A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Effect of different surgical positions on the cerebral venous drainage: a pilot study using healthy volunteers.

Excessive neck flexion and rotation in certain surgical positions may cause kinking of the internal jugular vein that obstructs cerebral venous blood flow and results in elevated intracranial pressure. The objective of this study was to measure internal jugular vein flow and identify potential impediments to venous flow in supine, prone, and park bench positions using non-anaesthetised volunteers. Twenty-seven volunteers were recruited. Venous flow rate was derived from ultrasound measurements of the vessel cross-sectional area and flow velocity. Change from supine to prone position produced a significant increase in both jugular vein cross-sectional areas without affecting venous flows. In the right park bench position, the right internal jugular vein cross-sectional area decreased from 1.2 to 0.9 cm(2) (p = 0.027) without substantive changes in mean venous flow rate (p = 0.91) when compared with supine. In summary, the internal jugular vein flow was not compromised by either prone or park bench positions in non-anaesthetised volunteers, and careful positioning may prevent kinking of the jugular vein. Further studies in anaesthetised and ventilated patients are needed to validate these results for clinical practice.

Impact of outpatient interventions made at an ambulatory cancer centre oncology pharmacy in Singapore.

OBJECTIVES: To evaluate the clinical significance of interventions made by pharmacists in an oncology pharmacy in Singapore and their acceptance rate and to identify common drug-related problems and workflow-related interventions. METHODS: A two-month prospective intervention study was conducted at National Cancer Centre Singapore. During the study, pharmacists documented the reason for intervening and its related drug(s). Each intervention was evaluated for its clinical significance by an expert panel: two oncologists and a pharmacist using a five-point scale. The Kendall's test of concordance and Cohen's weighted kappa were employed for analysis of agreement among the respondents. Other variables were analysed using descriptive statistics. RESULTS: A total of 331 interventions were recorded: 147 cases were due to missing chemotherapy orders while 184 cases had potential drug-related problems. Among the 184 cases, 60 cases were related to clarification of orders, while the others had drug-related problems. The Kendall's concordance coefficient was calculated to be 0.612 (p < 0.001) while weighted kappa test results showed fair agreement across the evaluators. Acceptance rate of interventions was 93%. Most commonly documented drugs requiring interventions were carboplatin, trastuzumab and capecitabine. CONCLUSIONS: About half of the documented interventions by pharmacists were evaluated as clinically 'significant' or 'very significant'.

Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicentre cross-sectional cohort study.

OBJECTIVES: Patients with schizophrenia treated with clozapine are at risk of acute myocarditis and dilated cardiomyopathy. However, there are no data on the prevalence of subclinical cardiomyopathy or its associations. METHODS: 100 consecutive patients with schizophrenia treated with clozapine for >1 year and without a history of cardiac pathology (group 1), 21 controls with a history of schizophrenia treated with non-clozapine antipsychotics for >1 year (group 2) and 20 controls without schizophrenia (group 3) were studied. Comprehensive evaluation by clinical examination, ECG, transthoracic echocardiography including left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) and biochemical profiles were performed. RESULTS: Patients with schizophrenia were of similar age, but had higher body mass index (BMI), rates of smoking and hyperlipidaemia than controls. Patients with schizophrenia had received clozapine or non-clozapine antipsychotics for a mean duration of 6.8±5.3 and 9.7±6.1 years, respectively. Patients taking clozapine demonstrated globally impaired LVEF (58.3%: group 1 vs 62.2%: group 2 vs 64.8%: group 3, p<0.001) and GLS (-16.7%: group 1 vs -18.6%: group 2 vs -20.2%: group 3, p<0.001). Moreover, LVEF was <50% in 9/100 (9%) patients receiving clozapine and in non-clozapine schizophrenia patients or healthy controls, but this was not statistically significantly different (analysis of covariance, p=0.19). Univariate analysis in patients taking clozapine found that impaired LV was not predicted by high-sensitivity troponin T, but was associated with features of the metabolic syndrome (including increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), high-sensitivity C reactive protein and BMI), elevated neutrophil count, elevated heart rate, smoking and N-terminal probrain natriuretic peptide. In patients taking clozapine, multivariable analysis identified elevated neutrophil count and low HDL-C as the only independent predictors of impaired GLS. CONCLUSIONS: Asymptomatic mild LV impairment is common in patients with schizophrenia receiving long-term clozapine treatment and is associated with neutrophilia and low HDL-C.

Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study.

BACKGROUND: Systemic opioids are immunosuppressive, which could promote tumour recurrence. We, therefore, test the hypothesis that supplementing general anaesthesia with neuraxial analgesia improves long-term oncological outcomes in patients having radical prostatectomy for adenocarcinoma. METHODS: Patients who had general anaesthesia with neuraxial analgesia (n=1642) were matched 1:1 based on age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease with those who had general anaesthesia only. Medical records were reviewed. Outcomes of interest were systemic cancer progression, recurrence, prostate cancer mortality, and all-cause mortality. Data were analysed using stratified proportional hazards regression, the Kaplan-Meier method, and log-rank tests. The median follow-up was 9 yr. RESULTS: After adjusting for comorbidities, positive surgical margins, and adjuvant hormonal and radiation therapies within 90 postoperative days, general anaesthesia only was associated with increased risk for systemic progression [hazard ratio (HR)=2.81, 95% confidence interval (CI) 1.31-6.05; P=0.008] and higher overall mortality (HR=1.32, 95% CI 1.00-1.74; P=0.047). Although not statistically significant, similar findings were observed for the outcome of prostate cancer deaths (adjusted HR=2.2, 95% CI 0.88-5.60; P=0.091). CONCLUSIONS: This large retrospective analysis suggests a possible beneficial effect of regional anaesthetic techniques on oncological outcomes after prostate surgery for cancer; however, these findings need to be confirmed (or refuted) in randomized trials.

An evaluation of antimicrobial prophylaxis in paediatric surgery and its financial implication.

OBJECTIVE: To assess the appropriateness of use of antimicrobial prophylaxis in paediatric surgery in Singapore. METHODS: A prospective evaluation of the use of antimicrobial prophylaxis in paediatric patients undergoing surgery in KK Hospital, Singapore was carried out from September and December 2001. Process measures for the study included adherence to local or international guidelines, choice and dose of antimicrobial agent and timing and duration of prophylaxis. Outcome measures included surgical site and other related infections. A cost analysis was also performed to look at the extra expenditure due to any excessive use of antimicrobials. RESULTS: A total of 171 patients with a mean age of 5.7 years (SD=4.5) were included in the study. Among the 117 (68.4%) elective and 54 (31.6%) emergency procedures, 22 cases (12.8%) were fully compliant with the guidelines. The most frequently encountered non-compliance types were unnecessary prolongation of prophylaxis (54.4%), inappropriate choice of antibiotics (42.7%) and overdose of antibiotics (26.3%). The estimated extra cost to patients for the study period was Sing$13,879.41 (US 8164.36). CONCLUSION: The results showed a significantly high level of inappropriate use of antimicrobial prophylaxis in paediatric surgery in Singapore. However, when the individual factors such as appropriate choice of antibiotics, appropriate timing and duration were considered, the situation was very similar to the results obtained from overseas studies.

Recurrent respiratory papillomatosis.

A 6-year-review of patients who presented with recurrent respiratory papillomatosis (RRP) to our hospital from January 1996 to December 2001 was carried out. Ten cases were identified, of which six were juvenile-onset RRP. Hoarseness was the most common symptom, noted in nine (90%) patients. Other clinical presentations included cough, stridor and aphonia. All patients had glottic papillomas; two had multiple sites of involvement. One patient underwent a tracheostomy that revealed papillomas over the trachea, bronchus and lung parenchyma. Half of the patients were Chinese. Of the six cases of juvenile-onset RRP, three patients were Malay, two Chinese and one Indian. Three Chinese and one German patient had adult-onset RRP. Among the juvenile-onset RRP cases, the mean age at presentation was 2 years, while for adult-onset RRP, it was 42 years. Juvenile-onset RRP was more common in females. There were more papillomas over more sites in patients with juvenile-onset RRP than with adult-onset disease. Subglottic involvement was noted in the juvenile-onset RRP cases. All patients were treated with CO2 laser therapy, but there was complete remission of the papillomas in only two cases.

Surgical intervention in traumatic facial nerve paralysis.

A four years review from June 1998 to June 2002 of traumatic facial nerve paralysis from temporal bone fractures that required surgical intervention is presented. The aim of this clinical presentation was to determine the current pattern of cases with traumatic facial paralysis which required surgical intervention at our center. There were six cases, of which four (66%) were longitudinal fractures, one each (17%) had transverse fracture and fracture over the lateral wall of mastoid. Hearing loss (83%) was the commonest associated clinical symptom. All cases underwent decompression via the transmastoid surgical approach. Intraoperative findings revealed oedema of facial nerve involving vertical segment and horizontal segment in three cases each respectively. Two cases had concomitant bony impingement. The facial nerve functions in four cases (66%) and one case recovered to House Brackmann grade 2 and 4, 12 months and 3 months respectively postsurgery. The case with transverse fracture remained as House Brackmann grade 5 after two years.

Complications of otitis media requiring surgical intervention.

BACKGROUND: Although the incidence of complications of otitis media that require surgical interventions has decreased substantially over the past few years, it is a prevailing condition for which clinicians should remain vigilant. METHODS: We conducted a 3-year review [June 1998 to June 2001] in our hospital of surgical records of patients with complications of otitis media that were treated surgically. RESULTS: There were 16 patients with complications of otitis media, of which nine [56%] were intracranial; brain abscess and lateral sinus thrombosis were the most common intracranial complications. Extracranial complications were present in 15 [94%] of the patients; mastoid abscess [40%] was the most common extracranial complication. Seven [44%] patients had two or more concomitant complications. All patients with intracranial complications recovered well with no neurological deficits after aggressive antibiotic therapy and initial surgical treatment by neurosurgeons. Modified radical mastoidectomy was the most common surgical otological procedure that was performed in these cases. CONCLUSIONS: Aggressive antibiotic therapy and combined management of cases by otologists and neurosurgeons are the key to reducing the morbidity and mortality of the serious complications of otitis media.

The small muscle-specific protein Csl modifies cell shape and promotes myocyte fusion in an insulin-like growth factor 1-dependent manner.

We have isolated a murine cDNA encoding a 9-kD protein, Chisel (Csl), in a screen for transcriptional targets of the cardiac homeodomain factor Nkx2-5. Csl transcripts were detected in atria and ventricles of the heart and in all skeletal muscles and smooth muscles of the stomach and pulmonary veins. Csl protein was distributed throughout the cytoplasm in fetal muscles, although costameric and M-line localization to the muscle cytoskeleton became obvious after further maturation. Targeted disruption of Csl showed no overt muscle phenotype. However, ectopic expression in C2C12 myoblasts induced formation of lamellipodia in which Csl protein became tethered to membrane ruffles. Migration of these cells was retarded in a monolayer wound repair assay. Csl-expressing myoblasts differentiated and fused normally, although in the presence of insulin-like growth factor (IGF)-1 they showed dramatically enhanced fusion, leading to formation of large dysmorphogenic "myosacs." The activities of transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer-binding factor (MEF)2, were also enhanced in an IGF-1 signaling-dependent manner. The dynamic cytoskeletal localization of Csl and its dominant effects on cell shape and behavior and transcription factor activity suggest that Csl plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.

Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway.

Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies. Here we show that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat latissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineurin, mobilizes satellite cells and causes a switch to glycolytic metabolism. We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.

Long-term renal function in heart transplant recipients receiving cyclosporine therapy.

BACKGROUND: Immunosuppression with cyclosporine has improved allograft function and reduced both morbidity and mortality in organ transplantation. However, cyclosporine-induced nephrotoxicity still is a concern. The purpose of our study was to evaluate the effects of cyclosporine on renal function in orthotopic heart transplant recipients. METHODS: Thirty-nine patients who received transplants from 1985 to 1991 and had at least three yearly glomerular filtration rate measurements posttransplantation by 125I-iothalamate clearance method were included in the study. In addition, serum creatinine (before and after transplantation) and cyclosporine doses were analyzed. RESULTS: Maintenance immunosuppression at 1 year consisted of prednisone (0.1 mg/kg/day), azathioprine (2 mg/kg/day), and cyclosporine (12-hour trough level 100 to 150 ng/ml by fluorescence polarization immunoassay). The mean serum creatinine at 1 year was significantly higher than the mean pretransplantation serum creatinine (1.51 +/- 0.32 versus 1.28 +/- 0.38, p < 0.05) and stabilized after the first year. The mean glomerular filtration rate by 125I-iothalamate clearance method was 70.6 +/- 20.3 ml/min/1.73 m2 (range 32 to 105) at 1 year and remained relatively stable during the follow-up period of up to 7 years. Creatinine clearance calculated by the Cockcroft and Gault formula overestimated the true glomerular filtration rate after the third year. The mean cyclosporine dosage was significantly lower after the first-year dose of 3.9 +/- 1.8 mg/kg/day (p < 0.05). Three patients in 39 started hemodialysis at 5, 7, and 10 years after transplantation. CONCLUSION: Our data indicate that the adequacy of renal function is preserved with long-term cyclosporine therapy in heart transplant recipients.

Histopathology of restenosis after stenting of narrowed coronary arteries after cardiac transplantation during the teenage years.

This study describes the detailed histopathologic appearance of human coronary arteries at 3 weeks, and 3 and 7 months after stent implantation in a cardiac transplant recipient. There was modest arterial injury associated with stent implantation, and immunocytochemistry staining provided evidence that a proliferative response from the adventitia contributes to neointimal hyperplasia.

Variations in the relative mRNA levels of actins and myosin heavy chains do not produce corresponding differences in their proteins in the adult human heart.

This paper examines the quantitative relationship between the expression of myosin heavy chain (MHC) and actin at both the levels of their mRNAs and their proteins. Explanted human left ventricle tissues were obtained from non-diseased (ND) individuals and from dilated cardiomyopathy (DCM) patients with terminally failing hearts who underwent heart transplantation. We found: (1) there are substantial differences in the stoichiometry of sarcomeric MHC and actin transcripts in hearts of DCM patients as well as in ND individuals; (2) there are substantial differences between levels of total sarcomeric actin transcripts from different individual patients; (3) by and large variations in transcript levels between samples from the same heart are much less than between samples from different hearts; and (4) the ratio of MHC to sarcomeric actin proteins expressed by different ND and DCM hearts remains essentially constant. We conclude that the human ventricle can accommodate a substantial imbalance between sarcomeric MHC and actin mRNA levels while maintaining a constant ratio of their corresponding proteins.

Skeletal muscle mass and exercise performance in stable ambulatory patients with heart failure.

The purpose of this study was to determine whether skeletal muscle atrophy limits the maximal exercise capacity of stable ambulatory patients with heart failure. Body composition and maximal exercise capacity were measured in 100 stable ambulatory patients with heart failure. Body composition was assessed by using dual-energy X-ray absorption. Peak exercise oxygen consumption (VO2peak) and the anaerobic threshold were measured by using a Naughton treadmill protocol and a Medical Graphics CardioO2 System. VO2peak averaged 13.4 +/- 3.3 ml.min-1.kg-1 or 43 +/- 12% of normal. Lean body mass averaged 52.9 +/- 10.5 kg and leg lean mass 16.5 +/- 3.6 kg. Leg lean mass correlated linearly with VO2peak (r = 0.68, P < 0.01), suggesting that exercise performance is influences by skeletal muscle mass. However, lean body mass was comparable to levels noted in 1,584 normal control subjects, suggesting no decrease in muscle mass. Leg muscle mass was comparable to levels noted in 34 normal control subjects, further supporting this conclusion. These findings suggest that exercise intolerance in stable ambulatory patients with heart failure is not due to skeletal muscle atrophy.

Hemodynamic exercise testing. A valuable tool in the selection of cardiac transplantation candidates.

BACKGROUND: Peak exercise oxygen consumption (Vo2), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise Vo2 can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis. METHODS AND RESULTS: Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22 +/- 7%; mean peak Vo2, 12.9 +/- 3.0 mL. min-1.kg-1). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (P < .0001). Survival in patients with peak Vo2 of > 14 mL.min-1.kg-1 (88%) was not different from that of patients with peak Vo2 of < or = 14 mL.min-1.kg-1 (79%) (P = NS). However, survival was worse in patients with peak Vo2 of < or = 10 mL.min-1.kg-1 (52%) versus those with peak Vo2 of > 10 mL.min-1.kg-1 (89%) (P < .0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak Vo2 dichotomized at 10 mL. min-1.kg-1 (risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak Vo2 of < or = 10 mL.min-1.kg-1 had an extremely poor 1-year survival rate (38%). CONCLUSIONS: Both CO response to exercise and peak exercise Vo2 provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.

Different electrophoretic techniques produce conflicting data in the analysis of myocardial samples from dilated cardiomyopathy patients: protein levels do not necessarily reflect mRNA levels.

A variety of electrophoretic techniques were used to search for potential causes of human dilated cardiomyopathy (DCM). Northern blots were used to quantify alpha-cardiac and alpha-skeletal muscle actins, and beta-myosin heavy chain mRNAs which are the predominant expressed isoform species. We found a wide range of mRNA levels expressed in both DCM and nondiseased (ND) samples of left ventricles. However, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) gels of the same heart samples revealed a stable and constant ratio of actin and myosin. Dystrophin deficiency might account for the DCM symptoms and so dystrophin levels of DCM and ND samples were evaluated using Western blots probed with monoclonal antibodies for the N-, C- and mid-rod portions of this protein. We found that dystrophin levels were constant in all 29 DCM and 5 ND samples suggesting that dystrophin deficiency is probably not a contributing cause. We explored the possibility that terminal failure may be due to an apoptotic-like event in the cardiomyocytes. Zymograms of DCM and ND samples revealed a significant increase in DNase I activity in the DCM group compared to the ND samples. These data raise the possibility that end-stage failure may be associated with apoptosis.