Lower N-Acetyl-Aspartate Levels in Prefrontal Cortices in Pediatric Bipolar Disorder: A (1)H Magnetic Resonance Spectroscopy Study

Objective: The few studies applying single-voxel(1)H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former. Method: We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 +/- 2.9 years) and 38 healthy controls (79 female, mean age 13.9 +/- 2.7 years). We conducted multivoxel in vivo (1)H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups. Results: In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls. Conclusions: Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(1):85-94.

Prognostic relevance of TTF-1 and MMP-9 expression in advanced lung adenocarcinoma

Background: The thyroid transcription factor-1 (TTF-1) is a tissue-specific transcription factor that Could playan important role in cell differentiation and morphogenesis of lung tumors. Matrix metalloproteinase-9 (MMP-9) is a protease commonly expressed in non-small cell lung cancer, conferring angiogenic and metastatic potential. Methods: We assessed TTF-1 and MMP-9 tumor expression by immunohistochemistry in 51 patients with lung adenocarcinoma, stage 11113 or IV, treated with platinum regimens. A bicategorical prognostic model was obtained using the Kaplan-Meier method, COX regression, and conjunctive consolidation. Results: The median expression of TTF-1 was 30.0% (range: 0-85.9%). All tumors expressed MMP-9 (median: 78.7%: range: 15.2-96.1%). Median survival was 41.6 weeks, with estimated 1- and 2-year survival rates of 45.0% and 22.0%, respectively. Poor performance status (Karnofsky scale) - hazards ratio(HR): 1.03. 95% confidence interval (CI): 1.01-1.06: low TTF-1 expression (<40%) - FIR: 4.00, 95% CI: 1.75-9.09: and high MMP-9 expression (>= 80%) - HR: 2.82, 95% CI: 1.30-6.08 were independent prognostic factors. Patients could be stratified in three death risk groups according to markers expression: low risk (high TTF-1 and low MMP-9; median survival: 127.6 weeks), intermediate risk (low TTF-1 OF high MMP-9; median survival: 39.0 weeks): and high risk (low TTF-1 and high MMP-9: median survival: 16.4 weeks). Conclusion: TTF-1 and MMP-9 tumor expression as detected by immunohistochemistry may allow identification of different, clinically meaningful, prognostic groups of advanced lung adenocarcinoma patients treated with platinum regimens. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

HEMODYNAMIC AND PERFUSION END POINTS FOR VOLEMIC RESUSCITATION IN SEPSIS

Sepsis is the systemic inflammatory response syndrome secondary to a local infection, and severe sepsis and septic shock are the more devastating scenarios of this disease. In the last decade, considerable achievements were obtained in sepsis knowledge, and an international campaign was developed to improve the treatment of this condition. However, sepsis is still one of the most important causes of death in intensive care units. The early stages of sepsis are characterized by a variety of hemodynamic derangements that induce a systemic imbalance between tissue oxygen supply and demand, leading to global tissue hypoxia. This dysfunction, which may occur in patients presenting normal vital signs, can be accompanied by a significant increase in both morbidity and mortality. The early identification of high-risk sepsis patients through tissue perfusion markers such as lactate and venous oxygen saturation is crucial for prompt initiation of therapeutic support, which includes early goal-directed therapy as necessary. The purpose of this article was to review the most commonly used hemodynamic and perfusion parameters for hemodynamic optimization in sepsis, emphasizing the physiological background for their use and the studies that demonstrated their effectiveness as goals of volemic resuscitation.

Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment

Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer`s disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE*E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2 +/- 210.5; 581.9 +/- 379.4; and 777.5 +/- 467.8 pg/l respectively; P < 0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8 +/- 463.0; stable MCI, 724.0 +/- 343.4; P = 0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR = 3.0 CI(95%) [1.2-7.8], P = 0.02). We also found a significant interaction between the APOE*E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR = 4.4 CI(95%) [1.6-12.1], P = 0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE*E4, may predict a worse cognitive outcome in patients with MCI.

Myocardial Perfusion Imaging Is a Strong Predictor of Death in Women

OBJECTIVES We sought to assess the prognostic value and risk classification improvement using contemporary single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) to predict all-cause mortality. BACKGROUND Myocardial perfusion is a strong estimator of prognosis. Evidence published to date has not established the added prognostic value of SPECT-MPI nor defined an approach to detect improve classification of risk in women from a developing nation. METHODS A total of 2,225 women referred for SPECT-MPI were followed by a mean period of 3.7 +/- 1.4 years. SPECT-MPI results were classified as abnormal on the presence of any perfusion defect. Abnormal scans were further classified as with mild/moderate reversible, severe reversible, partial reversible, or fixed perfusion defects. Risk estimates for incident mortality were categorized as <1%/year, 1% to 2%/year, and >2%/year using Cox proportional hazard models. Risk-adjusted models incorporated clinical risk factors, left ventricular ejection fraction (LVEF), and perfusion variables. RESULTS All-cause death occurred in 139 patients. SPECT-MPI significantly risk stratified the population; patients with abnormal scans had significantly higher death rates compared with patients with normal scans, 13.1% versus 4.0%, respectively (p < 0.001). Cox analysis demonstrated that after adjusting for clinical risk factors and LVEF, SPECT-MPI improved the model discrimination (integrated discrimination index = 0.009; p = 0.02), added significant incremental prognostic information (global chi-square increased from 87.7 to 127.1; p < 0.0001), and improved risk prediction (net reclassification improvement = 0.12; p = 0.005). CONCLUSIONS SPECT-MPI added significant incremental prognostic information to clinical and left ventricular functional variables while enhancing the ability to classify this Brazilian female population into low-and high-risk categories of all-cause mortality. (J Am Coll Cardiol Img 2011;4:880-8) (C) 2011 by the American College of Cardiology Foundation

EUS-guided percutaneous endoscopic gastrostomy for enteral feeding tube placement

Background: Patients without adequate abdominal-wall transillumination are at a high risk of developing complications after PEG. Objective: We evaluated the feasibility and utility of EUS to guide PEG in patients lacking abdominal-wall transillumination. Design: Single-center case series. Setting: Tertiary-referral center. Patients: Six patients who lacked adequate abdominal-wall transillumination and 2 patients with a large laparotomy scar deemed to be at high risk of developing complications after PEG. Interventions: Patients underwent EUS-guided PEG and deployment of a standard enteral feeding tube. Main Outcome Measurements: Technical success and complication rates. Results: PEG was Successful Under EUS guidance in 5 of 8 patients. Causes of failure included all inadequate EUS window because of a prior Billroth 1 gastrectomy in one and suspected bowel interposition in 2 patients. There were no complications. Limitations: A small number of patients, uncontrolled study, and short follow-up period. Conclusions: This technique may facilitate deployment of PEG in patients who lack adequate abdominal-wall transillumination.

Gastrointestinal stromal tumor in Brazil: Clinicopathology, immunohistochemistry, and molecular genetics of 513 cases

The aim of the present study was to evaluate the clinicopathological, immunohistochemical, and molecular genetic features of gastrointestinal stromal tumors in Brazil and compare them with cases from other countries. Five hundred and thirteen cases were retrospectively analyzed. HE-stained sections and clinical information were reviewed and the immunohistochemical expression of CD117, CD34, smooth-muscle actin, S-100 protein, desmin, CD44v3 adhesion molecule, p53 protein, epidermal growth factor receptor, and Ki-67 antigen was studied using tissue microarrays. Mutation analysis of KIT and platelet-derived growth factor receptor-alpha genes was also performed. There was a slight female predominance (50.3%) and the median age at diagnosis was 59 years. The tumors were mainly located in the stomach (38.4%). Immunohistochemistry showed that CD117 was expressed in 95.7% of cases. Epidermal growth factor receptor expression was observed in 84.4% of tumors. p53 protein expression was found only in 2.6% of cases but all belonged to the high-risk group for aggressive behavior according to the National Institutes of Health consensus approach. No CD44v3 adhesion molecule expression was detected. KIT exon 11 mutations were the most frequent (62.2%). The present data confirm that gastrointestinal stromal tumors in Brazilian patients do not differ from tumors occurring in other countries.

Obesity, estrone, and coronary artery disease in postmenopausal women

Objectives: The link between obesity and endogenous estrogen with coronary artery disease (CAD) in postmenopausal women is uncertain. In this prospective study we analyzed the association of body mass index (BMI) and blood levels of estrone in postmenopausal women with known CAD or with a high risk factor score for CAD. Methods: Participants were 251 female clinic patients aged 50-90 years who were postmenopausal and not using estrogen therapy. Clinical and behavioral characteristics and fasting blood for estrone and heart disease risk factors were collected at baseline, and again at I and 2 years. Women were grouped according to their BMI (kg/m(2)) as normal (18.5 <= BMI < 25), overweight (25 <= BMI < 30) or obese (BMI >= 30), and by low and high estrone levels (< 15 and >= 15 pg/mL, respectively). Fatal and nonfatal events were recorded for 2 years after baseline. Results: Women with a low estrone level were older, thinner, and had less hypertension, diabetes, and lower triglyceride and glucose levels. BMI was positively associated with estrone levels, hypertension, and diabetes and inversely associated with HDL cholesterol. There were 14 deaths, 8 attributed to CAD. The Kaplan-Meier survival curve showed a nonsignificant trend (p = 0.074) of greater all cause mortality in women with low estrone levels (< 15 mL). In this model, adjusted for BMI, age [OR 1.08; p = 0.03], C-reactive protein [OR = 1.24; p = 0.024] and hypertension [OR = 6.22; p = 0.003] were independent predictors of all cause mortality. Conclusions: Postmenopausal women with low estrone levels (< 15 pg/mL) had a trend for increased mortality over the next 2 years. Larger, longer studies are needed. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Prognostic Impact of MYCN, DDX1, TrkA, and TrkC Gene Transcripts Expression in Neuroblastoma

Background. The aims of this study were to define the mRNA expression profiles of MYCN, DDX1, TrkA, and TrkC in biopsy tumor samples from 64 Brazilian patients with neuroblastomas of different risk stages and to correlate altered expression with prognostic values. Procedure. Patients were retrospectively classified into low- (n = 11), intermediate- (n = 18), and high-risk (n = 35) groups using standard criteria. The mRNA levels of the above genes were measured by quantitative real-time polymerase chain reaction. Univariate analyses were performed and survival curves were plotted by the Kaplan-Meier method. Results. Of the 64 patients, 53% were female and 62.5% were older than 18 months. The 5-year overall survival (OS) for the entire cohort was 40.3%, with inferior median OS in patients identified in the intermediate- and high-risk groups. A significant difference in OS with respect to TrkA mRNA expression was found for the high-risk group vs. either the low- or intermediate-risk groups (P < 0.01, log rank test). Within the intermediate-risk group, neuroblastoma patients with positive TrkA mRNA expression had better clinical outcomes than patients with no TrkA transcript expression (P = 0.004). Another difference in OS was only found between the intermediate- and high-risk groups (P < 0.027, log rank test). No significant correlation of mRNA expression and survival outcome could be detected for the MYCN, DDX1. Conclusions. Positive expression of TrkA mRNA may be a clinically useful addition to the current risk classification system, allowing the identification of NB tumors with favorable prognosis. Pediatr Blood Cancer 2011; 56: 749-756. (c) 2010 Wiley-Liss, Inc.

Increases in circulating matrix metalloproteinase-9 levels following fibrinolysis for acute pulmonary embolism

Introduction: Fibrinolyis is one of the first line therapies in high risk pulmonary embolism (PE) according to current guidelines. Previous studies showed that brinolytic therapy with tPA (tissue plasminogen activator, or alteplase) upregulates the concentrations of matrix metalloproteinases (MMPs) and contributes to hemorrhagic transformation after cardioembolic stroke. However, no previous study has described the circulating MMPs levels following fibrinolysis for acute PE. Materials and Methods: We serially measured the circulating levels of MMPs (MMP-9 and MMP-2) and their endogenous inhibitors, the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in alteplase and in streptokinase-treated patients with acute PE by gelatin zymography and by enzyme-linked immunosorbent assays, respectively. Results: We found that therapy of PE streptokinase or with alteplase is associated increased pro-MMP-9, but not MMP-2, concentrations for up to 24 hours, whereas no significant changes were found in TIMP-1 or TIMP-2 concentrations. This alteration returned to normal 3 to 5 days after thrombolysis. This is the first study reporting on MMPs alterations following fibrinolysis for acute PE. Conclusions: We found transient increases in circulating pro-MMP-9 levels following fibrinolysis for acute PE. Our findings support the hypothesis that increased MMP-9 levels may underlie the risk of intracerebral hemorrhage or other bleeding complication of thrombolysis for acute PE, and the use of MMP inhibitors may decrease such risk. (C) 2010 Elsevier Ltd. All rights reserved.

Evaluation of the vaccination status in pediatric renal transplant recipients

To assess the immunization status of pediatric renal transplant patients followed at a single center in Brazil, vaccination charts of all patients aged between one and 18 yr were analyzed both pre- and post-transplantation. Appropriate immunization was defined according to the National Immunization Program (routine vaccines) - for all Brazilian children - and the Special Immunobiological Agents Program that also includes special vaccines for immunodeficient or other high-risk children. A total of 46 patients was evaluated (mean age 13.7 yr; range 4-17 yr). Vaccination charts were found to be up to date in only two patients (4.3%) pretransplant and in two (4.3%) post-transplant. Although 36 patients (62.2%) in the pretransplant phase and 24 (52.1%) in the post-transplant phase had been vaccinated according to the National Immunization Program, they had not received the special vaccines indicated for their immunocompromised condition. Therefore, despite being followed at a referral center, almost all patients presented an incomplete immunization status pre- and post-transplant. This probably reflects missed opportunities and medical/parental apprehension related to vaccination of patients with chronic renal insufficiency, dialysis or kidney transplantation. Efforts should be made to ensure adequate vaccination in children with kidney diseases, especially before kidney transplantation.

Hyperplastic polyposis - Association with colorectal cancer

Hyperplastic polyposis is a loosely defined syndrome initially thought not to confer a clinically important predisposition to colorectal cancer. The aim of the current study was to examine the clinical, histologic, and molecular features of a prospective series of cases meeting a strict definition of the condition. Twelve patients were identified, seven of whom had developed colorectal cancer. Most polyps were hyperplastic, but 11 patients also had polyps containing dysplasia as either serrated adenomas. mixed polyps, or traditional adenomas. The mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11%(p < 0.05). Microsatellite instability (MSI) was present in 3 of 47 hyperplastic polyps and two of right serrated adenomas. Kras was mutated in 8 of 47 hyperplastic polyps and two of eight serrated adenomas. No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q. Two of seven cancers showed a high level of MSI. It is concluded that hyperplastic polyposis is associated with a high risk of colorectal cancer. Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium. A higher proportion of dysplastic polyps is associated with increased cancer risk. Clonal generic changes are observed in some hyperplastic polyps and serrated adenomas.

Evaluation of the Frequency of Micronuclei in Exfoliated Cells from Oral Lesions Previously Identified by Toluidine Blue

Objective: Patients using a removable prosthesis are susceptible to a variety of oral lesions that may progress to cancer. Toluidine blue (TB) staining is used to identify premalignant lesions, but the results are still controversial. Since micronuclei (MN) are a biomarker of genetic instability, the objective of this study was to determine the frequency of MN in white lesions of the oral mucosa and to compare the results with those of the TB test. Study Design: The study included 20 removable prosthesis users with white lesions that were previously classified as toluidine positive or negative. The frequency of MN was evaluated in exfoliated cells from lesions and normal mucosa. Nuclear anomalies were also registered. Results: A significant increase (p < 0.05) in the frequency of MN was observed in exfoliated cells from lesions compared to normal mucosal cells, and no relationship was seen with TB staining. Lifestyle factors or gender did not influence the results. Conclusions: The frequency of MN is a sensitive biomarker and can be used to predict genomic instability in white oral lesions. The MN assay may serve as a good parameter in the battery of tests used to identify high-risk individuals, contributing to the identification of the biological conditions of oral lesions. Copyright (C) 2011 S. Karger AG, Basel

Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma

MC1R gene variants have previously been associated with red hair and fair skin color, moreover skin ultraviolet sensitivity and a strong association with melanoma has been demonstrated for three variant alleles that are active in influencing pigmentation: Arg151Cys, Arg160Trp, and Asp294His. This study has confirmed these pigmentary associations with MC1R genotype in a collection of 220 individuals drawn from the Nambour community in Queensland, Australia, 111 of whom were at high risk and 109 at low risk of basal cell squamous cell carcinoma. Comparative allele frequencies for nine MC1R variants that have been reported in the Caucasian population were determined for these two groups, and an association between prevalence of basal cell carcinoma, squamous cell carcinoma, solar keratosis and the same three active MC1R variant alleles was demonstrated [odds ratio=3.15 95% CI (1.7, 5.82)]. Three other commonly occurring variant alleles: Val60Leu, Val92Met, and Arg163Gln were identified as having a minimal impact on pigmentation phenotype as well as basal cell carcinoma and squamous cell carcinoma risk. A significant heterozygote effect was demonstrated where individuals carrying a single MC1R variant allele were more likely to have fair and sun sensitive skin as well as carriage of a solar lesion when compared with those individuals with a consensus MC1R genotype. After adjusting for the effects of pigmentation on the association between MC1R variant alleles and basal cell carcinoma and squamous cell carcinoma risk, the association persisted, confirming that presence of at least one variant allele remains informative in terms of predicting risk for developing a solar-induced skin lesion beyond that information gained through observation of pigmentation phenotype.

The future of cognitive and behavioral therapies in the prevention and early management of psychosis: Opportunities and risks

Behavioral and cognitive interventions for people with psychosis have a long and distinguished history, although the evidence for their application to young people remains limited. We anticipate that the next decades will show substantial research into psychological intervention for this population. Important targets will include the management of environmental stressors, reduction of substance misuse, and promotion of early treatment. Psychological management of positive symptoms, depression, and suicidal behavior will continue to be critical objectives. Important secondary prevention goals will be the retention of cognitive functioning, vocational options, social skills, and social network support, including appropriate family support. We expect primary prevention to include both universal programs and interventions for adolescents at particularly high risk. Technical innovations will include increasing use of Internet-based intervention and behavior cueing devices. Pressures for intervention brevity will continue, as will problems with the systematic delivery of effective procedures.