The effect of differences in trial design on estimates of efficacy of olanzapine in randomized studies.

BACKGROUND: Differences in trial design may affect estimates of efficacy of psychotropic drugs. The purpose of this meta-analysis is to evaluate whether the use of Olanzapine (OLZ) as either investigational or control drug affects the observed efficacy of OLZ. METHODS: We performed a search for Randomized-Controlled Trials (RCTs) in which the efficacy of OLZ is assessed in patients with schizophrenia or schizoaffective disorder. We assessed overall efficacy of OLZ and performed subgroup analyses of studies with OLZ as intervention or comparator. Mixed-effect meta-regression analyses were performed. RESULTS: Of the 25 RCTs included, OLZ was considered as investigational drug or active control in 13 and 12 studies, respectively. The reduction of PANSS score was greater in trials in which OLZ was used as investigational drug. Multivariate meta-regression models showed that a higher PANSS score at baseline and trial duration were the main predictors of greater PANSS score reduction. CONCLUSIONS: Trials with OLZ used as investigational drug differ from those of trials with OLZ as comparator for baseline PANSS scores and study duration; these differences may produce differences in estimates of efficacy. As a consequence, the severity of illness at enrollment and trial duration should be carefully considered to ensure the reliability of indirect comparisons among antipsychotics.

Eating psychopathology in ballet dancers: a meta-analysis of observational studies.

OBJECTIVE: To assess whether ballet dancers have higher eating psychopathology mean scores than the general population. METHODS: Meta-analysis of cross-sectional observational studies comparing the scores of one or more of the validated eating psychopathological scales between ballet dancers and any control groups. RESULTS: Twelve studies were included in the metanalysis. Ballet dancers had a significantly higher EAT score (12 studies retrieved, SMD 0.82 [95% CI 0.44-1.19], p < 0.00001, I2 = 84)]; subgroup analysis suggested a possible role of control subjects' choice in explaining heterogeneity. Scores on the EDI subscales of Drive for Thinness, Bulimia, and Body dissatisfaction were available from four studies; Drive for Thinness was higher in ballet dancers (SMD 0.62 [0.01, 1.22]), as well as the Bulimia scale (SMD 0.38 [0.02, 0.73], p = 0.04) and the Body Dissatisfaction scale (SMD 0.34 [0.15, 0.53]). Data on Perfectionism, Interpersonal problems, Ineffectiveness, and Maturity fears, were available from three studies. Higher scores in Perfectionism (SMD 0.68 [0.24, 1.12] p = 0.02), Interpersonal problems (SMD 0.24 [0.02, 0.47], in Inefficacy, (SMD 2.18 [1.31, 3.06]) were found for ballet dancers; on the other hand, Maturity fears scores were not significantly different between ballet dancers and controls (IV-MD = 0.15 [- 0.07, 0.36]). Seven studies reported tests not performed elsewhere. DISCUSSION: Ballet dancers show a higher level of restriction and drive for thinness than controls, and they may be, therefore, at higher risk for the development of eating disorders. Available studies do not allow the discrimination of dysfunctional eating attitudes and behaviors from adaptive responses. LEVEL OF EVIDENCE: Level I (evidence obtained from systematic reviews and meta-analyses).

Taking a look at the calibration of a CCD detector with a fiber-optic taper.

At the Structural Biology Center beamline 19BM, located at the Advanced Photon Source, the operational characteristics of the equipment are routinely checked to ensure they are in proper working order. After performing a partial flat-field calibration for the ADSC Quantum 210r CCD detector, it was confirmed that the detector operates within specifications. However, as a secondary check it was decided to scan a single reflection across one-half of a detector module to validate the accuracy of the calibration. The intensities from this single reflection varied by more than 30% from the module center to the corner of the module. Redistribution of light within bent fibers of the fiber-optic taper was identified to be a source of this variation. The degree to which the diffraction intensities are corrected to account for characteristics of the fiber-optic tapers depends primarily upon the experimental strategy of data collection, approximations made by the data processing software during scaling, and crystal symmetry.

Looking at my body. Similarities and differences between anorexia nervosa patients and controls in body image visual processing.

BACKGROUND: Body image distortion is a core symptom of eating disorders. Functional magnetic resonance imaging (fMRI) studies on body image processing, described different patterns of neural response, mainly involving the inferior and superior parietal lobules, and the dorsolateral prefrontal cortex (DLPFC), with conflicting results. METHODS: The neural response to the view of their own body pictures (normal size and distorted) was evaluated in 18 female anorexia nervosa (AN) restricting type patients, and in 19 healthy female subjects (HC) using fMRI. Clinical assessment was performed by means of the structured clinical interview for DSM-IV and self-reported questionnaires. RESULTS: In response to the body image distortion, patients and controls showed an inverse pattern of activation, with the widest extent of activation in the oversize condition in AN, while in the undersize condition in HC. AN and HC showed a similar pattern of neural response to the view of their own body, with an increased activation in the extrastriate body area, superior and inferior parietal lobule and prefrontal areas, although the extent of activation in HC was more limited as compared with AN patients. Increased activity in AN patients, compared with HC, was observed in the DLPFC in response to the oversized body picture and a significant correlation was found in AN patients between DLPFC activation and eating disorder psychopathology. CONCLUSIONS: Our findings suggest the existence of a continuum from normalcy to pathology in neural response to body image, and confirm the clinical relevance of body image distortion in AN, reinforcing the key role of attentive, executive and self-evaluation networks in AN visual processing of own distorted body image.

Diabetes mellitus as a risk factor for depression. A meta-analysis of longitudinal studies.

AIM: The present meta-analysis is aimed at the assessment of the risk of incident clinical depression and/or depressive symptoms in patients with diabetes. METHODS: A Medline search was performed on December 30th, 2011, using the search string: "diabetes AND (depression OR antidepressant)", selecting longitudinal studies that assessed the risk of incident depression in subjects with or without diabetes. Study design and characteristics were verified for each study. A meta-analysis was performed for unadjusted and adjusted risk ratios of incident depression in subjects with diabetes using a random effect model. Additional analyses were performed to assess heterogeneity, publication bias and specific hazard ratios for several possible confounders. RESULTS: Of the 1898 retrieved studies, 16 were included in the meta-analysis, enrolling 497,223 subjects, with a mean follow-up of 5.8 years and 42,633 cases of incident depression. A higher incidence of depression was found in diabetic subjects (1.6% vs 1.4% yearly), with unadjusted and adjusted risk [95% confidence interval] of 1.29 [1.18-1.40] (p<0.001) and 1.25 [1.10-1.44] (p=0.001), respectively. CONCLUSIONS: Diabetes is associated with a significantly increased risk for depressive symptoms. Pathogenetic mechanisms connecting diabetes with depression deserve further exploration.

Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development?

The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- α and γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.

Childhood traumata, Dexamethasone Suppression Test and psychiatric symptoms: a trans-diagnostic approach.

BACKGROUND: Childhood traumatic events and functional abnormalities of the hypothalamus-pituitary-adrenal (HPA) axis have been widely reported in psychiatric patients, although neither is specific for any diagnosis. Among the limited number of studies that have evaluated these topics, none has adopted a trans-diagnostic approach. The aim of the present research is to explore the relationship between childhood stressors, HPA axis function and psychiatric symptoms, independent of the diagnosis. METHOD: A total of 93 moderate to severely ill psychiatric out-patients of Florence and Pisa University Psychiatric Units and 33 healthy control subjects were recruited. The assessment consisted of salivary cortisol pre- and post-low dose (0.5 mg) Dexamethasone, early and recent life events, 121 psychiatric symptoms independent of diagnosis, SCID, BPRS. RESULTS: In total, 33.5% of patients were Dexamethasone Suppression Test (DST) non-suppressors, compared with 6.1% of controls (p=0.001). Among patients, non-suppression was associated with particular symptoms (i.e. depressive and psychotic), but not to any specific diagnosis. Early stressful life events were significantly associated with higher salivary cortisol levels, with DST non-suppression and with approximately the same subset of symptoms. A recent stressful event seemed to be associated to the HPA response only in those subjects who were exposed to early traumata. CONCLUSIONS: Our report suggests a relationship between life stress, HPA axis and psychopathology. A cluster of specific psychiatric symptoms seems to be stress related. Moreover, it seems that an abnormal HPA response is possibly triggered by an excessive pressure in vulnerable individuals.

Development of a real-time timing-shutter performance monitor for protein crystallography.

In order to accurately monitor shutter timing events and long-term shutter performance, a timing-shutter monitor has been developed. This monitor uses a photodiode to capture X-ray-induced fluorescence from the shutter blade in synchrony with goniometer rotation to measure shutter opening and closing delay times, as well as the total time that X-rays are exposed to the sample during crystallographic data frames.

Eating disorders in patients with type 1 diabetes: a meta-analysis.

A meta-analysis of controlled studies on prevalence of eating disorders in Type 1 diabetes was performed in order to assess differences between diabetic and non-diabetic female subjects. All controlled studies using the Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised (DSM Ill-R) or the DSM Fourth Edition (DSM IV) criteria for interview-based diagnosis were included in the analysis. The total sample was composed of 748 and 1587 female subjects with and without diabetes, respectively. The prevalence of anorexia nervosa (AN) in Type 1 diabetic subjects was not significantly different from that of controls (0.27 vs 0.06%), while that of bulimia nervosa and of the two conditions combined was significantly higher in diabetic patients (1.73 vs 0.69%, and 2.00 vs 0.75%, respectively; both p < 0.05). Type 1 diabetes is associated with a higher prevalence of bulimia nervosa in females.

Comparison among different insulin sensitivity indices in obese patients.

AIMS: Recently, several indices have been proposed for the measurement of insulin sensitivity (IS). We set out to make a comparison between fasting insulin, and different IS indices in obese subjects. PATIENTS AND METHODS: Fasting and post load (75 g) glucose and insulin were measured in a consecutive series of 767 (626 F, 141 M) obese (body mass index > 30 kg/m(2)) out-patients, with no known history of diabetes (DM). Mean (+/- sd) age was 46.7 +/- 13.8 years in females and 45.6 +/- 14.3 years in males. Indices of IS based on fasting homeostasis assessment model (HOMA) and post-load (ISI) glucose and insulin and either parameter (1A, and 1B scores) were determined. RESULTS: DM was diagnosed in 21.4% of females, and 20.6% of males, and impaired glucose tolerance in 24% females and 21.3% males. Fasting and post-load glucose, triglyceride and HDL-cholesterol were correlated with all indices in both sexes (P < 0.05). The relative risk of different conditions in the upper quartile of ISI was similar to that observed in the upper quartile of HOMA. The HOMA index was similarly associated with low HDL-cholesterol and hypertriglyceridaemia as fasting insulin, while it showed a greater association with diabetes; ISI was similarly associated with all three conditions as the HOMA index. CONCLUSIONS: Indices of IS based on fasting glucose and insulin show a greater association with diabetes, but not with other abnormalities related to insulin resistance, when compared with fasting insulin levels. Indices based on post-load glucose and insulin do not offer any advantage over those based on fasting values.

Differential signatures of bacterial and mammalian IMP dehydrogenase enzymes.

IMP dehydrogenase (IMPDH) is an essential enzyme of de novo guanine nucleotide synthesis. IMPDH inhibitors have clinical utility as antiviral, anticancer or immunosuppressive agents. The essential nature of this enzyme suggests its therapeutic applications may be extended to the development of antimicrobial agents. Bacterial IMPDH enzymes show biochemical and kinetic characteristics that are different than the mammalian IMPDH enzymes, suggesting IMPDH may be an attractive target for the development of antimicrobial agents. We suggest that the biochemical and kinetic differences between bacterial and mammalian enzymes are a consequence of the variance of specific, identifiable amino acid residues. Identification of these residues or combination of residues that impart this mammalian or bacterial enzyme signature is a prerequisite for the rational identification of agents that specifically target the bacterial enzyme. We used sequence alignments of IMPDH proteins to identify sequence signatures associated with bacterial or eukaryotic IMPDH enzymes. These selections were further refined to discern those likely to have a role in catalysis using information derived from the bacterial and mammalian IMPDH crystal structures and site-specific mutagenesis. Candidate bacterial sequence signatures identified by this process include regions involved in subunit interactions, the active site flap and the NAD binding region. Analysis of sequence alignments in these regions indicates a pattern of catalytic residues conserved in all enzymes and a secondary pattern of amino acid conservation associated with the major phylogenetic groups. Elucidation of the basis for this mammalian/bacterial IMPDH signature will provide insight into the catalytic mechanism of this enzyme and the foundation for the development of highly specific inhibitors.

Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase.

IMP dehydrogenase (IMPDH) is an essential enzyme that catalyzes the first step unique to GTP synthesis. To provide a basis for the evaluation of IMPDH inhibitors as antimicrobial agents, we have expressed and characterized IMPDH from the pathogenic bacterium Streptococcus pyogenes. Our results show that the biochemical and kinetic characteristics of S. pyogenes IMPDH are similar to other bacterial IMPDH enzymes. However, the lack of sensitivity to mycophenolic acid and the Km for NAD (1180 microM) exemplify some of the differences between the bacterial and mammalian IMPDH enzymes, making it an attractive target for antimicrobial agents. To evaluate the basis for these differences, we determined the crystal structure of the bacterial enzyme at 1.9 A with substrate bound in the catalytic site. The structure was determined using selenomethionine-substituted protein and multiwavelength anomalous (MAD) analysis of data obtained with synchrotron radiation from the undulator beamline (19ID) of the Structural Biology Center at Argonne's Advanced Photon Source. S. pyogenes IMPDH is a tetramer with its four subunits related by a crystallographic 4-fold axis. The protein is composed of two domains: a TIM barrel domain that embodies the catalytic framework and a cystathione beta-synthase (CBS) dimer domain of so far unknown function. Using information provided by sequence alignments and the crystal structure, we prepared several site-specific mutants to examine the role of various active site regions in catalysis. These variants implicate the active site flap as an essential catalytic element and indicate there are significant differences in the catalytic environment of bacterial and mammalian IMPDH enzymes. Comparison of the structure of bacterial IMPDH with the known partial structures from eukaryotic organisms will provide an explanation of their distinct properties and contribute to the design of specific bacterial IMPDH inhibitors.