Strong dose response after immunotherapy with PQ grass using conjunctival provocation testing.

BACKGROUND: Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose. METHODS: Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31-41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship. RESULTS: In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature. CONCLUSIONS: PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.

Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy.

BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

Utilising green and bluespace to mitigate urban heat island intensity.

It has long been recognised that cities exhibit their own microclimate and are typically warmer than the surrounding rural areas. This 'mesoscale' influence is known as the urban heat island (UHI) effect and results largely from modification of surface properties leading to greater absorption of solar radiation, reduced convective cooling and lower water evaporation rates. Cities typically contain less vegetation and bodies of water than rural areas, and existing green and bluespace is often under threat from increasing population densities. This paper presents a meta-analysis of the key ways in which green and bluespace affect both urban canopy- and boundary-layer temperatures, examined from the perspectives of city-planning, urban climatology and climate science. The analysis suggests that the evapotranspiration-based cooling influence of both green and bluespace is primarily relevant for urban canopy-layer conditions, and that tree-dominated greenspace offers the greatest heat stress relief when it is most needed. However, the magnitude and transport of cooling experienced depends on size, spread, and geometry of greenspaces, with some solitary large parks found to offer minimal boundary-layer cooling. Contribution to cooling at the scale of the urban boundary-layer climate is attributed mainly to greenspace increasing surface roughness and thereby improving convection efficiency rather than evaporation. Although bluespace cooling and transport during the day can be substantial, nocturnal warming is highlighted as likely when conditions are most oppressive. However, when both features are employed together they can offer many synergistic ecosystem benefits including cooling. The ways in which green and bluespace infrastructure is applied in future urban growth strategies, particularly in countries expected to experience rapid urbanisation, warrants greater consideration in urban planning policy to mitigate the adverse effects of the UHI and enhance climate resilience.

Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar.

OBJECTIVE: To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. METHODS: 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 microg (ex-actuator, equivalent to 1,600 microg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry. RESULTS: There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC(0 - inf)) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t1/2) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups. CONCLUSION: After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.

The monoterpenes of Artemisia tridentata ssp. vaseyana, Artemisia cana ssp. viscidula and Artemisia tridentata ssp. spiciformis.

Monoterpenes from three different members of the Anthemideae family, Artemisia tridentata ssp. vaseyana, Artemisia cana ssp. viscidula and Artemisia tridentata ssp. spiciformis were isolated and their structures determined using spectroscopic techniques. A total of 26 irregular and regular monoterpenes were identified. Among these, 20 had previously been identified in the Anthemideae family. Of the remaining six, four were known, but previously unidentified in this family. 2,2-Dimethyl-6-isopropenyl-2H-pyran, 2,3-dimethyl-6-isopropyl-4H-pyran and 2-isopropenyl-5-methylhexa-trans-3,5-diene-1-ol were isolated from both A. tridentata ssp. vaseyana and A. cana ssp. viscidula. The irregular monoterpene 2,2-dimethyl-6-isopropenyl-2H-pyran has a carbon skeleton analogous to the biologically important triterpene squalene. Two additional irregular monoterpenes, artemisia triene and trans-chrysanthemal were isolated from A. cana ssp. viscidula and lavandulol was isolated from A. tridentata ssp. spiciformis. This is the first time a compound possessing a lavandulyl-skeletal type has been found in the Anthemideae family.

Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly.

OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and tolerance of epoetin alfa administered subcutaneously (s.c.) once weekly (q.w.) and three times weekly (t.i.w.). METHODS: An open-label, randomized, parallel-design study was conducted in 36 healthy adults with hemoglobin (Hb) levels of 11.7 14.0 g/dl for women and 13.0-14.8 g/dl for men. Subjects were randomized to epoetin alfa 150 IU/kg s.c. t.i.w. or 40,000 IU s.c. q.w. for 4 weeks. Serum erythropoietin concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). Pharmacokinetic parameters [peak serum concentration (Cmax), mean predose trough concentration (Cmin), time to Cmax (tmax), clearance after s.c. administration (CL/F), area under the plasma concentration time curve (AUC), and terminal elimination half-life (t 1/2)] were calculated using model-independent methods. Mean changes from baseline and AUC of percentage reticulocytes, Hb, and total red blood cell (RBC) concentrations over the 1-month study period were calculated. RESULTS: The Cmax values for serum epoetin alfa q.w. were six times and AUC(0-168) values three times that of the t.i.w. regimen. Time profiles of changes in percentage reticulocytes, Hb, and total RBC over 1 month were similar between regimens. The rate of increase in Hb was similar for the two groups, and both groups exhibited a 3.1-g/dl increase in mean Hb levels from baseline through day 29. Changes in ferritin levels were generally similar between groups and reflected expected use of iron stores for Hb production. Epoetin alfa administered t.i.w. or q.w. was well tolerated and no serious adverse events occurred. CONCLUSION: The pharmacodynamic responses were equivalent between groups despite expected differences in total erythropoietin exposure. These results indicate that the epoetin alfa 150 IU/kg t.i.w. and 40,000 IU q.w. regimens can be considered clinically equivalent.

Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis.

BACKGROUND: Many human prostate cancer cells have escaped the apoptotic effects of natural regulators of cell growth such as transforming growth factor betal (TGF beta-1) and tumor necrosis factor (TNF). METHODS: Prostate cancer cell growth was investigated by treating with antioxidants. DU-145 (androgen-unresponsive), LNCaP (androgen-responsive), and ALVA-101 (androgen moderately responsive) were grown in RPMI-1640 medium supplemented with bovine fetal calf serum and antibiotics, and were treated with various antioxidants for 1-7 days. Cell growth was then determined with the Cell Titer 96 AQ assay, and apoptosis was assessed by cell death detection ELISA, nuclear morphology, and TUNEL techniques. RESULTS: Cells treated with or without (+/-)-alpha-tocopherol (vitamin E) for 1-7 days at concentrations from 0.078-2.5 microg/ml modestly affected cell growth compared to other antioxidants tested. Tocopherol produced a significant (P < 0.01) inhibition of ALVA-101 and LNCaP (10-24% of control; 0.078-2.5 microg/ml; at 6 days; n = 6). DU-145 cells were not growth-inhibited significantly. However, pyrrolidinedithiocarbamate (PDTC) produced a significant (P < 0.01, n = 6; 17-80% of control; 2.5-20 microg/ml; 1-7 days) inhibition of DU-145 and ALVA-101 cells. A significant (P < 0.01) and maximum inhibition of LNCaP cells occurred at all concentration of PDTC (2. 5-20 microg/ml). A third compound, diethyldithiocarbamic acid (DETC), incubated for 1-7 days, produced a significant dose response suppression of cell growth of DU-145 and ALVA-101 cells (P < 0.01; 14-88% of control; 1.25-80 microg/ml; n = 6). LNCaP cells were inhibited by DETC (P < 0.01; 28% of control; 1.25-80 microg/ml; n = 6). All three antioxidants tested stimulated apoptosis in actively dividing ALVA-101, DU-145, and LNCaP cells (P < 0.01; n = 6), but confluent cells were affected less. Testosterone had additive inhibitory effects when combined with PDTC in ALVA-101 cells; however, the other cell lines were not influenced. CONCLUSIONS: These results demonstrate that antioxidants modulate human prostate cancer cell proliferation by altering apoptosis in dividing cells, and this necrosis or apoptosis in confluent cells is not as effective.

Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir.

Zanamivir is a potent and specific inhibitor of influenza A and B virus neuraminidase, that is now approved for the treatment, and is currently under development for the prophylaxis of influenza. To assess the safety of this drug in asthmatics, 13 subjects with mild/moderate asthma [forced expiratory volume in 1 sec (FEV1)> or =70% predicted, reversibility of FEV1 to salbutamol > or =15%, concentration of methacholine causing a drop of 20% in the FEV1 (PC20FEV1)< or =8 mg ml(-1)], were recruited to a double-blind, randomized, placebo controlled, two way cross-over study. Subjects received 10 mg zanamivir as a dry powder (2 x 5 mg blisters via a Diskhaler Sovnn Plastics Ltd., Berkshire, U.K.), or a matching placebo, twice daily on day 1 and then four times daily from day 2 to day 14, in two separate periods separated by a washout period of 7 days. PC20FEV1 to methacholine was determined pre-study, on day 1 after the evening dose and on day 14 after the last dose of the study drug. FEV1 was measured pre-study and at regular intervals on days 1 and 14. Laboratory safety tests were performed on days 1, 7 and 15. Morning and evening peak expiratory flow rate (PEFR) and any adverse events were recorded in a diary card. Eleven subjects completed the study. One was withdrawn due to non-compliance, and one due to an adverse event that occurred during the placebo period. On day 1 the geometric mean PC20 for zanamivir was 36% lower than for placebo [ratio to placebo 0.64, (90% CI 0.44, 0.93)] and on day 14 this was 33% lower with zanamivir [ratio to placebo 0.67 (90% CI 0.38, 1.15)]. Both these confidence intervals were within the pre-defined interval of 'no clinically significant effect' of 0.25-4 (i.e. a change of two doubling doses of methacholine PC20FEV1 which was considered clinically significant). The time weighted mean FEV1 was 0.15 l (5.4%) lower for zanamivir on day 1 compared to placebo (90% CI 0.03, 0.28; P=0.050) and 0.01 l higher compared to placebo on day 14 (90%CI -0.12, 0.10; P=0.912). The day 1 changes were not associated with any significant symptoms or requirement for rescue bronchodilator therapy. Furthermore there was no apparent treatment difference over the 14 day dosing period in FEV1 data (90% CI: -0.11, 0.05, P=057). The mean morning PEFR was 4 l min(-1) less for zanamivir than for placebo (90% CI: -11, 3) and mean evening PEFR was 9 l min(-1) less (90% CI: -24, 5). The study treatments were well tolerated by the subjects with no clinically significant adverse events attributable to zanamivir treatment. Zanamivir inhaled as a dry powder does not significantly affect the pulmonary function and airway responsiveness of subjects with mild/moderate asthma and therefore its use in such patients subjects is not precluded.

Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group.

BACKGROUND: Montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta(2)-receptor agonist, each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction (EIB) in short-term studies. Direct comparisons between these agents in long-term studies are limited. OBJECTIVE: We sought to compare montelukast and salmeterol in the long-term treatment of EIB. METHODS: One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1) of at least 18% were randomized (double-blind) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks. Exercise challenge was repeated at day 3, week 4, and week 8 after randomization near the end of the dosing interval for both drugs. The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1) at week 8. RESULTS: Montelukast was effective in treating EIB without inducing tolerance and provided superior (P

Randomized trial of cyclosporine microemulsion (neoral) versus conventional cyclosporine in liver transplantation: MILTON study. Multicentre International Study in Liver Transplantation of Neoral.

BACKGROUND: The new microemulsion formulation of cyclosporine (Neoral) has been developed in an effort to improve the reliability of drug absorption. The objectives of this study were to assess the efficacy, safety, and tolerability of Neoral compared to the original formulation (Sandimmun) in liver transplant recipients. METHODS: In a double-blind, parallel group study conducted in 28 centers across Europe and the United States, patients receiving primary orthotopic liver allografts were randomized within 24 hr of transplantation, 198 to Neoral and 192 to Sandimmun. Patients with and without T-tube biliary drainage were included. Postoperatively, all patients also received intravenous (i.v.) cyclosporine, together with prednisolone and azathioprine. Antibody induction was excluded. Efficacy measures were rejections, graft failure, patient survival, and the efficacy of the study medication in achieving the desired cyclosporine blood levels. Safety was assessed by reported adverse events, blood pressure, serum creatinine, and other routine laboratory measurements. RESULTS: Kaplan-Meier analyses showed that the Neoral group performed better than the Sandimmun group, with the estimates for patients free of treated rejection and histologically confirmed rejection either showing or approaching statistical significance at the 5% level. By 52 weeks, 5.8% (95% confidence limits: -4.4-15.9%) fewer patients required treatment of acute rejection in the Neoral group. The proportion of patients experiencing at least one treated rejection episode by 2 weeks was 29.8% for Neoral and 43.2% for Sandimmun. For histologically confirmed rejection, these proportions were 32.8% and 44.3%, respectively. The proportion of patients experiencing at least one steroid-resistant rejection was 2.0% for Neoral and 6.3% for Sandimmun at week 2, and 3.0% and 9.9%, respectively, at week 3. All these differences were significant at P<0.05. By 52 weeks, graft failure was 6.3% on Neoral and 11.4% on Sandimmun, with respective patient survival figures of 85.4% and 85.8%. The median duration of the initial episode of i.v. cyclosporine was 4.0 days for Neoral, compared to 6.5 days for Sandimmun (P<0.001). Within the first 2 weeks, a larger percentage of patients in the Neoral group reached the lower target level of cyclosporine (P< or =0.01). The weight-adjusted daily doses of study medication were lower in the Neoral group (median dose: 4.86 vs. 5.42 mg/kg/day, P=0.001), but the blood levels of cyclosporine showed no difference. For those with a T-tube, more of the patients on Neoral remained free of treated rejection throughout the study period (P=0.042, Wilcoxon). By week 2, 44.9% of these patients in the Sandimmun group required treatment for rejection compared to 30.2% in the Neoral group (P=0.007). There was no significant difference between the groups for serum creatinine, blood pressure, other biochemical and hematological variables, or reported adverse events. CONCLUSIONS: In liver transplantation in the normal clinical setting, the pharmacokinetic advantages of Neoral translate into clinical superiority over Sandimmun without a negative impact on safety. Recent data indicate that it is not optimal to use i.v. cyclosporine initially in this type of study, but the benefit was seen despite this. In keeping with the previous pharmacokinetic studies, patients managed by T-tube biliary drainage, and hence with no or limited bile available in the gastrointestinal tract, did particularly well with Neoral.

The Spacehaler for delivery of salbutamol: a comparison with the standard metered-dose inhaler plus Volumatic spacer device.

The Spacehaler is a new, compact, pressurized aerosol device that uses the same canister as a conventional metered-dose inhaler (MDI). Its design, however, reduces the velocity of the aerosol cloud that emerges from the inhaler, thereby reducing the amount of the non-respirable fraction of the drug delivered to the patient. Large volume spacers achieve a similar effect, but they are bulky and therefore inconvenient to use and carry around. This study compared the bronchodilator effect of 200 micrograms salbutamol delivered by the Spacehaler to that of an MDI used with a Volumatic spacer (MDI plus spacer) in patients with reversible obstructive airways disease. Twenty-five patients with asthma, having a forced expiratory volume in 1 s (FEV1) between 50 and 90% predicted and a reversibility of > or = 15% to 200 micrograms salbutamol given by the conventional (standard) MDI entered the study. On two separate study days, they inhaled 200 micrograms salbutamol either via the Spacehaler or the MDI plus spacer. To maintain blinding, they received placebo on both study days via the alternate device. Their FEV1, forced vital capacity (FVC) and peak expiratory flow (PEF) were measured before and at regular intervals for 6 h after inhalation. Assessment of equivalence between the two devices was based on whether the 90% confidence interval for the difference between the weighted mean FEV1 was within +/- 0.25 1. Patient preference was assessed by a questionnaire at the end of the second study day. Twenty-four patients completed the study. Both devices produced a significant improvement in FEV1 (P < 0.02). The upper and lower 90% confidence limits for the difference in weighted mean FEV1 between the devices was +/- 0.041, and the 99% confidence limits were +0.061 and -0.071. The weighted means for FVC and PEF, and the duration of effect and peak responses for FEV1, FVC and PEF also showed no difference between the two devices. Patients found no difficulty in using the Spacehaler, and 20 out of 24 patients (83.3%) preferred it to the MDI plus spacer. The bronchodilator effect of 200 micrograms salbutamol administered by a Spacehaler was equivalent to that produced by an MDI plus spacer in this group of patients with reversible airways obstruction. The majority of patients preferred it to a large volume spacer.

Carvedilol versus verapamil in chronic stable angina: a multicentre trial.

OBJECTIVE: In a multicentre, double-blind, parallel group study, the anti-anginal and the anti-ischaemic efficacy of 12 weeks of therapy with the vasodilating beta-adrenoceptor-blocker carvedilol 25 mg b.i.d. was compared with verapamil 120 mg t.i.d. METHODS: During a 2-week placebo run-in period, patients were required to have two treadmill exercise tests (modified Bruce Protocol) differing by not more than 15% with regard to total exercise time (TET). Of 313 patients enrolled, 248 were randomized and 212 completed the study according to the protocol. RESULTS: The primary variable TET was analysed using the Cox Proportional Hazards Model to take into account censored values due to the patient stopping the exercise test for reasons other than angina. Forty-three per cent of patients allocated to carvedilol and 36% to verapamil did not stop with angina at the final visit. There was no difference in the TET between the groups, the risk ratio being 1.14 in favour of carvedilol (90% CI 0.85-1.52). TET increased from 378 s at baseline to 436 s at the final visit in the carvedilol group and from 386 to 438 s in the verapamil group. Results for time to angina and time to 1 mm ST-segment depression were similar. Compared to verapamil, carvedilol significantly reduced HR, systolic BP and rate pressure product at peak exercise. Analysis of 48 h Holter monitor data showed a greater reduction of HR and PVCs with carvedilol. Lown grading improved in both groups. Adverse events were reported by 48% (3.2% serious adverse events) of patients taking carvedilol and 58% (5.7% serious adverse events) taking verapamil. CONCLUSION: Carvedilol is at least as effective as verapamil in the management of chronic stable angina and demonstrated a favourable adverse event profile.

The Stamy procedure: a retrospective analysis of clinical outcome in stress incontinence.

OBJECTIVE: To review the clinical outcome of treatment by the modified Stamy procedure in 26 patients with genuine stress incontinence. DESIGN: A retrospective study of women with stress incontinence who underwent a modified Stamy procedure over a 2-year period between January 1991 and January 1993, of postoperative complications and the success rate three months after surgery. SUBJECTS: Twenty-six women presenting with symptomatic stress incontinence. INTERVENTIONS: All patients underwent a modified Stamy procedure. They were reviewed in the gynaecology clinic after three months. MAIN OUTCOME MEASURES: All patients were assessed by clinical examination for postoperative complications, subsequent voiding difficulties, and for recurrence or persistence of incontinence. RESULTS: The most common complications were retention of urine (23%), infection (19%), postoperative persistent pain (12%), urge incontinence (8%) and primary haemorrhage requiring transfusion (4%). The stress incontinence was subjectively cured in 81% and objectively cured in 72% when examined at three months postoperatively. CONCLUSIONS: Modified Stamy procedure is a useful operation for women with stress incontinence and it is associated with a low incidence of postoperative complications.

A retrospective evaluation of early carcinoma of the cervix treated surgically in a Provincial General Hospital.

OBJECTIVE: To assess the safety of Wertheim-Meigs hysterectomy for stage I and IIA carcinoma of the cervix performed at a Provincial General Hospital in Sri Lanka. DESIGN: A retrospective analysis of 16 cases managed from January 1992 to March 1993. SETTING: Provincial General Hospital in Sri Lanka. PATIENTS AND METHODS: Patients with either stage I or IIA carcinoma of the cervix were subjected to Wertheim-Meigs hysterectomy. All patients opted for surgery over radiotherapy when given the choice. Complications within the first 60 days were retrospectively analysed. RESULTS: Immediate operative mortality was nil, although two patients had massive haemorrhage during surgery. Injury to the pelvic colon occurred in one patient. Post-operative pyrexia (n = 16), persistent oozing from suction drains (n = 4), prolonged ileus (n = 6) and bladder dysfunction (n = 4) were the immediate post-operative complications. Average post-operative stay in the hospital was 12 days. CONCLUSIONS: Early carcinoma of the cervix treated by Wertheim-Meigs hysterectomy carries a low incidence of immediate post-operative mortality and morbidity when performed with the resources available at a Provincial General Hospital.

Mechanisms of abnormal glucose metabolism during the treatment of acute severe asthma.

Twenty-five patients with acute severe asthma were treated with oxygen, corticosteroids and either salbutamol or aminophylline by intravenous infusion. Blood glucose, plasma insulin and glucagon were measured during the first 24 hours of treatment. Salbutamol and aminophylline rapidly caused hyperglycaemia, accompanied by a rise in insulin and a fall in plasma glucagon. At first the increase in plasma insulin was insufficient to restore normoglycaemia, but by 24 hours homeostasis was restored. The early submaximal insulin response was attributed to the fasting caused by breathlessness. There was no evidence of an increase in hormone secretion caused by direct beta 2-adrenergic stimulation of the pancreatic islets. The effect of corticosteroids on blood glucose over the period of study was considerably less than the contribution of either salbutamol, or aminophylline.

Traumatic papillary muscle dysfunction: attempted mitral-valve repair and eventual prosthetic replacement.

A previously healthy young man sustained a deceleration chest injury. Severe mitral regurgitation was confirmed by Doppler and cardiac catheterisation. The mitral valve and subvalvular apparatus appeared normal at the subsequent surgery. Papillary muscle dysfunction was considered to be the principal cause of the regurgitation. Mitral-valve repair failed to preserve the competence of the valve, leading to successful mitral-valve replacement. Histology of the papillary muscle showed necrosis, confirming the original diagnosis. Post-traumatic papillary muscle dysfunction is concluded to be one of the cause of severe mitral regurgitation. Appropriate treatment is valve replacement rather than attempting conservative management.

Pulmonary Kaposi's sarcoma in two recipients of renal transplants.

Among 350 recipients of renal transplants seen at the Riyadh Military Hospital, 12 developed Kaposi's sarcoma. Two of these sarcomas presented primarily as a problem of diffuse lung infiltrates in an immunocompromised host. In one the diagnosis was established by transbronchial lung biopsy. Withdrawal of immunosuppression led to satisfactory radiological resolution in both patients.

The transfer factor and its subdivisions in patients with pulmonary emboli.

The carbon monoxide transfer factor and its subdivisions, the pulmonary membrane diffusing capacity and the pulmonary capillary volume were measured in fourteen subjects following submassive pulmonary emboli, as demonstrated by a ventilation-perfusion scan, and in fourteen matched controls. Transfer factor and alveolar volume were significantly lower in patients with pulmonary emboli (p less than 0.02). Patients were given six weeks anticoagulant therapy and the measurements repeated three months later. There was a significant increase in the transfer factor and the alveolar volume (p less than 0.01) and the membrane diffusing capacity (p less than 0.05). It has previously been assumed that the reduction in the transfer factor following a pulmonary embolus is due to a reduction in the pulmonary capillary volume. Results of this study however, suggest that it is more likely to be due to a loss of alveolar volume, at least in subjects with submassive emboli.