Dose response and atypical antipsychotics in schizophrenia

Based on information from clinical trials, both the efficacy and adverse effects of conventional antipsychotics in the treatment of schizophrenia are dose related. The overlapping nature of these dose-response profiles limits the use of these agents. Atypical antipsychotics provide greater relief across the comorbid symptom domains of schizophrenia, but dose-response studies and clinical experience have revealed that some of these drugs also have dose limitations. This article reviews the dose-response relationships of the atypical antipsychotics as presented predominantly in pivotal, randomised studies (double-blind and otherwise).Limited data indicate that clozapine shows dose-related efficacy up to 600 mg/day in patients with treatment-resistant schizophrenia. However, higher dosages of clozapine may be associated with the risk of seizures. Risperidone demonstrates dose-related adverse events that compromise efficacy. The dose-response relationships for ziprasidone, quetiapine and aripiprazole are less well established. The efficacy of olanzapine appears to be dose related within the recommended dosage range of 10-20 mg/day, but clinical trials that have explored higher dosages suggest improved efficacy. Furthermore, the higher doses are not associated with a significantly increased incidence of adverse events.Further studies are clearly needed to fully characterise the dose-response relationships of atypical antipsychotics.     

Using Physiome standards to couple cellular functions for rat cardiac excitation-contraction.

Scientific endeavour is reliant upon the extension and reuse of previous knowledge. The formalization of this process for computational modelling is facilitated by the use of accepted standards with which to describe and simulate models, ensuring consistency between the models and thus reducing the development and propagation of errors. CellML 1.1, an XML-based programming language, has been designed as a modelling standard which, by virtue of its import and grouping functions, facilitates model combination and reuse. Using CellML 1.1, we demonstrate the process of formalized model reuse by combining three separate models of rat cardiomyocyte function (an electrophysiology model, a model of cellular calcium dynamics and a mechanics model) which together make up the Pandit-Hinch-Niederer et al. cell model. Not only is this integrative model of rat electromechanics a useful tool for cardiac modelling but it is also an ideal framework with which to demonstrate both the power of model reuse and the challenges associated with this process. We highlight and classify a number of these issues associated with combining models and provide some suggested solutions.     

DAT1 and COMT Effects on Delay Discounting and Trait Impulsivity in Male Adolescents with Attention Deficit/Hyperactivity Disorder and Healthy Controls

Choice impulsivity has been linked to dopamine function and is consistently observed in attention deficit/hyperactivity disorder (ADHD) as a preference for smaller-immediate over larger-delayed rewards using choice-delay paradigms. More sophisticated delay discounting paradigms have yielded inconsistent results. Context and sample characteristics may have contributed to these variations. In this study we examine the effect of type (real vs hypothetical) and magnitude of reward as well as of variation in dopamine genes on choice impulsivity. We selected 36 male adolescents with ADHD-combined subtype (ADHD-CT) and 32 controls (mean age=15.42, SD=2.05) to form four roughly equally sized subgroups on the basis of DAT1_10/6 haplotype dosage (2 copies and <2 copies). Participants, who were also genotyped for the COMT_val158met and DRD4_48bp−VNTR polymorphisms, performed a hypothetical and a real-time discounting task and provided self-ratings of trait impulsivity. The ADHD-CT group discounted rewards more steeply than controls only in the hypothetical task, with delay, but not reward magnitude, influencing choices. They also rated themselves as more impulsive compared with controls. DAT1_10/6 dosage and the COMT_Val158Met genotype predicted trait impulsivity and discounting rates in the hypothetical task, but not in the real-time task. Our results directly link variation in genes putatively influencing dopamine signaling in the prefrontal cortex (COMT_Val158Met) and the striatum (DAT1_10/6) with discounting rates in a hypothetical task (but not a real-time task) and self-ratings of trait impulsivity in ADHD-CT and healthy controls. The lack of magnitude effects in the hypothetical task suggests that discounting in this task may be influenced by different processes in ADHD-CT than in healthy controls.     

The role of transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma

BACKGROUND: For many years in the United States transbronchial needle aspiration (TBNA) has been used with flexible bronchoscopy to diagnosis bronchogenic carcinoma, but very few data are available from the United Kingdom. METHODS: All bronchoscopies performed for suspected bronchial carcinoma at Papworth Hospital, Cambridge, United Kingdom, over the last 3 years were reviewed retrospectively. Patients with peribronchial disease, as evidenced by submucosal infiltration or extrinsic compression on bronchoscopy, were selected for TBNA. Patients with computed tomography evidence of subcarinal lymphadenopathy were also included. In total we identified 78 patients: 67 with peribronchial disease and 21 with subcarinal lymphadenopathy. All 78 patients underwent TBNA, and in 8 of these TBNA was performed in 2 sites. RESULTS: Malignancy was confirmed in 66 of the 78 patients. TBNA was positive in 31/66 (47%) of the patients who had proven bronchogenic carcinoma. Additional staging information was obtained in 9/21 patients (42.8%) who underwent subcarinal lymph node aspiration. We also found that TBNA was diagnostic in 1 patient with tuberculosis and 1 with sarcoidosis. There was only 1 important TBNA complication, which was a small pneumothorax. CONCLUSION: In our preliminary experience with selected patients suspected to have bronchogenic carcinoma (based on peribronchial disease or subcarinal lymphadenopathy), we found TBNA a safe and useful tool.     

Nocturnal Body Movements and Hypoxemia in Middle-Aged Females After Lower Abdominal Surgery Under General Anesthesia: A Study With the Static-Charge-Sensitive Bed (SCSB)

Objective. The aim of this study was to evaluate the feasibility of the static-charge-sensitive-bed (SCSB) combined with pulse oximetry (SpO₂) for postoperative monitoring and to determine variables which could be used for evaluating the quality of postoperative sleep and breathing. Methods. The frequency of body movements and the perioperative breathing abnormalities were assessed using the SCSB and pulse oximeter in 15 female ASA-class I–II patients undergoing elective lower abdominal surgery under general anesthesia. Anesthesia and control of postoperative pain followed standard practice. The patients were monitored during one preoperative and three consecutive postoperative nights. Movements were analyzed according to their duration and time interval. The effect of opioids was evaluated by measuring arterial oxyhemoglobin saturation (SpO₂) with pulse oximetry for one hour before and two hours after administration of standard doses of oxycodone. Results. The total movement time per hour increased during the first postoperative night (p = 0.003). Conversely, periodic movement activity decreased significantly during the three postoperative nights (p = 0.05, p < 0.001, p = 0.007). The mean SpO₂ decreased during the first postoperative night (95.5% vs. 94.2%, p = 0.002), but returned to the preoperative level during the following nights. No episodes of apnea with significant oxygen desaturation (a decrease in SpO₂<5%) were observed. Opioid administration was associated with decreased mean SpO₂ (94.8% vs. 93.6%, p = 0.02), but did not lead to clinically significant hypoxemia (lowest observed SpO₂ 89.8%). Conclusions. Postoperative periodic movement activity was suppressed, but sleep remained fragmented with frequent body movements. In our middle-aged non-obese females (ASA I–II), no severe postoperative hypoxemia was observed during the three-nights postoperative survey. Perioperative movement monitoring with the SCSB was a valuable tool in rejecting movement artefacts of SpO₂ and in evaluating general sleep quality.     

Genetic variation in estrogen receptor, C-reactive protein and fibrinogen does not predict the plasma levels of inflammation markers after longterm hormone replacement therapy

Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, are associated with the risk of atherothrombosis. Plasma levels of these markers of inflammation are affected by hormone replacement therapy (HRT) and modulated by smoking. We studied whether genetic variation in the estrogen receptor- 1 (ESR1), CRP and fibrinogen-beta genes influences the plasma levels of inflammation markers after HRT. Plasma CRP and fibrinogen were measured after five years follow-up in healthy postmenopausal women (per-protocol group) who were randomised to hormone therapy (n=187) or no treatment (n=249). The effect of HRT, smoking and genetic variations in ESR1 (PvuII and XbaI), CRP (1444C/T) and fibrinogen-beta (FGB, -455G/A) were determined. The plasma concentration of CRP was higher in the HRT group than in the control group (2.03 mg/l and 1.41 mg/l, respectively; p < 0.001), while the concentration of fibrinogen was lower in the HRT group than in the control group (3.02 g/l and 3.20 g/l, respectively; p < 0.001), indicating that it is unlikely that inflammation is the common underlying pathway. There was a significant interaction between smoking and HRT on the fibrinogen (p=0.02), but not on the CRP concentration (n.s.). Genetic polymorphisms in ESR1, CRP and fibrinogen were not associated with an effect of HRT on the CRP and fibrinogen plasma levels, and no significant interaction with smoking was observed. In conclusion, higher plasma levels of CRP and lower plasma levels of fibrinogen were observed in women using HRT; however, genetic polymorphisms in ESR1, CRP and FGB were not associated with these effects of HRT.