Altered growth in male peroxisome proliferator-activated receptor gamma (PPARgamma) heterozygous mice: involvement of PPARgamma in a negative feedback regulation of growth hormone action.

The peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPARgamma allele has been mutated reveals that male PPARgamma heterozygous (PPARgamma +/-) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARgamma- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARgamma +/- mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARgamma +/- mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARgamma +/- mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARgamma in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARgamma mutant mice.

Combined impact of negative lifestyle factors on cardiovascular risk in children: a randomized prospective study.

PURPOSE: Negative lifestyle factors are known to be associated with increased cardiovascular risk (CVR) in children, but research on their combined impact on a general population of children is sparse. Therefore, we aimed to quantify the combined impact of easily assessable negative lifestyle factors on the CVR scores of randomly selected children after 4 years. METHODS: Of the 540 randomly selected 6- to 13-year-old children, 502 children participated in a baseline health assessment, and 64% were assessed again after 4 years. Measures included anthropometry, fasting blood samples, and a health assessment questionnaire. Participants scored one point for each negative lifestyle factor at baseline: overweight; physical inactivity; high media consumption; little outdoor time; skipping breakfast; and having a parent who has ever smoked, is inactive, or overweight. A CVR score at follow-up was constructed by averaging sex- and age-related z-scores of waist circumference, blood pressure, glucose, inverted high-density lipoprotein, and triglycerides. RESULTS: The age-, sex-, pubertal stage-, and social class-adjusted probabilities (95% confidence interval) for being in the highest CVR score tertile at follow-up for children who had at most one (n = 48), two (n = 64), three (n = 56), four (n = 41), or five or more (n = 14) risky lifestyle factors were 15.4% (8.9-25.3), 24.3% (17.4-32.8), 36.0% (28.6-44.2), 49.8% (38.6-61.0), and 63.5% (47.2-77.2), respectively. CONCLUSIONS: Even in childhood, an accumulation of negative lifestyle factors is associated with higher CVR scores after 4 years. These negative lifestyle factors are easy to assess in clinical practice and allow early detection and prevention of CVR in childhood.

Emotionally negative stimuli can overcome attentional deficits in patients with visuo-spatial hemineglect.

Left unilateral spatial neglect resulting from right brain damage is characterized by loss of awareness for stimuli in the contralesional side of space, despite intact visual pathways. We examined using fMRI whether patients with neglect are more likely to consciously detect in the neglected hemifield, emotionally negative complex scenes rather than visually similar neutral pictures and if so, what neural mechanisms mediate this effect. Photographs of emotional and neutral scenes taken from the IAPS were presented in a divided visual field paradigm. As expected, the detection rate for emotional stimuli presented in the neglected field was higher than for neutral ones. Successful detection of emotional scenes as opposed to neutral stimuli in the left visual field (LVF) produced activations in the parahippocampal and anterior cingulate areas in the right hemisphere. Detection of emotional stimuli presented in the intact right visual field (RVF) activated a distributed network of structures in the left hemisphere, including anterior and posterior cingulate cortex, insula, as well as visual striate and extrastriate areas. LVF-RVF contrasts for emotional stimuli revealed activations in right and left attention related prefrontal areas whereas RVF-LVF comparison showed activations in the posterior cingulate and extrastriate visual cortex in the left hemisphere. An additional analysis contrasting detected vs. undetected emotional LVF stimuli showed involvement of left anterior cingulate, right frontal and extrastriate areas. We hypothesize that beneficial role of emotion in overcoming neglect is achieved by activation of frontal and limbic lobe networks, which provide a privileged access of emotional stimuli to attention by top-down modulation of processing in the higher-order extrastriate visual areas. Our results point to the importance of top-down regulatory role of the frontal attentional systems, which might enhance visual activations and lead to greater salience of emotional stimuli for perceptual awareness.

Age above 60 years is not a negative predictive factor for combined antiviral therapy with pegylated interferon alpha and ribavirin in hepatitis C patients

Background: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral hepatitis C therapy. However, elderly patients often show relevant fibrosis or cirrhosis which is a known negative predictive factor, making it difficult to interpret age as an independent predictive factor. Methods: From the framework of the Swiss hepatitis C cohort (SCCS), we collected data from 545 antiviral hepatitis C therapies, including data from 67 hepatitis C patients ≥ 60 y who had been treated with PEG-interferon and ribavirin. We analyzed host factors (age, gender, fibrosis, haemoglobin, depression, earlier hepatitis C treatment), viral factors (genotype, viral load) and treatment course (early virological response, end of treatment response, SVR). Generalised estimating equations (GEE) regression modelling was used for the primary end point (SVR), with age ≥ 60 y and < 60 y as independent variable and gender, presence of cirrhosis, genotype, earlier treatment and viral load as confounders. SVR was analysed in young and elderly patients after matching for these confounders. Additionally, classification tree analysis was done in elderly patients using these confounders. Results: SVR analyzed in 545 patients was 55%. In genotype 1/4, SVR was 42.9% in 259 patients < 60 y and 26.1% in 46 patients ≥ 60 y. In genotype 2/3, SVR was 74.4% in 215 patients < 60 y and 84% in 25 patients ≥ 60 y. However, GEE model showed that age had no influence on achieving SVR (Odds ratio 0.91). Confounders influenced SVR as known from previous studies (cirrhosis, genotype 1/4, previous treatment and viral load >600'000 IE/ml as negative predictive factors). When young and elderly patients were matched (analysis in 59 elderly patients), SVR was not different in these patient groups (54.2% and 55.9%, resp.; p=0.795 in binomial test). The classification tree-derived best criterion for SVR in elderly patients was genotype, with no further criteria relevant for predicting SVR in genotype 2/3. In patients with genotype 1/4, further criteria were presence of cirrhosis and low viral load <600'000 IE/ml in non-cirrhotic patients. Conclusions: Age is not a relevant predictive factor for achieving SVR, when confounders were taken into account. In terms of effectiveness of antiviral therapy, age does not play a major role and should not be regarded as relevant negative predictive factor. Since life expectancy in Switzerland at age 60 is more than 22 y, hepatitis C therapy is reasonable in elderly patients with known relevant fibrosis or cirrhosis, because interferon-based hepatitis C therapy improves survival and reduces carcinogenesis.

β-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intraabdominal Candidiasis.

Rationale: Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established. Objectives: The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-β-d-glucan (BG) antigenemia for diagnosis of IAC. Methods: Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared. Measurements and Main Results: Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46-9,557) in IAC versus 99 pg/ml (8-440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. β-Glucan decreased in IAC responding to therapy and increased in nonresponse. Conclusions: BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.

Blood levels of brain-derived neurotrophic factor correlate with several psychopathological symptoms in anorexia nervosa patients

Background: Evidence of a role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of eating disorders (ED) has been provided by association studies and by murine models. BDNF plasma levels have been found altered in ED and in psychiatric disorders that show comorbidity with ED. Aims: Since the role of BDNF levels in ED-related psychopathological symptoms has not been tested, we investigatedthe correlation of BDNF plasma levels with the Symptom Checklist 90 Revised (SCL-90R) questionnaire in a total of 78 ED patients. Methods: BDNF levels, measured bythe enzyme-linked immunoassay system, and SCL-90R questionnaire, were assessed in a total of 78 ED patients. The relationship between BDNF levels and SCL-90R scales was calculated using a general linear model. Results: BDNF plasma levels correlated with the Global Severity Index and the Positive Symptom Distress Index global scales and five of the nine subscales in the anorexia nervosa patients. BDNF plasma levels were able to explain, in the case of the Psychoticism subscale, up to 17% of the variability (p = 0.006). Conclusion: Our data suggest that BDNF levels could be involved in the severity of the disease through the modulation of psychopathological traits that are associated with the ED phenotype.

Lack of CB1 receptor activity impairs serotonergic negative feedback

Serotonergic and endocannabinoid systems are important substrates for the control of emotional behavior and growing evidence show an involvement in the pathophysiology of mood disorders. In the present study, the absence of the activity of the CB1 cannabinoid receptor impaired serotonergic negative feedback in mice. Thus, in vivo microdialysis experiments revealed increased basal 5-HT extracellular levels and attenuated fluoxetine-induced increase of 5-HT extracellular levels in the prefrontal cortex of CB1 knockout compared to wild-type mice. These observations could be related to the significant reduction in the 5-HT transporter binding site density detected in frontal cortex and hippocampus of CB1 knockout mice. The lack of CB1 receptor also altered some 5-HT receptors related to the 5-HT feedback. Extracellular recordings in the dorsal raphe nucleus revealed that the genetic and pharmacological blockade of CB1 receptor induced a 5-HT1A autoreceptor functional desensitization. In situ hybridization studies showed a reduction in the expression of the 5-HT2C receptor within several brain areas related to the control of the emotional responses, such as the dorsal raphe nucleus, the nucleus accumbens and the paraventricular nucleus of the hypothalamus, whereas an overexpression was observed in the CA3 area of the ventral hippocampus. These results reveal that the lack of CB1 receptor induces a facilitation of the activity of serotonergic neurons in the dorsal raphe nucleus by altering different components of the 5-HT feedback as well as an increase in 5-HT extracellular levels in the prefrontal cortex in mice.

Asymmetry of Functional Connectivity in Schizophrenia at Different Spatial Scales

Introduction: The interhemispheric asymmetries that originate from connectivity-related structuring of the cerebral cortex are compromised in schizophrenia (SZ). Recently, we have revealed the whole-head topography of EEG synchronization in SZ (Jalili et al. 2007; Knyazeva et al. 2008). Here we extended the analysis to assess the abnormality in the asymmetry of synchronization, which is further motivated by the evidence that the interhemispheric asymmetries suspected to be abnormal in SZ originate from the connectivity-related structuring of the cortex. Methods: Thirteen right-handed SZ patients and thirteen matched controls, participated in this study and the multichannel (128) EEGs were recorded for 3-5 minutes at rest. Then, Laplacian EEG (LEEG) were calculated using a 2-D spline. The LEEGs were analysis through calculating the power spectral density using Welch's average periodogram method. Furthermore, using a state-space based multivariate synchronization measure, S-estimator, we analyzed the correlate of the functional cortico-cortical connectivity in SZ patients compared to the controls. The values of S-estimator were obtained at three different special scales: first-order neighbors for each sensor location, second-order neighbors, and the whole hemisphere. The synchronization measures based on LEEG of alpha and beta bands were applied and tuned to various spatial scales including local, intraregional, and long-distance levels. To assess the between-group differences, we used a permutation version of Hotelling's T2 test. For correlation analysis, Spearman Rank Correlation was calculated. Results: Compared to the controls, who had rightward asymmetry at a local level (LEEG power), rightward anterior and leftward posterior asymmetries at an intraregional level (first- and second-order S-estimator), and rightward global asymmetry (hemispheric S-estimator), SZ patients showed generally attenuated asymmetry, the effect being strongest for intraregional synchronization. This deviation in asymmetry across the anterior-to-posterior axis is consistent with the cerebral form of the so-called Yakovlevian or anticlockwise cerebral torque. Moreover, the negative occipital and positive frontal asymmetry values suggest higher regional synchronization among the left occipital and the right frontal locations relative to their symmetrical counterparts. Correlation analysis linked the posterior intraregional and hemispheric abnormalities to the negative SZ symptoms, whereas the asymmetry of LEEG power appeared to be weakly coupled to clinical ratings. The posterior intraregional abnormalities of asymmetry were shown to increase with the duration of the disease. The tentative links between these findings and gross anatomical asymmetries, including the cerebral torque and gyrification pattern in normal subjects and SZ patients, are discussed. Conclusions: Overall, our findings reveal the abnormalities in the synchronization asymmetry in SZ patients and heavy involvement of the right hemisphere in these abnormalities. These results indicate that anomalous asymmetry of cortico-cortical connections in schizophrenia is amenable to electrophysiological analysis.

Node-negative T1-T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy?

PURPOSE: To evaluate the influence of concomitant chemotherapy on loco-regional control (LRC) and cancer-specific survival (CSS) in patients with T1-T2 N0 M0 anal cancer treated conservatively by primary radiotherapy (RT). MATERIALS AND METHODS: Between 1976 and 2008, 146 patients with T1 (n=29) or T2 (n=117) N0 M0 anal cancer were treated curatively by RT alone (n=71) or by combined chemoradiotherapy (CRT) (n=75) consisting of mitomycin C±5-fluorouracil. Univariate and multivariate analyses were performed to assess patient-, tumor- and treatment-related factors influencing LRC and CSS. RESULTS: With a median follow-up of 62.5 months (interquartilerange, 26-113 months), 122 (84%) patients were locally controlled. The five-year actuarial LRC, CSS and overall survival for the population were 81.4%±3.6%, 91.9%±2.6%, and 75.4%±3.9%, respectively. The five-year LRC and CSS for patients treated with RT alone and with CRT were 75.5%±6.0% vs. 86.8%±4.1% (p=0.155) and 88.5%±4.5% vs. 94.9%±2.9% (p=0.161), respectively. In the multivariate analysis, no clinical or therapeutic factors were found to significantly influence the LRC and CSS, while the addition of chemotherapy was of borderline significance (p=0.065 and p=0.107, respectively). CONCLUSIONS: In the management of node negative T1-T2 anal cancer, LRC and CSS tend to be superior in patients treated by combined CRT, even though the difference was not significant. Randomized studies are warranted to assess definitively the role of combined treatment in early-stage anal carcinoma.

A-8a Summary of Food Stamp Errors Active and Negative Cases, April-September 2004

A-8a Summary of Food Stamp Errors Active and Negative Cases, Apr. 2004 - Sept. 2004

A-8a Summary of Food Stamp Errors Active and Negative Cases, October 2004-March 2005

A-8a Summary of Food Stamp Errors Active and Negative Cases, Oct. 2004 - Mar. 2005

False-negative PCR result due to gene polymorphism: the example of Neisseria meningitidis.

Early treatment of meningococcal meningitis is mandatory but may negate the cerebrospinal fluid culture. Etiological diagnosis then mainly relies on PCR. Here, we report a case of false-negative results for real-time PCR for a Neisseria meningitidis serogroup B isolate with a polymorphism in the ctrA gene.

Renal and neurohormonal responses to increasing levels of lower body negative pressure in men.

BACKGROUND: The stimulation of efferent renal sympathetic nerve activity induces sequential changes in renin secretion, sodium excretion, and renal hemodynamics that are proportional to the magnitude of the stimulation of sympathetic nerves. This study in men investigated the sequence of the changes in proximal and distal renal sodium handling, renal and systemic hemodynamics, as well as the hormonal profile occurring during a sustained activation of the sympathetic nervous system induced by various levels of lower body negative pressure (LBNP). METHODS: Ten healthy subjects were submitted to three levels of LBNP ranging between 0 and -22.5 mm Hg for one hour according to a triple crossover design, with a minimum of five days between each level of LBNP. Systemic and renal hemodynamics, renal water and sodium handling (using the endogenous lithium clearance technique), and the neurohormonal profile were measured before, during, and after LBNP. RESULTS: LBNP (0 to -22.5 mm Hg) induced an important hormonal response characterized by a significant stimulation of the sympathetic nervous system and gradual activations of the vasopressin and the renin-angiotensin systems. LBNP also gradually reduced water excretion and increased urinary osmolality. A significant decrease in sodium excretion was apparent only at -22.5 mm Hg. It was independent of any change in the glomerular filtration rate and was mediated essentially by an increased sodium reabsorption in the proximal tubule (a significant decrease in lithium clearance, P < 0.05). No significant change in renal hemodynamics was found at the tested levels of LBNP. As observed experimentally, there appeared to be a clear sequence of responses to LBNP, the neurohormonal response occurring before the changes in water and sodium excretion, these latter preceding any change in renal hemodynamics. CONCLUSIONS: These data show that the renal sodium retention developing during LBNP, and thus sympathetic nervous stimulation, is due mainly to an increase in sodium reabsorption by the proximal segments of the nephron. Our results in humans also confirm that, depending on its magnitude, LBNP leads to a step-by-step activation of neurohormonal, renal tubular, and renal hemodynamic responses.

Localized fibrous tumours of the pleura: 15 new cases and review of the literature.

OBJECTIVE: To present a series of localized fibrous tumours of the pleura (LFTP), to define the clinical and histopathological diagnostic criteria of this tumour, and to determine the optimal treatment and follow-up. METHODS: Review of the charts of the patients with the diagnosis of LFTP (formerly called benign fibrous mesothelioma), as well as of all the histological sections, including immunohistochemical stains. Review of the literature with special emphasis on the clinical and histological criteria of malignancy. RESULTS: During the last 30 years, we found 15 patients with a complete clinical chart and histological material, particularly paraffin blocks of the tumour. The mean age was 57 years (range 27-79). Eight patients were asymptomatic, and the remaining seven presented with non-specific symptoms. All but one had complete resection of the tumour, including partial lung resection in two and partial chest wall resection in three. The diagnosis was confirmed by histological review in 15 cases. Immunohistochemical stainings showed positivity for vimentin in all cases, for CD 34 in 80%, but were consistently negative for cytokeratins. Nine tumours were histologically classified as malignant. Among them, five recurred, two of which were responsible for death. One benign tumour recurred after 1 year, and was treated successfully by repeat resection and radiotherapy. Overall, 13 patients (86%) were alive with no evidence of disease between 10 months and 27 years after the first resection. CONCLUSIONS: LFTP is a rare tumour which has a benign clinical course in over 80% of the cases, and is asymptomatic in half the patients. The diagnosis is difficult to establish before operation. Treatment consists of complete resection including adjacent structures if necessary. The clinical behaviour of LFTP cannot be predicted on the basis of histological aspects only. If histologically malignant tumours are more prone to recurrence and poor outcome, broad-based and locally invasive tumours bear a higher risk of recurrence. Long term follow-up is therefore mandatory in all cases in order to perform early re-resection when recurrence occurs.