The future United Kingdom anaesthetic workforce: training, education, and role boundaries for anaesthetists and others.

Anaesthesia is the largest hospital-based specialty in the UK, and the activities of the anaesthesia workforce underpin the care of all patients in the hospital sector. Changes in the way care will be delivered in the future will impact on the workforce as a consequence of patient requirements and funding issues. This article considers these and other factors in the context of the current and future workforce.

Targeting gene expression to cones with human cone opsin promoters in recombinant AAV.

Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long- and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.

Outcomes of postoperative septic arthritis after anterior cruciate ligament reconstruction.

Arthroscopically guided reconstruction of the anterior cruciate ligament is a common orthopaedic procedure. While many associated complications have been described in the literature, postoperative septic arthritis has received little attention. Although rare after anterior cruciate ligament reconstruction, septic arthritis can have devastating consequences. From a group of 831 consecutive patients, we report 4 (0.48%) who sustained septic arthritis. All patients had similar symptoms and were treated by the same surgeon in the same manner. All underwent immediate arthroscopic lavage, open incision, drainage of associated wounds, debridement with graft retention, and treatment with intravenous and then oral antibiotics. The patients underwent an average of 2.75 procedures after the diagnosis to eradicate the infection and restore knee motion. All patients were evaluated at an average of 3 years after surgery. We found that previous knee surgery and meniscal repair were risk factors for the development of postoperative septic arthritis. The infection was successfully eradicated, the ligament graft was preserved, and knee stability and mobility were adequately restored in all patients. However, the clinical outcome of these patients appeared to be inferior to that of patients who had undergone uncomplicated anterior cruciate ligament reconstruction. This inferior outcome appeared to be secondary to damage to the articular cartilage from the infection.

Glucocorticoid resistant asthma: T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppressive agents.

We have previously shown that T-lymphocytes from clinically glucocorticoid (GC) resistant asthmatics are more refractory to dexamethasone suppression in vitro than those of GC sensitive asthmatics. We wished to extend these observations to compare three GCs used topically for asthma therapy (budesonide, beclomethasone dipropionate and fluticasone 17 alpha-propionate) and three immunosuppressive drugs (cyclosporin A, FK506 (tacrolimus) and mycophenolate mofetil) with dexamethasone for their antiproliferative effects on T-lymphocytes from GC sensitive and resistant asthmatics, and also to compare the rates of steroid metabolism by T-lymphocytes from these patients. Antiproliferative activity of the drugs was measured on peripheral blood T-lymphocytes activated with phytohaemagglutinin (PHA) and anti-CD3 antibody in vitro. The rates of total steroid metabolism and 20 alpha-hydroxylation by T-cell homogenates were measured using radiolabelled progesterone as an established probe substrate. Over a wide concentration range, T-lymphocytes from GC resistant asthmatics were significantly less inhibited by all four GCs as compared with cells from GC sensitive asthmatics. The median inhibitory concentrations (IC50) for inhibition of T-lymphocytes from the GC resistant asthmatics exceeded those likely to be achieved therapeutically by systemic administration (although higher concentrations might in theory be achieved locally in the bronchial mucosa by inhaled administration). In contrast, all three immunosuppressive drugs at putative therapeutic concentrations inhibited T-lymphocytes both from GC sensitive and resistant asthmatics with equivalent potency. The rates of total metabolism and 20 alpha-hydroxylation of steroid by homogenates of T-lymphocytes from GC sensitive and resistant asthmatics were equivalent. Thus, relative GC resistance in T-lymphocytes from GC resistant as compared with sensitive asthmatics is: 1) manifest with GC molecules of variable molecular structure; 2) not accompanied by elevated intracellular metabolism of steroids; and 3) overcome by immunosuppressive drugs which inhibit T-lymphocytes by non-GC-mediated mechanisms. We conclude that current anti-asthma glucocorticoids at therapeutic concentrations are unlikely to be of benefit for the therapy of glucocorticoid resistant asthma, and that other immunosuppressive drugs may have potential as therapeutic agents in these patients.

Excretion and metabolism of tipredane, a novel glucocorticoid, in the rat, mouse, monkey, and human.

The excretion and metabolism of [3H]tipredane, a novel glucocorticoid, has been studied in mice, rats, marmosets, rhesus and cynomolgus monkeys, and humans. After oral administration, [3H]tipredane was rapidly absorbed, metabolized, and excreted into urine and feces. In mice and male rats, radioactivity was excreted primarily into feces or bile, whereas in female rats, monkeys, and humans, excretion was mainly via the renal route. Some sex differences in the proportions excreted into urine and feces were noted in rodents, with females eliminating relatively more radioactivity in urine. Tipredane was shown to be extensively metabolized, but the routes were highly species-dependent and, in the rat, they were sex-dependent. Unchanged tipredane was not detected in any urine, bile, or blood extracts. Urinary and blood extract profiles indicated that there were between 10 and 30 metabolites in rats and mice, the majority of which constituted < 2% of the dose. In these species, the major pathways involved loss of the thioethyl moiety, S-oxidation of the thiomethyl group, and saturation of the adjacent saturated C16-17 bond. Hydroxylation of the steroid B-ring was seen in the 7 alpha-position in mice and female rats, and in the 6 beta-position in male rats. Metabolism of tipredane in rhesus and cynomolgus monkeys and humans was similar, but less extensive and different to that seen in rodents. The major products, the 6 beta-hydroxylated sulfoxide and sulfone metabolites of tipredane, accounted for 21-36% of the dose in human and monkey urine, and were also major components in blood. In contrast to mice and rats, S-oxidation and an unsaturated C16-17 bond were evident in primates. Metabolism of tipredane was rapid and complex, with significant species differences, although the disposition in rhesus and cynomolgus monkeys seemed to be similar to humans.

Induction of rodent hepatic drug-metabolizing enzyme activities by the novel anticonvulsant remacemide hydrochloride.

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme induction. To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague-Dawley rats dosed by gavage with FPL 12924AA (250 mg base.kg-1.day-1 for 28 days) or an equivalent volume of vehicle (controls). The interpretation of the findings was aided by comparison with the effects of phenobarbitone (75 mg.kg-1.day-1 ip for 4 days) and beta-naphthoflavone (a single intraperitoneal dose at 80 mg.kg-1.day-1). No significant changes in total hepatic P450 levels (1.44 +/- 0.40 nmol.mg-1 vs. 1.31 +/- 0.19 nmol.mg-1 in controls) or ethoxyresorufin O-deethylase activity (a CYP1A induction probe) were observed after remacemide treatment. The pattern of induction produced by remacemide was very similar to that observed with phenobarbitone. The nonspecific CYP-dependent reaction ethoxycoumarin O-deethylation was induced approximately 2-fold. The specific CYP2B markers pentoxyresorufin O-depentylase and 16 beta-hydroxytestosterone production were both increased markedly by FPL 12924AA (approximately 100- and 20-fold, respectively). 2 beta- and 6 beta-Hydroxytestosterone production were also elevated, indicating the induction of CYP3A1/2. Similar effects on isoform-selective P450-dependent activities were observed in male and female mice treated with remacemide as part of a dose-ranging study.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum F-protein concentration following halothane or isoflurane anaesthesia.

We have investigated the prevalence of hepatic injury following uncomplicated anaesthesia using a sensitive and specific marker of hepatic damage, the serum F-protein concentration. The median variation in serum F-protein in fit adults over six days is 16 ng/ml, minimum 0 ng/ml, maximum 36 ng/ml. A significant rise in serum F-protein was demonstrated six days following anaesthesia and surgery, but not earlier after 3 or 24 h. There was no significant difference between patients who received halothane (n = 12) or isoflurane (n = 13). These changes were not related to duration of anaesthesia, quantity of delivered volatile agent or mode of ventilation. Hepatocellular damage may occur following anaesthesia for minor surgery.

Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme, in the rat.

1. The route of elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme (ACE), has been investigated in the anaesthetized rat. Comparisons have been made with other ACE inhibitors. 2. Bile and urine samples were collected over a 5 hour period following a single i.v. dose of ACE inhibitor (2 mumol kg-1). Samples were bioassayed for ACE inhibitory activity using affinity-purified rabbit lung ACE and the amounts of the active form of inhibitor present in each sample were calculated by comparison with a standard curve. 3. FPL 63547 was rapidly and extensively excreted as the diacid in the bile but appeared in the urine in negligible amounts. The bile:urine ratio was 21.4:1 indicating a marked preference for the biliary route. A similar elimination profile was observed when the compound was dosed in its active form (FPL 63547 diacid), 87.9% of which was found in the bile over the 5 h collection period, with a bile: urine ratio of 14.6:1. 4. The marked preference of FPL 63547 for biliary elimination was not shared by the other ACE inhibitors tested in this study. Lisinopril demonstrated the opposite pattern, being excreted almost exclusively by the kidney (bile:urine ratio 0.06:1). Enalapril was eliminated in approximately equal amounts in bile and urine (ratio 0.7:1) while spirapril diacid showed a slight preference for the bile (ratio 2.6:1). 5. The physical chemical properties of FPL 63547 diacid may be responsible for its unusual preference for biliary elimination. In particular, the amphipathic character and strong acid functionality of the compound are thought to favour transport into the bile. 6. Elimination by the biliary route will be preferred in patients whose renal function is impaired as a result of disease or age. In such patients the elimination of renally-excreted ACE inhibitors is known to be compromised, resulting in compound accumulation and the need for closer monitoring. Therefore, the elimination profile of FPL 63547, if confirmed in man, may prove to be clinically advantageous.

The predominance of IgG3 and IgM isotype antimitochondrial autoantibodies against recombinant fused mitochondrial polypeptide in patients with primary biliary cirrhosis.

Autoantibodies against inner mitochondrial membrane proteins are a hallmark of primary biliary cirrhosis. Specifically, these antimitochondrial autoantibodies recognize two polypeptides of approximately 70 and 52 kD, respectively. Although the specificity of antimitochondrial autoantibodies has been studied for the past 2 decades, the complementary DNA encoding the major primary biliary cirrhosis-specific 70 kD antigen has only recently been cloned. The availability of the recombinant autoantigen has resulted in the development of a highly sensitive and specific ELISA to detect antimitochondrial autoantibodies and to determine their immunoglobulin isotypes. We report herein that IgG3 is the predominant isotype of antimitochondrial autoantibodies in a group of 74 primary biliary cirrhosis patients. This finding is significant in light of the genomic immunoglobulin in heavy chain gene arrangement. Ninety-three per cent of primary biliary cirrhosis patients possessed IgG3 antimitochondrial autoantibodies with titers of 1:10(3) or higher; 32% of these patients possessed titers of 10(4), 29% at 10(5) and 7% at 10(6). IgM antimitochondrial autoantibodies were next most prevalent; 63% of the patients were positive and 50% of these patients showed titers of 10(3), 43% at 10(4) and 6% at 10(5). Other isotypes were present but in much lower titer and occurrence. Isotypes of antimitochondrial autoantibodies reactive to the 52 kD antigen were also determined using immunoblotting techniques. The predominance of IgG3 and IgM were similarly observed. Finally, the serum immunoglobulin isotype levels of primary biliary cirrhosis patients were compared with healthy normal adults by radial immunodiffusion. Serum IgG3 and IgM were very elevated in primary biliary cirrhosis; with IgG3 at 5.5-fold and IgM at 4.3-fold above normals.(ABSTRACT TRUNCATED AT 250 WORDS)

Duty to warn third parties.

KIE: The 1976 Tarasoff decision in California imposes a duty on psychotherapists to take action to prevent a dangerous patient from harming another party. Subsequent court cases have elaborated on this duty, which poses a serious threat to the confidentiality of the therapist patient relationship. Concern has also arisen about the application of the duty to self-inflicted harm, property damage, or unidentified victims; expansion of the duty beyond warning victims; and prediction of dangerousness. After reviewing the pertinent court actions, the author briefly suggests ways for therapists to handle these issues.^ieng