Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59.

Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

The different trajectories of antipsychotic response: antipsychotics versus placebo.

BACKGROUND: It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response. METHOD: We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different. RESULTS: Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories ('Partial responder' and 'Responder') accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug-placebo difference was in the 'Dramatic responders', seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories. CONCLUSIONS: Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The 'Dramatic responders' (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug-placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action.

Patient perception of dyskinesia in Parkinson's disease.

OBJECTIVE: To evaluate the perception of patients with Parkinson's disease (PD) regarding dyskinesia. DESIGN: Multicentre survey. SETTING: Tertiary referral centres. PATIENTS: Patients with PD participated in a survey: those not on dopaminergic medications (group I), those on dopaminergic medications without dyskinesia (group II) and those on dopaminergic medications with dyskinesia (group III). INTERVENTION: After a short standardised description and explanation of dyskinesia was provided, patients were asked about the nature and source of prior knowledge of dyskinesia. They were then asked about their perceptions of dyskinesia. Patients in group III were also asked about the duration, the severity of dyskinesia and whether their perception of this problem had changed since its appearance. MAIN OUTCOME MEASURES: Level of concern regarding dyskinesia and whether their perception of dyskinesia would have changed their preference of treatment. Results 259 PD patients completed the survey (group I, 52; group II, 102; group III, 105). Patients with dyskinesia were significantly less concerned about dyskinesia than patients without dyskinesia and were more likely to choose dyskinesia over being parkinsonian. Patients who required fewer changes in medications because of dyskinesia were more likely to choose dyskinesia over parkinsonism. CONCLUSION: Patients with PD experiencing dyskinesia are less likely to be concerned about dyskinesia and more likely to prefer dyskinesia over parkinsonian symptoms than patients without dyskinesia.

Long-term morbidity from severe pneumonia in early childhood in The Gambia, West Africa: a follow-up study.

OBJECTIVE: To assess long-term outcomes in severe early childhood pneumonia in The Gambia. DESIGN: Observational cohort study of children hospitalised with severe pneumonia between 1992 and 1994 compared to age, sex, and neighbourhood-matched controls on measures of current general and pulmonary health. RESULTS: Of 83 children successfully traced, 68 of the 69 alive at follow-up agreed to participate. Thirteen per cent of cases and 4% of controls had lung disease clinically or on spirometry. Another 16 (13%) participants had abnormal spirometry but did not meet the American Thoracic Society technical criteria (formally 'inconclusive'). Odds ratios of lung disease among childhood pneumonia cases were 2.93 (95%CI 0.69-12.48, P = 0.1468) with inconclusives omitted; 2.53 (95%CI 0.61-10.59, P = 0.2033) with inconclusives included as normal; and 2.83 (95%CI 1.09-7.36, P = 0.0334) with inconclusives included as lung disease. Among deceased cases, most deaths were reported within weeks of discharge, suggesting a possible connection between admission and subsequent death. CONCLUSION: These African data, while not conclusive, add to previous data suggesting a link between severe early childhood pneumonia and later chronic lung disease. While larger-scale research is needed, increased awareness of possible long-term morbidity in children with severe pneumonia is warranted to limit its impact and optimise long-term health.

Pallidal stimulation in cervical dystonia: clinical implications of acute changes in stimulation parameters.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is successful in dystonia, but the role of each electrical parameters of stimulation is unclear. We studied the clinical effects of acute changes of different parameters of GPi-DBS in cervical dystonia (CD). METHODS: Eight CD patients with bilateral GPi-DBS at 28.6 +/- 19.2 (mean +/- SD) months after surgery were recruited. Mean improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity score was 54.5% compared to before surgery. Ten settings, including a combination of a wide range of pulse widths (PWs), low and high frequencies and voltage, were administered in a randomized double blinded fashion. Clinical benefit was assessed by two raters using the TWSTRS and by the patients using an analogue rating scale. RESULTS: The TWSTRS severity scores were reduced by 56.7% with stimulation at the best settings. Improvement was significantly associated with high frequency (> or = 60 Hz) and high voltage. Stimulation at 130 Hz showed the best clinical improvement. Increasing PWs (from 60 to 450 micros) did not result in a significant improvement. CONCLUSION: Frequency and amplitude appear to be the most important factors in the acute anti-dystonic effects in GPi-DBS patients with CD.

Impact of human donor lung gene expression profiles on survival after lung transplantation: a case-control study.

Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pretransplant molecular markers for predicting PGD. To identify distinctive donor lung gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD (development set, n = 26). Selected PCR validated predictive genes were tested by quantitative reverse transcription-polymerase chain reaction in an independent test set (n = 81). Our microarray analyses of the development set identified four significantly upregulated genes (ATP11B, FGFR2, EGLN1 and MCPH1) in the PGD samples. These genes were also significantly upregulated in donor samples of the test set of patients with poor outcomes when compared to those of patients with good outcomes after lung transplantation. This type of biological donor lung assessment shows significant promise for development of a more accurate diagnostic strategy to assess donor lungs prior to implantation.

A systematic review of longitudinal outcome studies of first-episode psychosis.

BACKGROUND: Existing outcome literature has had an over-representation of chronic patients and suggested a progressive course and poor outcome for schizophrenia. The current study aimed to recombine data of samples from longitudinal studies of first-episode psychosis (FEP) to describe outcome and its predictors. METHOD: A literature search (1966-2003) was conducted for prospective studies examining outcome in first-episode non-affective psychosis using the following key words: early, first, incident, episode, admission, contact, psychosis, schizophrenia, psychotic disorders, course, outcome, follow-up, longitudinal, cohort. These were pooled and analyzed using descriptive and regression analyses. RESULTS: Thirty-seven studies met the inclusion criteria, representing 4100 patients with a mean follow-up of 35.1+/-6.0 months. Studies varied in the categories of outcome used, the most common being 'good' (54% of studies) and 'poor' (34% of studies), variably defined. In studies reporting these categories, good outcomes were reported in 42.2% (3.5%) and poor outcomes in 27.1% (2.8%) of cases. Predictors associated with better outcome domains were: combination of pharmacotherapy and psychosocial therapy, lack of epidemiologic representativeness of the sample, and a developing country of origin. Use of typical neuroleptics was associated with worse outcome. Stratification analyses suggested that populations with schizophrenia only, and those with prospective design, were associated with worse outcome domains. CONCLUSIONS: Outcome from FEP may be more favorable than previously reported, and treatment and methodological variables may be important contributors to outcome. Significant heterogeneity in definitions and methodology limited the comparison and pooling of data. A multi-dimensional, globally used definition of outcome is required for future research.

Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans.

While current donor selection with clinical findings is generally effective, the imprecise nature of the assessment forces clinicians to remain on the conservative side. A reliable biological marker would assist donor selection and would improve donor organ utilization. We collected biopsies from 169 donor lungs before implantation. Expression levels of IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and IL-1beta were measured by quantitative real-time RT-PCR (qRT-PCR). Seventeen cases died within 30 days after transplantation. No donor factor was significantly associated with 30-day mortality. Univariate analysis of the 84 cases for development of the prediction model showed that IL-6, IL-8, TNF-alpha and IL-1beta were risk factors for mortality and IL-10 and IFN-gamma were protective factors. We analyzed the cytokine expression ratios of risk to protective cytokines. A stepwise logistic regression for 30-day mortality demonstrated that a model containing the ratio of IL-6/IL-10 was the most predictive (p = 0.0013). When applied to the remaining 85 cases for validation, the test of model fit was significant (p = 0.039). Using the cytokine ratio, we were able to define three risk groups with striking differences in survival (p = 0.0003). Multi-cytokine analysis of the donor lung graft with qRT-PCR shows significant promise as a strategy to biologically evaluate the donor lung prior to implantation.

A targeted review of study outcomes with short (< or = 7 mm) endosseous dental implants placed in partially edentulous patients.

BACKGROUND: Generally, threaded root-form endosseous dental implants are thought to perform poorly in short lengths (i.e., < 10 mm). However, whether modifications in implant surface geometry will improve performance of short threaded implants is less clear. METHODS: The relationship between dental implant failure rates and their surface geometry, length, and location (maxilla versus mandible) was explored in the published literature. Using a MEDLINE search (1985 through 2001), studies were sought with the following criteria: 1) data suitable to calculate failure rates of implant lengths < or = 7 mm versus > 7 mm; 2) data separable into maxillary versus mandibular results; 3) criteria for "failure" clearly defined; and 4) minimal functional period of 2 years. RESULTS: Twelve papers were identified as follows: eight with machined threaded implants, two with acid-treated threaded implants, and two with sintered porous-surfaced press-fit implants. The following results were found: 1) machined surface implants experienced greater failure rates than textured surface implants; 2) with the exception of sintered porous-surfaced implants, 7 mm long dental implants appear to have higher failure rates than those > 7 mm length; and 3) with textured surface implants, higher failure rates were more likely in the maxilla than in the mandible, but with machined surface implants there were no differences in failure rates between maxilla and mandible. CONCLUSIONS: Dental implant surface geometry is a major determinant in how well these implants perform in short lengths, defined here as lengths of < or = 7 mm. While threaded implants show higher failure rates in short versus longer lengths, sintered porous-surfaced implants perform well in the defined "short" lengths. More studies are needed to better assess the performance of short, acid-washed threaded implants.