Safety of concurrent administration of dexrazoxane and doxorubicin in the canine cancer patient.

Doxorubicin may cause a rare but serious cardiotoxicity. Dexrazoxane is a cardioprotectant drug used to reduce the risk of cardiotoxicity in human patients. In this study, 25 tumour-bearing dogs were treated with concurrent doxorubicin and dexrazoxane. The total number of doses of dexrazoxane given was 54 (range 1-5 doses per dog, median 2 doses). Five dogs received more than 165 mg m(2) cumulative doxorubicin dose before starting dexrazoxane. Haematologic, gastrointestinal and cardiovascular toxicities were considered tolerable. The combination of doxorubicin with dexrazoxane was well tolerated with minimal side-effects in this patient cohort. Future studies are required to evaluate potential cardioprotective effects of dexrazoxane given concurrently with doxorubicin.

PLEDs: clinical correlates.

OBJECTIVE: We reviewed our experience in 96 consecutive patients exhibiting periodic lateralized epileptiform discharges (PLEDs) on EEG. METHODS: EEG reports from January 1, 1999 to September 30, 2006 were screened for the term 'PLEDs' and its variants. A retrospective chart review, including examination of neuroimaging and other investigations, was conducted on each patient identified. RESULTS: Acute stroke, tumor and central nervous system infection were the most common etiologies, accounting for 26%, 12% and 12% of cases respectively. Acute hemorrhage and traumatic brain injury combined accounted for another 12%. Previously unreported etiologies included posterior reversible encephalopathy syndrome (PRES), familial hemiplegic migraine and cerebral amyloidosis. There were 9 cases of chronic PLEDs attributable to underlying cortical dysplasia or severe remote cerebral injury, all with an accompanying partial seizure disorder. A prominent role for alcohol withdrawal was noted, and in 6 cases was the sole etiological factor. Fever was present as a potential contributing factor in 40% of cases, and significant metabolic abnormalities in 35%. Seizure activity occurred in 85% of patients overall, but in 100% of patients with PLEDs Plus and BiPLEDs Plus. The overall mortality rate was 27%. Mortality among patients with BiPLEDs however was almost twice that, at 52%. CONCLUSIONS: This case series demonstrates the wide variety of potential PLED etiologies. It also emphasizes that despite advances in neurocritical care, the morbidity and mortality associated with PLEDs has changed little since their recognition four decades ago.

Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation.

BACKGROUND: Physicians managing patients with nonvalvular atrial fibrillation must consider the risks, benefits, and costs of treatments designed to restore and maintain sinus rhythm compared with those of rate control with antithrombotic prophylaxis. OBJECTIVE: To compare the cost-effectiveness of cardioversion, with or without antiarrhythmic agents, with that of rate control plus warfarin or aspirin. DESIGN: A Markov decision-analytic model was designed to simulate long-term health and economic outcomes. DATA SOURCES: Published literature and hospital accounting information. TARGET POPULATION: Hypothetical cohort of 70-year-old patients with different baseline risks for stroke. TIME HORIZON: 3 months. PERSPECTIVE: Societal. INTERVENTION: Therapeutic strategies using different combinations of cardioversion alone, cardioversion plus amiodarone or quinidine therapy, and rate control with antithrombotic treatment. OUTCOME MEASURES: Expected costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: Strategies involving cardioversion alone were more effective and less costly than those not involving this option. For patients at high risk for ischemic stroke (5.3% per year), cardioversion alone followed by repeated cardioversion plus amiodarone therapy on relapse was most cost-effective ($9300 per QALY) compared with cardioversion alone followed by warfarin therapy on relapse. This strategy was also preferred for the moderate-risk cohort (3.6% per year), but the benefit was more expensive ($18,900 per QALY). In the lowest-risk cohort (1.6% per year), cardioversion alone followed by aspirin therapy on relapse was optimal. RESULTS OF SENSITIVITY ANALYSIS: The choice of optimal strategy and incremental cost-effectiveness was substantially influenced by the baseline risk for stroke, rate of stroke in sinus rhythm, efficacy of warfarin, and costs and utilities for long-term warfarin and amiodarone therapy. CONCLUSIONS: Cardioversion alone should be the initial management strategy for persistent nonvalvular atrial fibrillation. On relapse of arrhythmia, repeated cardioversion plus low-dose amiodarone is cost-effective for patients at moderate to high risk for ischemic stroke.

Quality and customers: Type 2 change in mental health delivery within health care reform.

The traditional separation of mental health and medical programs is problematic because mental health issues are inseparable from the larger medical system. By contrast, a collaborative primary care model of mental health care, augmented and supported by secondary specialty mental health services, has the potential to optimize quality and cost goals while reinforcing health care reform principles. The flexibility of mental health treatment in this delivery structure provides opportunities to customize services according to patient and purchaser expectations.

Regulation of cell growth by recombinant oncostatin M.

Oncostatin M is a novel growth regulator originally isolated from differentiated human histiocytic lymphoma cells and activated T-lymphocytes based on its ability to inhibit the growth of A375 melanoma cells. We report here that oncostatin M is a widely acting regulator which alters the growth and/or morphology of cells derived from a variety of cancer cell types. At picomolar concentrations, recombinant oncostatin M inhibited the growth of 13/24 tumor cell lines. Six out of 7 lung cancer cell lines were inhibited by oncostatin M, but none of 6 colon cancer cell lines were affected. Oncostatin M also stimulated the growth of some normal cells (3/6), indicating that it, like many growth regulators, is bifunctional. Oncostatin M receptors appear necessary but not sufficient for a growth response to oncostatin M, since none of the cell lines lacking receptor responded to oncostatin M, whereas many but not all cell lines with receptor responded to oncostatin M. Receptor size (Mr congruent to 150,000) was similar for cells in which growth was inhibited, stimulated, or unaffected by oncostatin M.

Bile acid binding to dietary casein: a study in vitro and in vivo.

1. Studies were carried out in vitro using an ultracentrifugation method to quantify bile acid binding to the different components of a Lundh test meal, and to determine what factors influence bile acid binding to one of the components (casein). We validated the ultracentrifugation method by showing good agreement with the equilibrium dialysis method. Studies were carried out in vivo on jejunal aspirate from 10 ileal resection patients in order to determine whether bile acid binding to casein could be demonstrated, and whether this influenced aqueous-phase bile acid and fatty acid concentrations. 2. In vitro, the Lundh test meal was found to adsorb bile acid. The protein content of the meal (casein) alone accounted for this binding, which was abolished by use of casein hydrolysate. The binding to casein was a saturable process. Both binding affinity and binding capacity were significantly greater for taurocholate at pH 4.5 than at pH 6.5, and for dihydroxylated than for trihydroxylated bile acid, suggesting that hydrophobic bonding was involved. 3. In vivo, jejunal samples aspirated at pH greater than 6 from 10 ileal resection patients showed 25% binding of bile acid to protein. On substitution of amino acids for casein, mean binding was reduced to 16% (P less than 0.05), residual binding being attributed to endogenous protein. This was associated with an increase in fatty acid solubilization from 28% to 60% (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Ileal resection: effect of cimetidine and taurine on intrajejunal bile acid precipitation and lipid solubilisation.

We have investigated whether pH-dependent bile acid precipitation limits lipid solubilisation after ileal resection, and whether treatment with cimetidine, or taurine improves solubilisation. Nine ileal resection patients were treated with placebo, cimetidine and taurine in random order for two weeks each. Upper jejunal content was aspirated and pooled according to pH for three hours after a standard Lundh test meal. On placebo, 50% of the bile acids were precipitated at pH less than 5, compared with only 26% at pH greater than 6, whilst aqueous-phase lipid concentration tended to be lower at pH less than 5 than at pH greater than 6 (5.1 vs 8.2 mmol/l). On cimetidine mean pH rose, particularly during the third hour (6.6 vs 5.8, p less than 0.05), associated with a reduction in bile acid precipitation (13.9 vs 33.1%, p less than 0.05), and an increase in aqueous-phase lipid concentration (10.4 vs 6.6 mmol/l, p less than 0.05). On taurine, the proportion of taurine conjugated bile acids increased (67 vs 22%, p less than 0.01), but there was no significant change in bile acid precipitation or lipid solubilisation. Lower jejunal samples were aspirated similarly from five of these patients on no treatment, and all were at pH greater than 6; apparent 'precipitation' was reduced (16.4 vs 28.1%), but lipid solubilisation did not improve. These findings suggest that pH dependent bile acid precipitation can limit lipid solubilisation within the jejunum after ileal resection, and that these effects can be reduced by cimetidine but not by taurine. Cimetidine may have a role in ileal resection patients with severe steatorrhoea unresponsive to dietary fat restriction.

Effect of intrajejunal acidity on lipid digestion and aqueous solubilisation of bile acids and lipids in health, using a new simple method of lipase inactivation.

We have investigated whether acid-mediated bile acid precipitation, pancreatic enzyme inactivation, and fatty acid partitioning occur in health when intraluminal pH falls below 5. In order to assess lipolysis and aqueous solubilisation of lipid, we first developed a new technique for inactivating lipase in jejunal aspirate (acid inactivation), and showed it to be more effective and simpler than the established technique (heat inactivation). We then studied 14 healthy subjects, aspirating jejunal content for three hours after a liquid meal, and pooling according to pH. Eighteen per cent of the total aspirate was collected at pH less than 5 compared with 56% at pH greater than 6 (p less than 0.01). Forty eight per cent of the bile acids were precipitated at pH less than 5 compared with 18% at pH greater than 6 (p less than 0.01), leading to a reduction in aqueous phase bile acid concentration at low pH (2.1 mmol/l at pH less than 5 vs 5.8 mmol/l at pH greater than 6, p less than 0.01). Lipase activity was reduced at low pH (133 IU/l at pH less than 5 vs 182 IU/l at pH greater than 6, p less than 0.01), leading to reduced lipolysis at low pH (14% at pH less than 5 vs 32% at pH greater than 6, p less than 0.01). Aqueous phase lipid concentration was reduced at low pH (3.5 mmol/l at pH less than 5 vs 12.5 mmol/l at pH greater than 6, p less than 0.01). This reduction was less dependent on bile acid precipitation than on lipase inactivation and fatty acid partitioning. We conclude that intraluminal acidity influences aqueous solubilisation of bile acids and lipid in health.

Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentrations in pancreatic steatorrhoea due to cystic fibrosis.

We have investigated whether jejunal hyperacidity leads to bile acid precipitation and thus limits lipid solubilisation in patients with pancreatic steatorrhoea. Jejunal contents from 12 adults with steatorrhoea due to cystic fibrosis were aspirated for three hours after a liquid test meal, and pooled according to their pH. Thirty eight per cent of the total aspirate was collected at pH less than 5 in cystic fibrosis, compared with 18% in healthy controls (p less than 0.05). Forty six per cent of the bile acids were precipitated at pH less than 5, compared with 15% at pH greater than 6 (p less than 0.01), leading to reduced aqueous phase bile acid concentration at low pH (4.7 mmol/l at pH less than 5 vs 12.5 mmol/l at pH greater than 6, p less than 0.01). Aqueous phase lipid concentrations were reduced at low pH (5.6 mmol/l at pH less than 5 vs 10.2 mmol/l at pH greater than 6, p less than 0.01). Lipolysis and total fatty acid concentrations were greatly reduced and did not vary with pH. We therefore conclude that jejunal hyperacidity leads to bile acid precipitation in pancreatic steatorrhoea due to cystic fibrosis, and imposes a further limitation on lipid solubilisation over that of lipase deficiency.

Hyperthyroidism and acute bronchial asthma.

Asthma may be very mild, at times hard to diagnose; beta blockade should be used only with great caution. An asthmatic who becomes thyrotoxic should be closely monitored for deterioration of the asthma.

Bedtime cimetidine maintenance treatment: optimum dose and effect on subsequent natural history of duodenal ulcer.

Sixty patients, whose duodenal ulcers had healed endoscopically after six weeks of treatment with cimetidine 1 g/day in divided doses, were treated with maintenance cimetidine 800 mg at bedtime for six months. Eighteen relapsed endoscopically (30%). Of the 42 still in remission, 36 then completed a six month double-blind comparison of bedtime cimetidine 400 mg and placebo. Twelve of the 19 (63%) cimetidine-treated patients and 10 of 17 (59%) placebo-treated patients relapsed within six weeks (NS). This high relapse rate on cimetidine contrasts with our earlier trial, in which the six week relapse rate was only two out of 21 (10%) on bedtime cimetidine 800 mg and 16 out of 24 (66%) on placebo (P less than 0.0005). Apart from the difference in the dose of cimetidine, both our trials used the same experimental protocol during the double-blind part of the trial. In the earlier trial, however, there was no period of pretreatment with maintenance cimetidine as in the present trial. The pattern of placebo relapse was similar in both trials. We conclude that bedtime cimetidine maintenance treatment does not alter the long-term natural history of duodenal ulcer once it has been withdrawn; and that either tolerance to cimetidine develops during long-term maintenance treatment, or that bedtime cimetidine maintenance treatment in the conventional dose of 400 mg is not as effective as 800 mg in prevention of endoscopic relapse, although it does reduce symptoms.

H-2-associated differences in replicated strains of mice divergently selected for body weight.

A random-bred strain (Q) was established and divided into six replicates. Each replicate was divergently selected for 6-week weight (for over 30 generations) and each had an unselected control. We have investigated the H-2 haplotype of individual mice of the 18 selected Q strains to determine whether selection for size had also selected for H-2 or H-2-linked genes. From the results it appeared that only the H2b and H-2q haplotypes were present in the foundation stock. A large number of individuals of the six small sublines were of H-2b haplotype, while the majority of those of the six large sublines were of the H-2q haplotype. Individuals in the six control strains were H-2b, H-2q or both (i.e., H-2 heterozygotes and/or H-2 recombinants). These results suggest that control of body size is associated with H-2 or an H-2-linked gene(s).

Mallory-Weiss: suture plication without gastrotomy.

A new method of surgical treatment is described for the Mallory-Weiss tear that is not controlled by conservative measures. This technique uses a team approach combining endoscopy with simultaneous laparotomy to plicate the Mallory-Weiss tear without opening the gastrointestinal tract. We believe this method offers equal or better vision of the lesion than gastrotomy and will significantly lower the morbidity and perhaps the mortality associated with violating the integrity of the gastrointestinal tract.