Prospective comparison of plain abdominal radiography with conventional and digital renal tomography in assessing renal extracorporeal shock wave lithotripsy patients

Most publications citing the effectiveness of renal extracorporeal shock wave lithotripsy have used plain abdominal radiography to assess residual calculi after treatment. We compared radiologist sensitivity and specificity in the detection of calculi on plain abdominal radiographs versus conventional film-screen and digital renal tomograms in extracorporeal shock wave lithotripsy patients. Of the patients 50 were imaged before and within 24 hours after lithotripsy. Six radiologists evaluated the resultant 300 studies for the presence and location of calculi. The mean sensitivity for digital tomograms was 83% for pre-lithotripsy and post-lithotripsy studies, which was significantly higher than for plain abdominal radiography and conventional tomography after lithotripsy. However, there were significantly more false positive stone diagnoses associated with digital tomogram interpretation. Signal detection analysis verified the over-all superiority of digital tomography for post-extracorporeal shock wave lithotripsy imaging. Calculus detection by conventional and digital tomography is superior to detection by plain abdominal radiography. However, because we did not perform delayed imaging, it is not possible to say what impact digital tomography might have on the management of extracorporeal shock wave lithotripsy patients.     

Organ hypertrophy and responses of colon microbial populations of growing swine to high dietary protein

Thirty-two castrated male crossbred growing pigs (average initial wt 26.9 kg) were used to determine the effect of a high level of dietary protein (37%) compared with a normal level of protein (15%) on enterobacteria and Campylobacter sp. inhabitation in the large intestine and on visceral organ hypertrophy and the interrelationships between these two factors. Pigs were kept in pairs (eight pens of two pigs/diet) and fed their respective diets and libitum. Eight pigs (two pens of two pigs fed each diet) were killed at wk 4, 8, 12 and 16 without fasting. Fecal samples were obtained every 2 wk from animals scheduled for necropsy at 16 wk, and colon contents were obtained from all pigs at necropsy; samples were enumerated individually for enterobacteria and Campylobacter sp. Weights of heart, lungs, liver, kidneys, perirenal fat and empty stomach, small intestine and large intestine were recorded at necropsy. Stomach, cecum and proximal colon were sectioned for histopathologic examination. Daily body weight gain was depressed by high dietary protein, but liver and kidneys were heavier in the high protein group than in controls at each time interval. Mild lymphoid hyperplasia of Peyer's patches in the small intestine in some pigs in both groups was indicative of antigenic stimulation but not of pathologic significance. There was no effect of diet on counts of enterobacteria or Campylobacter sp. in feces or colon contents during the 16-wk experiment. We conclude that the hypertrophic response of the tissues of growing pigs to high dietary protein is not the result of the presence of Campylobacter sp. or enterobacteria in the colon contents.     

Sex differences in the distribution of adipose tissue in the Djungarian hamster Phodopus sungorus

Female Djungarian hamsters (Phodopus sungorus) have proportionately more adipose tissue in superficial depots than males of similar age and body composition. In both sexes, the proportion in superficial depots increases with increasing fatness. This species may be useful as a model for human obesity because it becomes as obese as modern humans without genetic, surgical or dietary manipulation and the sex differences in adipose tissue distribution resemble those of humans.     

Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis

BACKGROUND: Patients with cystic fibrosis have received more intravenous antibiotic courses as median survival has steadily increased. A number of centres have adopted a policy of regular (three monthly) rather than on demand intravenous antipseudomonal antibiotics. More widespread bacterial antibiotic resistance has resulted from this increased antibiotic use. Most Pseudomonas aeruginosa strains remain fully sensitive to colistin but its use has been resisted owing to concerns about neurotoxicity and nephrotoxicity. A study was carried out to assess the safety and efficacy of intravenous colistin in the treatment of acute respiratory exacerbations in adult patients with cystic fibrosis. METHODS: Patients with chronic Pseudomonas aeruginosa colonisation who presented with protocol defined respiratory tract exacerbations were randomised to receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti- pseudomonal antibiotic. Comparisons of the absolute values of respiratory function tests on days 1, 5, and 12 and of overnight oxygen saturation on days 1 and 12 were the primary outcome measures. Patient's weight, clinical and chest radiographic scores, and peripheral blood markers of inflammation were also documented. The effect of each treatment regimen individually was assessed by the change in clinical measurements from baseline values. Adverse renal effects were monitored by measurement of serum levels of urea and electrolytes, creatinine clearance, and ward urine testing. Neurotoxicity was monitored by direct questioning for symptoms. RESULTS: Fifty three patients, 18 of whom entered the study twice, were enrolled. The mean forced expiratory volume in one second (FEV1) increased significantly in both groups, mean forced vital capacity (FVC) only with dual therapy. Both groups showed a non-significant increase in overnight oxygen saturation. All patients showed clinical improvement. Thirty seven adverse neurological events (two severe) were reported in 33 patients in the monotherapy group and 37 (none severe) in 36 patients in the dual therapy group. One patient withdrew because of severe weakness and dizziness. All other adverse neurological events were well tolerated and resolved during or shortly after treatment. Significant changes were seen in mean serum urea levels in both groups, but in only four patients to a level above the normal range, and in creatinine clearance in the dual therapy group. At 24 month follow up no long term adverse consequences from intravenous colistin were found in patients who completed the study. CONCLUSIONS: Intravenous colistin is an effective treatment for Pseudomonas aeruginosa associated pulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect of each treatment regimen suggests a greater efficacy when colistin is combined with a second antibiotic to which the pseudomonas shows in vitro sensitivity. Changes in renal function should be monitored.


     

Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

The effects of noradrenaline and insulin on lipolysis in adipocytes isolated from nine different adipose depots of guinea-pigs.

The rates of glycerol release in adipocytes isolated from nine identified adipose depots of sedentary or exercised guinea-pigs were measured in the presence of adenosine deaminase and 10(-9) to 10(-5) M noradrenaline and/or 1-1000 muunit/ml of bovine insulin. Twenty minutes of exercise increased the basal noradrenaline-stimulated rates of lipolysis in all depots, but these effects, and their interactions with in vitro application of the neurotransmitter differed between depots, showing that the long-lasting effects of exercise and the response to acute application of NA involve different mechanisms that may occur separately or together in different adipose depots. In general, large depots had the highest resting rates of lipolysis and the lowest responses to both noradrenaline and insulin, and lipolysis was only slightly different from the basal rate in adipocytes incubated with mixtures of the two agents. The two small intermuscular depots had the lowest unstimulated rates of lipolysis, but the fastest change and greatest maximum response to both agents. Noradrenaline-stimulated lipolysis was most effectively inhibited by small quantities of insulin in these depots. Different combinations of these properties were demonstrated in two smaller superficial depots, the mesenteric and omental depot, and in the cardiac depots. The data demonstrate the physiological inhomogeneity of both 'subcutaneous' and 'intra-abdominal' depots, and are consistent with the hypothesis that intermuscular adipose tissue interacts locally with adjacent muscle. Noradrenaline-stimulated lipolysis was more effectively inhibited by 100 muunit/ml insulin in adipocytes from the mesenteric and omental depot in those from any other site. A possible role for this property in the enlargement of this depot in hyperinsulinaemia in humans is proposed.     

Formation of pyridinium species of haloperidol in human liver and brain

Recent interest in the neurotoxicity of haloperidol is based on its oxidation in rodents to the pyridinium derivative, HPP⁺, a structural analog of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP⁺). Recently, we reported that HPP⁺ and a newly identified reduced pyridinium, RHPP⁺, were present in blood and urine of haloperidol-treated schizophrenics and that the concentrations of RHPP⁺ exceeded those of HPP⁺. In this study, we examined pathways for formation of RHPP⁺ in subcellular fractions of human liver (n=5) and brain (basal ganglia;n=5). The major pathway was reduction of HPP⁺ (20 µM) to RHPP⁺ in cytosol (0.17–0.39 and 0.03–0.07 µM RHPP⁺/g cytosolic protein per h in liver and brain, respectively). The reactions were inhibited significantly by menadione and in brain also by daunorubicin. The inhibition profile, cytosolic location and strict NADPH dependence suggest that the enzymes involved are ketone reductases. A second pathway was oxidation of reduced haloperidol (50 µM), a major metabolite of haloperidol in blood and brain, to RHPP⁺. In liver microsomes, 0.17–0.63 µmol RHPP⁺ was formed /g microsomal protein per h. A potent inhibitor of the pathway was ketoconazole (IC₅₀, 0.8 µM), which suggests that P-450 3A isozymes could be involved. In brain mitochondria but not microsomes, reduced haloperidol (120 µM) was oxidised to RHPP⁺ at a small but significant rate (0.005–0.020 µmol RHPP⁺/g mitochondrial protein per h) which was not attenuated by SKF 525A, quinidine, ketoconazole, or monoamine oxidase inhibitors. Further studies are warranted to establish the biological importance of these metabolites in vivo.     

Patient and parental attitudes toward genetic screening and its implications at an adult cystic fibrosis centre

General population screening for cystic fibrosis carrier status in the United Kingdom would detect 72% of at-risk couples. Proper counselling would allow these couples to make informed reproductive choices, including the possibility of prenatal diagnosis and the termination of an affected pregnancy. However, children with cystic fibrosis born in this decade, given optimum treatment, now have an average life expectancy of 40 years, and there is no unanimity of opinion on how, where, when, or even if, screening should be offered. The purpose of this questionnaire-based study was to examine the attitudes of an adult clinic population who have grown up with cystic fibrosis, and of their parents, towards genetic screening programmes and the controversies and ethical dilemmas surrounding such programmes in cystic fibrosis. Both patients and parents supported prenatal screening (88% and 90%) and the option of terminating an affected pregnancy (68% and 84%). Only 22% of patients and 10% of parents felt that screening should be limited to families with a history of cystic fibrosis, and 19% and 6%, respectively, that prenatal diagnosis should be restricted to those with a previous child with cystic fibrosis. Despite the negative aspects of any screening programme and the acknowledged ethical problems peculiar to cystic fibrosis, the conclusion of our patients and parents who have lived intimately with the illness is that there should be the option of utilising information available from genetic screening for cystic fibrosis to guide reproductive choices. Pilot programmes to define the optimum management of such screening should continue.     

Growth of whole body and organs of growing rats during feed restriction and subsequent realimentation

Fifty-six Sprague-Dawley male rats (average body weight 70.6 +/- SD 11.6 g) were divided into two equal groups. One group was fed a 17% protein (N x 6.25) diet ad libitum for 42 d (Control). The second group was fed the same diet at 60% of the intake of the Control group for 14d (Restricted) and ad libitum for the remaining 28 d. Three rats per group were euthanized on d 1 and five rats per group on d 7, 14, 21, 28, and 42 and weights of the body, heart, spleen, liver, kidneys, epididymal fat, empty stomach, large and small intestines, and length of the left femur were recorded. The empty stomach, large and small intestines were dried to constant weight at 65 degrees C and assayed for crude protein content. Body weight, feed efficiency, weights of the heart, liver and epididymal fat were significantly reduced, while relative weight of the stomach and crude protein content of the small intestine were significantly increased in the restricted group during the period of feed restriction. Body and organ weights, however, compensated and caught up with control values within 14 d of feed rehabilitation and, by 28 d of realimentation, body weight, heart, liver and stomach weights were significantly greater in restricted than in control rats. Femur length was reduced by feed restriction, but continued to increase during restriction and realimentation. Gastrointestinal tract segments were less affected by feed restriction and responded more quickly to realimentation than the whole body.