. Use of this low-prime, custom circuit reduced both hemodilution and cost. A connection off the cell salvage pump offers fast retransfusion of shed blood during partial exsanguination. Minimal heparinization and citrate anticoagulation appears to reduce coagulopathy.
Adult↗
Potentiation by chronic ethanol treatment of the mitochondrial permeability transition.
Mitochondria isolated from rats chronically fed ethanol were more sensitive to induction of the mitochondrial permeability transition (MPT) by a variety of agents than mitochondria isolated from isocalorically matched controls. The agents utilized have been implicated in both necrotic (Ca(2+)) and apoptotic (ceramide, GD3 ganglioside, and Bax) forms of cell killing and help promote pore opening by differing mechanisms. In each case it was found that concentrations of the inducing agents which promoted little or no pore opening in mitochondria isolated from pair matched controls produced massive MTP opening in mitochondria from chronically ethanol fed rats as evidenced by swelling. In all cases induction of the MPT was prevented by the presence of cyclosporin A.
Alcoholism↗
Chronic ethanol consumption causes alterations in the structural integrity of mitochondrial DNA in aged rats.
Chronic ethanol consumption adversely affects the respiratory activity of rat liver mitochondria. It causes increased cellular production of oxygen radical species and selectively decreases mitochondrial glutathione (GSH) levels. Here we show, using Southern hybridization techniques on total rat genomic DNA, that long-term (11-13 months) ethanol feeding, using the Lieber-DeCarli diet, results in a 36% (P <.05; n = 4) decrease in hepatic mitochondrial DNA (mtDNA) levels when compared with paired controls. UV quantitation of mtDNA isolated from hepatic mitochondria showed that chronic ethanol intake (11-13 months) causes a 44% (P <.01; n = 6) decrease in the amount of mtDNA per milligram of mitochondrial protein. No significant decline in mtDNA levels was seen in ethanol-fed animals maintained on the diet for 1 to 5 months. Ethanol feeding caused a 42% (P <.01; n = 4) and a 132% (P <.05; n = 3) increase in 8-hydroxydeoxyguanosine (8-OHdG) formation in mtDNA in animals maintained on the diet for 3 to 6 months and 10 to 11 months, respectively. In addition, agarose gel electrophoresis revealed a 49% increase (P <.05; n = 3) in mtDNA single-strand breaks (SSB) in animals fed ethanol for more than 1 year. These findings suggest that chronic ethanol consumption causes enhanced oxidative damage to mtDNA in older animals along with increased strand breakage, and that this results in its selective removal/degradation by mtDNA repair enzymes.
Aging↗
Review article: malnutrition and maltreatment--a comment on orlistat for the treatment of obesity.
The prevalence of obesity has doubled in the last 10 years and is now reaching epidemic proportions. There is a significant comorbidity and financial cost associated with this disorder. Orlistat is an intestinal lipase inhibitor that is approved for the treatment of obesity. Recent randomized, double-blind, placebo-controlled trials have demonstrated the benefit of orlistat used in conjunction with a hypocaloric (low-fat) diet in facilitating weight reduction and the long-term maintenance of this weight loss. Patients treated with orlistat lost a greater amount of initial body weight compared to those who received placebo. After 24 months of treatment, weight loss of more than 5% was maintained in a greater number of those treated with orlistat. This was associated with significant reductions in cardiovascular risk factors (cholesterol, LDL cholesterol, LDL:HDL cholesterol ratio). The main adverse events are related to fat malabsorption, with potential losses of fat-soluble vitamins and other compounds. Orlistat as a treatment for obesity, when prescribed within present guidelines, can aid modest weight loss in about one-third of patients. More importantly, it can assist in the maintenance of weight loss with major medical benefits for these patients.
Anti-Obesity Agents↗
Investigation of a large, commercially farmed rodent (Capybara) as a potential donor for pancreatic islet xenotransplantation.
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Animals↗
Oxidative damage to DNA in plaques of MS brains.
A major cause of clinical disability in multiple sclerosis (MS) is related to a degenerative process in the central nervous system (CNS) which ultimately develops from a potentially reversible inflammation and demyelination. The mechanism of this degenerative process within MS lesions is not completely understood. We hypothesize that oxidative damage to DNA secondary to inflammation may contribute to irreversible tissue alterations in a plaque. To test this assumption, we determined the level of a DNA oxidative marker, 8-hydroxy-deoxy-guanosine (8-OH-dG) in the normal appearing white matter (NAWM), plaque and cortical regions of cerebella from MS patients who suffered from severe cerebellar symptoms during the course of the disease, and in NAWM and cortical regions of cerebella from non-neurological controls. We found a significant increase in DNA oxidation within plaques compared to NAWM specimens in MS cerebella. A tendency for increase of oxidative markers in normal appearing cortical tissues located in the proximity of MS plaques was also observed when compared to those in control cortical specimens. Oxidative damage to DNA in MS lesions, and in neuron rich areas located in the proximity of these lesions is likely related to the release of reactive oxygen species (ROS) and nitric oxide (NO) during inflammation in the brain. This biochemical impairment of DNA and of other macromolecules may contribute to the development of severe clinical disability through the induction of degenerative changes within and outside of plaques in MS brains.
8-Hydroxy-2'-Deoxyguanosine↗
Increased oxidative damage to mitochondrial DNA following chronic ethanol consumption.
Ethanol consumption adversely affects the structural and functional integrity of hepatic mitochondria. Some of these effects may arise from the increased cellular levels of oxidizing radicals induced by ethanol feeding. Since DNA is a potential target of free radical damage, we investigated the effect of chronic ethanol feeding on oxidative modification of mtDNA. Mitochondria were isolated from the livers of control and ethanol-fed rats and the mtDNA analyzed for the presence of 8-hydroxydeoxyguanosine (8-OHdG). A 21% increase in the level of 8-OHdG was detected in mtDNA from animals that had been fed an ethanol-containing diet for 42-76 days (control, 3.98 +/- 0.5; ethanol, 4.8 +/- 0.9 8-OHdG/100,000dG). This difference increased to 43% in animals that had been fed ethanol for 105-164 days (control, 6.9 +/- 1.0; ethanol, 9.9 +/- 1.1 8-OHdG/100,000dG). This increase in mtDNA oxidation was accompanied by a decrease in the recovery of mtDNA (42-76 days: control, 88 +/- 11; ethanol 76 +/- 8 ng/mg mitochondrial protein; 105-164 days: control, 88 +/- 13; ethanol 62 +/- 14 ng/mg mitochondrial protein). The data presented demonstrate that chronic ethanol feeding leads to increased oxidative damage of hepatic mtDNA. This may in turn result in progressive mtDNA mutations and deletions and impaired mitochondrial function.
8-Hydroxy-2'-Deoxyguanosine↗
Bureaucracy to adhocracy. A possible structure for the Department of Health and Family Services.
At a meeting on Friday, 7 June 1996, the Minister for Health and Family Services, The Hon. Michael Wooldridge MP, asked the authors to prepare a paper on a possible structure for the Department of Health and Family Services. This followed our explanation to him of navigating women's and children's health service issues through the existing departmental structure. We had explained that such navigation included nearly all of the divisions within the department; and then within those divisions there were different branches responsible for different activities. It has been our experience that rarely do the different divisions, branches or sections exchange ideas, views or policies that might affect women and children. The result is a fragmented approach to this important group of the population. We know that this same approach, exists for other key population groups. This paper has been prepared at the request of the Minister, and follows an approach based on population and outcome.
Australia↗
Differential effects of chronic ethanol consumption on hepatic mitochondrial and cytoplasmic ribosomes.
The effects of chronic ethanol consumption on the properties of mitochondrial and cytoplasmic ribosomes were investigated in rat liver. Sedimentation properties of purified mitochondrial (55S) and cytoplasmic (80S) ribosomes were determined by analyses on sucrose density gradients. Mitochondrial ribosomes from control animals moved further in the gradients than did those isolated from ethanol-fed rats, which suggests that ethanol ribosomes have a lower molecular weight. In addition, mitochondrial from ethanol-fed animals contained a lower percentage of ribosomes present as the intact monosome, suggesting that ethanol may have an effect on the stability of the functional mitochondrial ribosomes. This was confirmed by the presence of the larger 39S subunit in preparations from ethanol-fed animals. No such ethanol-related alterations were seen with cytoplasmic ribosomes. The protein composition of mitochondrial cytoplasmic ribosomes was investigated using two-dimensional gel electrophoresis, followed by two-dimensional densitometry. As indicated by differences in protein staining intensity, ethanol consumption seemed to alter the concentration of seven mitochondrial ribosomal proteins. In contrast, no such changes were observed in the protein pattern from cytoplasmic ribosomes. Observations in this study provide for the possibility that alterations in the amounts of selected proteins in the mitochondrial ribosome lead to impaired assembly of the ribosome. These ethanol-related structural changes may be responsible for the decreased activity of mitochondrial ribosomes that results in impaired hepatic mitochondrial protein synthesis (W.B. Coleman and C.C. Cunningham, Biochim. Biophys, Acta 1058:178-186, 1991). Furthermore, this study reemphasizes the increased susceptibility of the hepatic mitochondrial translation system, compared with the cytoplasmic system to chronic ethanol consumption.
Animals↗
Isolation and characterization of rat liver mitochondrial ribosomes.
A procedure has been developed that allows characterization of mitochondrial ribosomes and quantitative analysis of the relative composition of constitutive ribosomal proteins. Purified mitochondrial ribosomes were isolated from two rat livers and shown to be active in catalyzing the polymerization of phenylalanine. They differ in sedimentation and spectral properties from cytoplasmic ribosomes isolated from the same livers. The number and relative composition of proteins present in active rat liver mitochondrial ribosomes were investigated using two-dimensional nonequilibrium pH gradient electrophoresis. There were 86 proteins found associated with mitochondrial ribosomes in contrast to 70 proteins found associated with cytoplasmic ribosomes. Comparison of electrophoretic patterns revealed that cytoplasmic ribosomal proteins were considerably more basic than their mitochondrial counterparts. Densitometry demonstrated that the relative changes in the concentrations of these proteins can be measured quantitatively. These procedures, developed for use with two rat livers, allow the rat to be used as an efficient model for further studies into disease states of mitochondrial translation.
Animals↗
Genotoxic effects of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) and nitrogen mustard-N-oxide (nitromin) in Walker carcinoma cells under aerobic and hypoxic conditions.
As judged by alkaline elution, exposure of Walker cells to either 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) or nitromin results in a dose-dependent increase in DNA damage due to single-strand breaks. With nitromin or SR 4233 there was little difference in the extent of DNA single-strand breaks between Walker cells incubated either hypoxically or aerobically. In contrast, there was a 24-fold enhancement in the differential hypoxic/aerobic response to SR 4233 in clonogenic studies. Following incubation of cells with nitrogen mustard, DNA cross-linking is observed. Bioreduction of nitromin would be expected to yield nitrogen mustard as the putative reactive metabolite. However, only DNA strand-breaks could be detected in Walker cells incubated with nitromin, suggesting that reduction of this pro-drug to nitrogen mustard was not a major activation pathway. In cells incubated under aerobic conditions, SR 4233 induces oxidative DNA damage, as indicated by the formation of 8-hydroxydeoxyguanosine, suggesting the involvement of futile redox cycling. In rats dosed with SR 4233 in vivo, significantly higher levels of 8-hydroxydeoxyguanosine could be detected in liver, compared to vehicle-dosed controls.
8-Hydroxy-2'-Deoxyguanosine↗
Immediate destruction of xenogeneic islets in a primate model.
Transplantation of pancreatic islets from other species to man has the potential to cure diabetes, but whether such islet grafts will be subject to damage due to natural antibody-mediated hyperacute rejection is unknown. We have examined the fate of islet xenografts in a recipient with direct relevance to man, the cynomolgus monkey. Rabbit islets were prepared by an intraductal collagenase technique and incubated in neat rabbit, human, or cynomolgus serum, with and without heat inactivation, for up to 6 days. Islets were analyzed by flow cytometry for IGG and IGM binding, and scored for viability by supravital staining. For in vivo studies, isolated islets were prepared from 4 New Zealand White rabbits (15-34 x 10(3) islets 70-85% purity) and transplanted beneath the kidney capsule of normal cynomolgus monkeys after aggregation in either a rabbit or monkey blood clot. The tissue was retrieved at various times up to 4 days after transplantation and processed for light and electron microscopy. The results showed that rabbit islets bind heterophile antibody of both IGG and IGM subtypes. There was slow loss of islet viability in vitro over 3 days of culture in neat human or cynomolgus serum. Destruction of islets in vivo was more rapid with visible damage within 6 hr associated with neutrophil infiltration. Subsequently, there was heavy mononuclear cell infiltration leading to total destruction within 4 days. The results suggest that immediate mechanisms of graft rejection, possibly compliment and neutrophil mediated, represent a major barrier to islet xenotransplantation in humans.
Animals↗
Differential effects of ethanol consumption on synthesis of cytoplasmic and mitochondrial encoded subunits of the ATP synthase.
The relative concentrations of several subunits of the mitochondrial F0.F1-ATP synthase were determined in mitochondria and submitochondrial particles prepared from the livers of ethanol-fed and control rats. The polypeptides were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and the stained gels were analyzed by densitometry for the relative concentrations of the ATP synthase subunits. A significant decrease in the relative concentration of the mitochondrial gene product, ATPase subunit 8, was observed in mitochondria and submitochondrial particles from ethanol-fed animals. The relative concentration of the other mitochondrial encoded ATPase subunit, ATPase 6, was also depressed, as confirmed in submitochondrial particles. In contrast, there were no significant ethanol-related depressions in subunits alpha, beta, and OSCP of the F0.F1 or the adenine nucleotide carrier in intact mitochondria. These results demonstrate that ethanol consumption causes a decrease in the content of mitochondrial synthesized subunits 6 and 8 whereas no effect is exerted on the concentrations of nuclear gene products of the ATP synthase complex. Likewise, the adenine nucleotide transporter, also a nuclear gene product, is unaffected by ethanol consumption.
Alcohol Drinking↗
Metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) by purified DT-diaphorase under aerobic and anaerobic conditions.
Purified DT-diaphorase [NAD(P)H (quinone acceptor) oxidoreductase (EC.1.6.99.2)] from Walker cells was used to investigate the reductive metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) under aerobic and anaerobic conditions. In the presence of NADPH, under aerobic conditions, HPLC analysis showed the four-electron reduction product 3-amino-1,2,4-benzotriazine (SR 4330) was the major reaction product. In contrast, anaerobically, the 2-electron reduction product 3-amino-1,2,4-benzotriazine-1-oxide (SR 4317) was the predominant metabolite. Anaerobic reduction of SR 4233 to the known metabolites SR 4317 and SR 4330, catalyzed by DT-diaphorase, was 3-fold higher than reduction under aerobic conditions. Anaerobically, approximately half of the substrate utilized could not be accounted for by the formation of known products. Aerobically, the majority of the SR 4233 lost could be accounted for by its conversion to SR 4317 and SR 4330. In Walker cells incubated with SR 4233 anaerobically, SR 4317 was the major metabolite formed. Dicoumarol (100 microM) had little effect on the rate of formation of this metabolite in this cell line or in a rat liver epithelial derived (JBJ) cell line. Dicoumarol did however partially reduce the induction of unscheduled DNA synthesis caused by SR 4233 in Walker cells but not in JB1 cells, suggesting the action of dicoumarol may be specific to Walker cells. It is concluded that DT-diaphorase plays only a minor role in the overall reduction of SR 4233 in the two cell lines studied.
Anaerobiosis↗
Acute lesions in rats caused by 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) or nitromin: a comparison with rates of reduction in microsomal systems from target organs.
Pathological lesions to male Fischer rats were investigated 24 h after the administration of 3-amino-1,2,4-benzotriazine-1,4- dioxide (SR 4233) or nitromin, two compounds which need to undergo bioreductive activation in order to exert their toxic effects. Although SR 4233 reduction leads to a putative free radical species while with nitromin a bifunctional alkylating agent is formed, in both instances, the bone marrow was a major target organ. However, the response of other organs to these compounds differed. SR 4233 caused lesions to the olfactory epithelium, liver, kidney and thymus. Nitromin caused focal haemorrhages on the intestine, which were reduced in germ-free rats. Rates of reduction of SR 4233 or nitromin were determined under anaerobic conditions using microsomal preparations from target tissues. With SR 4233 as a substrate, reductase activities were highest in the olfactory epithelium, 6 fold higher than in the liver. SR 4233 reductase activities generally correlated with those of NADPH:cytochrome c reductase or the concentration of cytochrome P-450 reductase protein in the affected organs while with nitromin, there appeared to be no such relationship. The present results support the concept that the expression of pathological damage in vivo is a multifactorial process and does not directly correlate with initial rates of reduction of either drug determined in vitro.
Animals↗