Planning for cardiac surgical services: advice from an Ontario consensus panel. For the Consensus Panel on Cardiac Surgical Services in Ontario and the Steering Committee of the Cardiac Care Network of Ontario.

The Cardiac Care Network of Ontario (CCN) Consensus Panel on Cardiac Surgical Services drew on the literature and its own expertise to recommend guidelines for expanding services. This report, which is not an official position paper of the Canadian Cardiovascular Society, presents these recommendations. Rates of surgery are linked to diagnostic capacity, requiring increases in interventional therapies to match increases in invasive diagnostic activity. For quality and efficiency, panel members recommend an annual minimum of 150 procedures per surgeon and 500 per centre; a centre should serve a minimum population of 500,000. Services should be as close to patients' homes as possible while maintaining recommended volumes. Expanding the CCN's cardiac surgery database to include other cardiac modalities will yield a more accurate assessment of waiting times. The panel recommends collaborative regional planning associations, mentorship arrangements between new and existing centres, prompt action on human resource shortages and exploration of alternative funding models.

Effects of valproate, vigabatrin and tiagabine on GABA uptake into human astrocytes cultured from foetal and adult brain tissue.

The antiepileptic agents sodium valproate (VPA), vigabatrin (VGB) and tiagabine (TGB) have been proposed to exert their effects, at least in part, by an action on the transport of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This information has, however, been gleaned from studies employing experimental systems derived from animal tissues. We have conducted preliminary studies of the effects of VPA, VGB and TGB on the transport of GABA into primary cultures of human astrocytes, derived from both adult and foetal tissues. Astrocytes were prepared from cerebral cortical tissue obtained from patients undergoing surgery for intractable epilepsy, and from spontaneously aborted foetuses (16-24 weeks gestation). The cells were isolated via a series of enzymatic digestions, grown under standard culture conditions for around 21 days and then assayed for GABA uptake activity. VPA (1,000 microM), VGB (100 microM) and TGB (200 nM) all significantly (p < 0.05) reduced the uptake of GABA into primary cultures of human adult astrocytes following a one hour exposure. VPA (1,000 microM) and VGB (100 microM) similarly reduced GABA uptake into astrocytes derived from human foetal tissue, while TGB (200 and 500 nM) was without effect. The results of these preliminary studies suggest that VPA and VGB reduce GABA transport into both adult- and foetally-derived human astrocytes, whereas TGB appears active only in cells cultured from adult brain. Delayed development of the GAT-1 transporter in foetal tissue could explain this observation.

Peripheral benzodiazepine receptors in platelets of epileptic patients.

Tolerance to the anticonvulsant effect of benzodiazepines is likely to involve changes at the central benzodiazepine-GABA receptor complex. Peripheral benzodiazepine receptors (pBZRs), which can be measured in platelets, may also be involved. Using a binding assay with [3H]-PK 11195 as radioligand, pBZRs were assayed in platelets of patients taking a variety of antiepileptic drugs (AEDs). Comparisons were made with untreated patients. pBZR receptor density (mean +/- s.e. mean) was increased vs controls (8083 +/- 557 fmol mg-1 protein) in the platelets of patients taking a polypharmacy regime including the benzodiazepine clobazam (12661 +/- 1011 fmol mg-1 protein, P < 0.005) and also in those receiving sodium valproate as monotherapy (15003 +/- 1756 fmol mg-1 protein, P < 0.01). The significance of these findings is unclear, but the use of a specific pBZR antagonist may be a promising avenue for investigating the mechanism of BZ tolerance and its prevention.

Lack of major effects on mouse brain adenosine A1 receptors of oral carbamazepine and calcium antagonists.

Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs.

Cholelithiasis in patients with variegate porphyria.

Four patients with variegate porphyria (VP) who developed symptoms attributable to cholelithiasis are described. Elective cholecystectomy was performed uneventfully in two of these patients in whom the diagnosis of porphyria had previously been made. The third patient was not known to have porphyria at the time of surgery and developed a fulminating attack which proved fatal. The major haem precursor overproduced in VP is protoporphyrinogen and protoporphyrin was present in the gallstones available for analysis. Our experience suggests that patients with VP have an increased risk of cholelithiasis which may be related to the overproduction of protoporphyrinogen and increased bile concentration of protoporphyrin.

Overconfidence among physicians and nurses: the 'micro-certainty, macro-uncertainty' phenomenon.

Overconfidence in clinicians was examined in two independently designed studies, each using a different research approach. The first study examined treatment choices of physicians in treating breast cancer, and the second rapid decision making among nurses working in Intensive Care Units. In both studies, individual respondents were highly confident they had made the right choice ('micro-certainty'), although there was no consensus across respondents as to what the optimal treatment would be ('macro-uncertainty'). The difference between micro-certainty of individuals and macro-uncertainty within the clinical community may cast some light on the persistence of practice variation. The implications of overconfidence in clinical treatment for patients, practitioners, and professional regulation are discussed.

Health care in Canada: current trends and issues.

Canada's universal health care system is perceived as threatened by rising costs, an aging population, and technological growth. This popular and successful program has largely kept costs under control while maintaining quality and ensuring equity. However, its success demonstrates the limits of medical care; remaining health problems are less amenable to improvement by merely improving access to traditional services. A widening view of health implies a larger health role in other policy arenas, and a larger group of legitimate participants; coordinating an evolving and expanding system becomes increasingly difficult. Policy options include some combination of laissez faire, business as usual, managed care, manpower regulation, and system change. Change implies controversy and conflict. Hard decisions are clearly ahead.

Variations in breast cancer treatment decisions and their impact in mounting trials.

Clinical trials are often hindered by insufficient participation. Difficulties may arise if a clinician is generally reluctant to enroll patients in clinical trials, if the clinician is unwilling to enroll a patient in a particular trial, or if the patient refuses to participate. In our three-stage survey of clinicians treating breast cancer, we found that a favorable orientation to trials in principle can be attenuated when clinicians do not like the treatment regimens in a particular trial. We also found a lack of consensus as to appropriate treatment for breast cancer coupled with a high confidence by individual clinicians in their own treatment decisions (a phenomenon we term "micro-certainty/macro-uncertainty"). Accordingly, in the most controversial situations, it may be hardest to mount trials. Trial design is also complicated by the variation among clinicians in the importance they assign to various patient characteristics in making their treatment decisions. This variation can lead to difficulties in establishing patient subgroups that will be accepted by the clinical community. The trial designer will need to be alert to these considerations; efforts to build consensus on which data are necessary and which therapies are acceptable should improve the design and application of clinical trials.

Who still prefers aggressive surgery for breast cancer? Implications for the clinical applications of clinical trials.

Conservative breast surgery and modified radical mastectomy may, according to recent reports, yield equivalent survival. Analysis of a 1985 Canada-wide study (N = 228) compared surgeons and oncologists still recommending modified radical mastectomy (30%) with those recommending less aggressive surgery (69%) for a hypothetical stage I patient. The groups did not differ significantly in most physician characteristics, estimated survival and cure probabilities, importance of most treatment goals, uncertainty about treatment choice, or most attitudinal responses. Although equally involved with and cognizant of the value of clinical trials, the modified radical group expressed more skepticism about the ability of trial results to be transferred to practice and to take sufficient account of patient uniqueness, indicating greater focus on variation than mean results. Trial results might be more readily adopted if they are reported in accessible data-bases, incorporating patient characteristics potentially relevant to treatment choice. This would allow clinicians to individualize treatment by analyzing patient subsets of their own choosing.

Enhanced oral bioavailability of meptazinol in cirrhosis.

Kinetic analysis was carried out after single intravenous (25 mg) and oral (200 mg) doses of the novel partial opioid agonist meptazinol (Meptid) in patients with non-cirrhotic liver disease (NCLD) and biopsy proven cirrhosis. Comparison was made with a group of patients with normal hepatic function. Elimination half-lives after the intravenous dose were slightly prolonged in the cirrhotics (n = 10; 4.2 +/- 0.6 h) compared with the control (n = 8; 2.7 +/- 0.2 h: p less than 0.05) and NCLD (n = 8; 3.2 +/- 0.5 h) groups. There was no significant difference in meptazinol plasma clearance between the groups (cirrhotics = 72 +/- 8 l/h; NCLD = 89 +/- 9 l/h; control = 83 +/- 10 l/h). After the oral dose, seven of 15 cirrhotic patients vomited but only one patient in each of the other groups was unable to tolerate the drug (p = 0.06). This may be explained by very much higher peak meptazinol concentrations in the cirrhotic (n = 8; 184 +/- 37 ng/ml, p less than 0.01) and NCLD (n = 8; 131 +/- 38 ng/ml, p less than 0.05) patients than those of the controls (n = 7; 53 +/- 12 ng/ml) reflecting a mean four-fold and two-fold increase in oral bioavailability respectively (cirrhotics: n = 8; 27.9 +/- 5.3%: p less than 0.001; NCLD: n = 7; 13.7 +/- 3.9% p less than 0.05; controls: n = 7; 6.5 +/- 1.3%). There was no evidence of accumulation after chronic dosing with 200 mg meptazinol four times daily for 13 doses in seven control, seven NCLD and six cirrhotic patients. There were no detectable differences in psychomotor function measured objectively using the Leeds Psychomotor Tester of subjectively by linear analogue scoring between the groups in all three parts of the study. The oral use of meptazinol in patients with chronic liver disease is associated more with the development of nausea and vomiting rather than excessive sedation. These data suggest that dosage reduction in cirrhotic patients is advisable particularly if the drug is taken by mouth.

The effect of verapamil on the pharmacokinetics of adriamycin.

The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.

Heme biosynthesis in Friend erythroleukemia cells: control by ferrochelatase.

The activities of the enzymes of heme biosynthesis (except protoporphyrin oxidase) have been followed during the induction of Friend cells in culture. All the enzyme activities increased after induction with dimethyl sulfoxide. The activities of the intermediate enzymes were much higher than those of delta-aminolevulinate synthase [succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37], the initial enzyme, or ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1), the final enzyme of the pathway. Ferrochelatase activity was not detectable in the uninduced cell. delta-Aminolevulinate synthase activity increased during the first 24 hr of induction; porphobilinogen deaminase activity began to increase after 48 hr and ferrochelatase activity, after 72 hr. However, the induction of heme synthesis followed the same time course as that of ferrochelatase activity, not that of delta-aminolevulinate synthase activity. The cellular growth medium was found to contain traces of protoporphyrins. Thus, ferrochelatase is shown to be rate limiting for heme synthesis during early stages of Friend cell induction. A Friend cell variant (Fw), which is not inducible except in the presence of exogenous hemin, was also studied. All the enzymes of heme synthesis except ferrochelatase were inducible by butyric acid. Ferrochelatase was not inducible by butyric acid or hemin plus butyric acid. These cells also excrete protoporphyrin, The failure to induce ferrochelatase activity is believed to be the cause of, not a consequence of, the noninducibility of this cell line.

Alcohol and absorption from the small intestine. 2. Effect of ethanol on ATP and ATPase activities in guinea-pig jejunum.

After the exposure of isolated segments of guinea-pig jejunum to 2% ethanol for one hour, a significant reduction (P less than 0-001) in the adenosine triphosphate content (ATP) was observed when compared with levels found in segments perfused with Krebs' solution. However, no alteration was noted in the activity of adenosine triphosphatase (ATPase). The chronic administration of 50% ethanol in a dose of 2-5 g/kg for two weeks did not affect either the ATP content or ATPase activity in jejunal mucosa.