A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2-/- phenotype.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α-androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

Eigenmodes of brain activity: Neural field theory predictions and comparison with experiment.

Neural field theory of the corticothalamic system is applied to predict and analyze the activity eigenmodes of the bihemispheric brain, focusing particularly on their spatial structure. The eigenmodes of a single brain hemisphere are found to be close analogs of spherical harmonics, which are the natural modes of the sphere. Instead of multiple eigenvalues being equal, as in the spherical case, cortical folding splits them to have distinct values. Inclusion of interhemispheric connections between homologous regions via the corpus callosum leads to further splitting that depends on symmetry or antisymmetry of activity between brain hemispheres, and the strength and sign of the interhemispheric connections. Symmetry properties of the lowest observed eigenmodes strongly constrain the interhemispheric connectivity strengths and unihemispheric mode spectra, and it is predicted that most spontaneous brain activity will be symmetric between hemispheres, consistent with observations. Comparison with the eigenmodes of an experimental anatomical connectivity matrix confirms these results, permits the relative strengths of intrahemispheric and interhemispheric connectivities to be approximately inferred from their eigenvalues, and lays the foundation for further experimental tests. The results are consistent with brain activity being in corticothalamic eigenmodes, rather than discrete "networks" and open the way to new approaches to brain analysis.

Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for Caesarean section.

BACKGROUND: The transversus abdominis plane (TAP) block involves injecting a large volume of local anaesthetic between the muscles of the abdominal wall. Plasma concentrations of ropivacaine after gynaecological laparotomy are potentially high enough to result in systemic toxicity, and there are pharmacokinetic reasons why pregnancy may increase susceptibility to local anaesthetic toxicity. METHODS: Adult female patients (n=30) undergoing elective Caesarean section under spinal anaesthesia received bilateral ultrasound-guided TAP blocks after wound closure (2.5 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood samples were collected at 10, 20, 30, 45, 60, 90, 120, 180 and 240 min following the block. Blood samples were assayed for total and free ropivacaine concentrations. Patients were assessed for symptoms of local anaesthetic toxicity. RESULTS: The mean [standard deviation (SD)] peak total concentration of ropivacaine occurred at 30 min post-injection and was 1.82 (0.69) µg ml(-1). The maximum detected concentration in any patient was 3.76 µg ml(-1) (at 10 min post-injection). Three patients reported symptoms of mild neurotoxicity, and the mean (SD) peak levels were elevated in these patients, 2.70 (0.46) µg ml(-1). CONCLUSIONS: TAP blocks can result in elevated plasma ropivacaine concentrations in patients undergoing Caesarean section, which may be associated with neurotoxicity.

A prospective randomised comparison of the LMA ProSeal™ versus endotracheal tube on the severity of postoperative pain following gynaecological laparoscopy.

Pain and postoperative nausea and vomiting (PONV) are common problems after gynaecologic laparoscopy. Two recent studies have shown that morphine requirements and PONV are lower when an LMA ProSeal™ is used, rather than an endotracheal tube (ETT), for female patients undergoing breast and gynaecological surgery. We conducted a patient and observer-blinded randomised controlled trial, recruiting non-obese women without gastro-oesophageal reflux undergoing laparoscopic gynaecological surgery. Patients received a standardised relaxant general anaesthetic and then were randomised to receive either an LMA ProSeal or an endotracheal tube. Patients were assessed at two and 24 hours post-anaesthesia. The primary outcome was postoperative pain score and secondary endpoints included morphine consumption, postoperative emesis and adverse upper airway symptoms. We recruited 116 patients to the study, 57 patients in the ETT group and 59 patients in the LMA ProSeal group. The patients were similar in demographic and surgical characteristics. At two hours, the ETT group was similar to the LMA ProSeal group in regards to pain scores (Visual Analogue Scale 3.0 vs 3.5, P=0.86), morphine consumption (7.2 vs 7.4 mg, P=0.56) and PONV (47.4 vs 47.5%, P=0.99). After 24 hours, pain scores and PONV rates were also similar. No significant difference in rates of sore throat or dysphagia was observed between the ETT and LMA ProSeal groups. No significant complications were attributable to either airway device. The LMA ProSeal did not decrease pain or PONV in patients undergoing gynaecological laparoscopy when compared to endotracheal intubation.

Interventions at caesarean section for reducing the risk of aspiration pneumonitis.

BACKGROUND: Various interventions are used as prophylaxis for aspiration pneumonitis in obstetric anaesthesia. This review, based on a Cochrane systematic review currently being updated, examines whether interventions given before caesarean section reduce the risk of aspiration pneumonitis. METHODS: Twenty-two studies, involving 2658 women providing data in a usable format for meta-analysis were identified. RESULTS: Compared to no treatment or placebo, there was a significant reduction in the risk of intra-gastric pH <2.5 with antacids (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.09-0.32), H2 antagonists (RR 0.09, 95% CI 0.05-0.18) and proton-pump antagonists (RR 0.26, 95% CI 0.14-0.46). H2 antagonists were associated with a reduced risk of intra-gastric pH <2.5 when compared with proton-pump antagonists (RR 0.39, 95% CI 0.16-0.97), but compared with antacids the findings were unclear. Combined use of antacids plus H2 antagonists was associated with a significant reduction in the risk of intra-gastric pH <2.5 when compared with placebo (RR 0.02, 95% CI 0.00-0.15) or compared with antacids alone (RR 0.12, 95% CI 0.02-0.92). CONCLUSION: The quality of evidence was weak and may not reflect a reduction in the risk of aspiration pneumonitis since none of the studies assessed substantive clinical outcomes or potential adverse effects. Further work is required to validate the suitability of surrogate markers of pH and gastric volume for clinical outcomes in the context of aspiration pneumonitis.

Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block.

BACKGROUND: The transversus abdominis plane block is a novel technique involving injection of local anaesthetic between the internal oblique and the transversus abdominis muscles of the abdominal wall. It is possible that injection of a large dose of local anaesthetic into a relatively vascular plane may result in toxic concentrations. One previously published study examined plasma lidocaine concentrations after transversus abdominus plane block and showed potentially toxic plasma concentrations. Although ropivacaine is most commonly used for this technique, plasma concentrations of ropivacaine after this block have not been reported previously. METHODS: Adult female patients undergoing elective open gynaecological surgery received bilateral ultrasound-guided transverse abdominal plane blocks before surgical incision (3 mg kg(-1) of ropivacaine diluted to 40 ml). Venous blood was collected each 15 min for the first hour, each 30 min for the second hour, and then at 3, 4, 12, and 24 h post-block. RESULTS: Twenty-eight patients were recruited. The mean (sd) peak total ropivacaine concentration occurred 30 min post-injection and was 2.54 (sd 0.75) µg ml(-1). The highest measured concentration was 4.00 µg ml(-1), also 30 min post-injection. Mean total concentrations remained above 2.20 µg ml(-1) for up to 90 min post-injection. The mean unbound peak venous concentration was 0.14 (0.05) µg ml(-1), and the peak was 0.25 µg ml(-1). CONCLUSIONS: Transversus abdominus plane block using 3 mg kg(-1) of ropivacaine produces venous plasma concentrations that are potentially neurotoxic, although broadly consistent with plasma levels found after injection at other comparable sites.

A prospective observational study of the effect of night duty on the cognitive function of anaesthetic registrars.

The issue of fatigue in hospital medical staff represents a potential health and safety risk to both staff and patients, and is receiving worldwide interest. We aimed to characterize the cognitive performance of anaesthetic registrars before and after a series of night shifts. We enrolled nine full-time anaesthetic trainees in an Australian adult tertiary-referral hospital. We conducted a cross-over observational study which tested cognitive performance in participants before and after seven consecutive night shifts and compared this with performance before and after seven consecutive day shifts. Cognitive function was measured using a computerized assessment tool. Participants completed a mean of 62.5% of the requested testing (seven participants completed 87%). There was no significant change in performance before or after any day shift, nor at the commencement of each night shift. There was near perfect accuracy in performance in all tests at all times. There was a statistically significant deterioration in speed of performance for detection and identification tasks at the end of night shift as the week progressed. Anaesthetic registrars demonstrate a significant decline in cognitive performance after a series of night shifts.

Evaluating the performance of the Framingham risk equations in a population with diabetes.

AIMS: The Framingham risk equations are widely used to estimate risk of coronary heart disease (CHD). The purpose of this study was to evaluate the reliability of these equations in predicting CHD risk in people with diabetes and the reliability of using imputed mean HDL-cholesterol values. METHODS: Data describing the baseline characteristics of recognized CHD risk factors for 938 people aged 30-74 years were extracted from the Cardiff Diabetes Database. Data describing CHD events were available for up to 4 years following the baseline year (1996). Several mathematical techniques were used to assess the reliability of predictions provided by the Framingham equations in this population. RESULTS: Thirty-four percent of males and 25% of females who experienced CHD events had a predicted 10-year CHD risk >/= 30%. Seventy-five percent of males and 58% of females had a predicted 10-year CHD risk >/= 20%. Using imputed HDL-cholesterol values, 26% of males and 6% of females who later developed CHD events had a 10-year CHD risk >/= 30%. Using imputed HDL-cholesterol values, the CHD risk predicted by the Framingham equations consistently underestimated the actual risk of CHD events. However, refitting the Framingham risk equations to the Cardiff data resulted in only marginal improvements in discriminatory capabilities. CONCLUSIONS: The Framingham risk equations can be unreliable when applied to the diabetic population, tending to underestimate an individual's probability of progressing to CHD; the equations perform marginally better in women than in men. The use of imputed mean HDL-cholesterol values improved the reliability of the estimates of risk.

Uveal melanomas in black patients: a case series and comparative review.

Uveal melanomas are rare in black patients. Of a total of 2586 patients with the diagnosis of posterior uveal melanoma who were managed in the Oncology Service at Wills Eye Hospital from 1974 to 1987, 10 patients (0.39%) were black. Data on patient age (mean: 53.9 years), sex (male-to-female ratio: 7:3), and relative frequency of disease between black (0.39% of total cases) and white patients were similar to that of previous reports. The distinguishing characteristics (incidence, risk factors, complications, and prognostic indicators) of uveal melanoma in black versus white patients also were reviewed.

Myeloma associated scleromyxedema with extensive involvement of small bowel.

The details of a patient with disseminated scleromyxedema related to multiple myeloma are presented. Investigation demonstrated extensive accumulation of mucopolysaccharides in the skin, bone marrow and the small bowel submucosa. The latter finding is a most unusual manifestation of scleromyxedema and appeared to correlate with the patient's symptoms on presentation.

Nasal catheter use in dacryocystorhinostomy.

A modification of the standard dacryocystorhinostomy (DCR) techniques using a self-retaining nasolacrimal catheter to act as a stent to improve the success rate of nasal ostium patency is described. A series of 21 DCRs performed on 19 patients is presented that includes eight procedures on previously failed DCRs, nine procedures on primary idiopathic obstruction of the nasolacrimal duct, and four procedures where trauma was the etiology. This technique has had no failures except for two procedures that failed because the catheter was too short. This prospective study over 3 years using this technique has resulted in no other cases of closure of the nasal ostium.

High-dose chemotherapy with busulphan and cyclophosphamide and bone-marrow transplantation for drug-sensitive malignancies in adults: a preliminary report.

The technique of high-dose chemotherapy and bone-marrow transplantation takes advantage of any potential dose-response effect in the treatment of cancer and the ability of infused marrow to circumvent severe myelotoxicity. We report our initial experience of 20 high-dose chemotherapy procedures with busulphan and cyclophosphamide as the treatment regimen. Autologous (14 patients), human leukocyte antigen-matched, sibling-allogeneic (five patients) and identical-twin (one patient) transplantations were performed in patients with leukaemias (12 patients), lymphomas (seven patients) or a germ-cell tumour (one patient). One in-hospital and one late death occurred as a result of the toxicity of high-dose chemotherapy. All evaluable patients demonstrated bone-marrow engraftment and became independent of blood transfusions. Five of six patients who were treated in partial remission or relapse obtained a complete remission. Seven patients have relapsed. Eleven patients currently are alive and disease-free and nine patients have returned to their full-time occupations. High-dose chemotherapy can be undertaken with an over-all morbidity that is similar to that which is experienced during the induction chemotherapy of acute leukaemia.

External fixation of complex open humeral fractures.

Seven cases of complex open humeral fractures treated by external fixation are reported. The external fixation allowed the associated injuries to nerves, arteries and soft tissues to be adequately treated. Four cases developed non-union and of these, three cases treated by bone-grafting and plating united, but the one case treated by intramedullary nail without bone-graft did not unite. Frame construction and pin placement are discussed. The recommended plan for treatment of these fractures is initial external fixation until adequate soft tissue healing is achieved and sepsis controlled. Then early bone-grafting and plating is advocated if there is no progressive fracture healing. The problems and advantages encountered in the use of external fixation are also described.

Oral idarubicin as single-agent treatment of acute nonlymphocytic leukemia in poor-risk patients.

Oral idarubicin was given as single-agent treatment of acute nonlymphocytic leukemia in 18 poor-risk patients. They comprised nine previously untreated elderly patients, age range 69-86, and nine relapsed pretreated patients, age range 41-76. Overall, two patients achieved complete remission (including one with preceding refractory anemia with excess of blasts) and seven achieved partial responses. Dose-limiting toxic effects were diarrhea and sepsis. In this limited study, oral idarubicin at a dose of 20-25 mg/m2/day X 3 was a well-tolerated drug with potent antileukemic effects. The oral formulation deserves more widespread evaluation.

Symptomatic ossicles of the lateral malleolus in children.

We describe three children with symptoms of damage to the attachment of an anomalous ossific centre of the lower fibular epiphysis. All three were aged 8 to 10 years at the time of the initial injury, had suffered recurrent ankle sprains and had well localised and consistent tenderness precisely at the site of the anomalous ossific centre. All their symptoms were relieved by excision of the ossicle with reconstitution of the fibular collateral ligament. Whilst a separate secondary centre of ossification at the lower fibula is present in 1% of healthy children between the ages of 6 and 12 years, the condition described is extremely uncommon. Excision of the fragment should be reserved for those patients with recalcitrant symptoms and with consistent tenderness precisely at the site of the accessory ossicle.

Terminal distributions along a 'knight's line' for a stochastic epidemic.

The model under consideration relates to the spread of a disease in a finite population where removal of infectives is allowed to occur. It is equivalent to a restricted random walk over a discrete grid of points interior to a trapezium. We consider an artificial barrier on the grid at which the epidemic ceases. The barrier is a semi-diagonal resembling the path of the knight in chess and allows some simplification of the analysis. In particular, we investigate the probability distribution along this barrier when time is infinite. Recursive relations are obtained for these terminal distributions and are used to develop an exact numerical method for their computation. In certain cases, a slight modification of the binomial distribution provides a good approximation to the actual distribution. A direct recursive method for calculating moments of the distribution is given and we show how the whole distribution may be recovered from these moments.

Vincristine neurotoxicity enhanced in combination chemotherapy including both teniposide and vincristine.

A high incidence of severe peripheral neuropathy occurred during the pilot study of a new regimen for the treatment of non-Hodgkin's lymphoma. The clinically observed incidence and severity of vincristine-induced peripheral neuropathy was considerably enhanced by the sequential use of vincristine and teniposide in this combination chemotherapy.