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.

Decreased recent thymus emigrant number in rheumatoid factor-negative polyarticular juvenile idiopathic arthritis

Objectives To determine TCR excision circle (TREC) levels, a marker of recent thymic emigrants, in the peripheral lymphocyte pool of rheumatoid factor-negative (RF circle divide) polyarticular juvenile idiopathic arthritis (JIA) children. Materials and methods We studied TREC levels in peripheral blood mononuclear cells (PBMC) in 30 RF circle divide polyarticular JIA children with active disease and in 30 age- and gender-matched healthy controls. Signal-joint TREC concentration was determined by real-time quantitative-PCR as the number of TREC copies/mu g PBMC DNA gauged by a standard curve with known number of TREC-containing plasmids. Results TREC levels in PBMC were significantly lower in JIA (4.90 +/- 3.86 x 10(4) TRECs/mu g DNA) as compared to controls (10.45 +/- 8.45 x 10(4) TRECs/mu g DNA, p=0.001). There was an inverse correlation between age and TREC levels in healthy children (r=-0.438, p=0.016) but not in JIA. No clinical association was observed between TREC levels and disease activity and use of oral steroids and methotrexate. Conclusions The finding of decreased PBMC TREC levels in RF circle divide polyarticular JIA children is consistent with a low proportion of recent thymus emigrants. This may interfere with the equilibrium between populations of polyclonal and naive T cells versus oligoclonal memory auto-reactive T cells and, therefore, may hinder the maintenance of immune tolerance in this disease.

Family Environment and Pediatric Major Depressive Disorder

Background: The risks for depression broadly include biological and environmental factors. Furthermore, having a family member suffering from major depression is also likely to have consequences for the family environment. Further research aimed at understanding the effects of having a child with major depression on family interaction patterns is warranted. Methods: We studied 31 families with an 8- to 17-year-old child (mean age +/- SD = 12.9 +/- 2.7 years) who met the DSM-IV criteria for major depressive disorder (MDD) and 34 families with no mentally ill children (mean age 8 SD = 12.6 +/- 2.9 years) or parents. Children and their parents were assessed with the K-SADS-PL (Kiddie Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version) interview. Parents completed the Moos Family Environment Scale (FES) to assess their perceptions of current family functioning. Data were analyzed using the nonparametric Wilcoxon-Mann-Whitney test. Results: Families of MDD children showed significantly different patterns of family functioning on FES subscales representing relationships and personal growth dimensions. The families with MDD children showed higher levels of conflict (p < 0.001) and lower levels of cohesion (p < 0.001), expressiveness (p = 0.003) and active-recreational orientation (p = 0.02) compared to the families without mentally ill children. Conclusion: Families with MDD children show a lower degree of commitment, provide less support to one another, provide less encouragement to express feelings and have more conflicts compared to families with no mentally ill children or parents. Interventions aimed at improving family dynamics may be beneficial to MDD children and their families. Copyright (C) 2010 S. Karger AG, Basel

Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: A single voxel (1)H spectroscopy study

Few proton magnetic resonance spectroscopy ((1)H spectroscopy) studies have investigated the dorsolateral prefrontal cortex (DLPFC), a key region in the pathophysiology of major depressive disorder (MDD). We used (1)H spectroscopy to verify whether MDD patients differ from healthy controls (HQ in metabolite levels in this brain area. Thirty-seven unmedicated DSM-IV MDD patients were compared with 40 HC. Subjects underwent a short echo-time (1)H spectroscopy examination at 1.5 T, with an 8-cm(3) single voxel placed in the left DLPFC. Reliable absolute metabolite levels of N-acetyl aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol, glutamate plus glutamine (Glu+Gln), and glutamate were obtained using the unsuppressed water signal as an internal reference. Metabolite levels in the left DLPFC did not statistically differ between MDD patients and HC. We found an interaction between gender and diagnosis on PCr+Cr levels. Male MDD patients presented lower levels of PCr+Cr than male HC, and female MDD patients presented higher levels of PCr+Cr than female HC. Moreover, length of illness was inversely correlated with NAA levels. These findings suggest that there is not an effect of diagnosis on the left DLPFC neurochemistry. Possible effects of gender on PCr+Cr levels of MDD patients need to be further investigated. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system

Chemokines are chemoattractant cytokines involved in the immune response of a wide variety of diseases. There are few studies assessing their role in opportunistic infections in HIV-infected patients. In this study, we measured CC and CXC chemokines in cerebrospinal fluid (CSF) samples obtained from 40 HIV-infected patients with or without opportunistic infections of the central nervous system (CNS). CSF samples were also analyzed for quantification of total protein, cell count and HIV-1 RNA. HIV+ patients with cryptococcal meningitis had higher levels of CCL2, CCL3, CCL5, CXCL9 and CXCL10 when compared to patients without opportunistic neurological infections. Furthermore, HIV+ patients with associated cryptococcal meningitis had higher levels of CCL3, CXCL9 and CXCL10 when compared to HIV+ patients with associated toxoplasmic encephalitis. CCL3 and CXCL9 levels were positively correlated with CSF HIV-1 RNA levels, CSF protein concentration, and CSF cell count. CXCL10 level was correlated with the CSF viral load and the CSF cell count and CCL5 level was correlated with the CSF cell count. In conclusion, the profile of chemokines in CSF of HIV patients may differ according to the modality of the presented opportunistic infection and according to other biological markers, such as viral load in CSF. These differences are probably related to different patterns of neuroinflammatory responses displayed by patients with different opportunistic neurological infections. (C) 2009 Elsevier B.V. All rights reserved.

Active tuberculosis and Mycobacterium tuberculosis latent infection in patients with HIV/AIDS

Objectives Tuberculosis (TB) remains an important disease associated with HIV infection and AIDS in Brazil, even in a setting of free access to antiretroviral therapy (ART) and TB treatment. In previous studies, isoniazid therapy (IT) for latent infection with Mycobacterium tuberculosis (LIMTb) was found to reduce the risk of TB by 62% in patients with a tuberculin test (TT)> 5 mm. The objectives of this study were to investigate the occurrence of TB, the prevalence of LIMTb and the coverage of the TT and IT, and to estimate the number of missed opportunities to prevent TB in patients with HIV/AIDS. Methods A random sample of patients with HIV/AIDS was selected; data from the medical files were obtained, and a TT was performed in consenting subjects. Results In the 203 subjects included in the study, TB occurrence was 13.3%, LIMTb prevalence was 20% and the coverage of the TT and IT was 59.2 and 55%, respectively. Patients with TB had a lower nadir CD4 cell count, but their CD4 recovery was comparable to that of non-TB patients. Patients with LIMTb always had a higher CD4 cell count. Conclusions By expanding the coverage of the TT and IT to nearly 100%, we could more than double the number of prevented cases of TB. TB prevention programmes must be reinforced to reduce the number of missed opportunities for diagnosis, and IT must be improved to reduce TB among patients with HIV/AIDS. Empowering patients with knowledge about TB, the preventive role of IT and the need for an annual TT may be the best way of lowing rates of TB in patients with HIV/AIDS.

Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey

Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population. We studied 953 subjects (aged 25-74 years) from a random sample of German residents. Risk factors had been determined at a baseline investigation in 1994/95. At a follow-up investigation, 10 years later, standardized echocardiography determined aortic valve morphology and aortic valve area (AVA) as well as left ventricular geometry and function. At the follow-up study, the overall prevalence of DAVD was 28%. In logistic regression models adjusting for traditional cardiovascular risk factors at baseline age (OR 2.0 [1.7-2.3] per 10 years, P < 0.001), active smoking (OR 1.7 [1.1-2.4], P = 0.009) and elevated total cholesterol levels (OR 1.2 [1.1-1.3] per increase of 20 mg/dL, P < 0.001) were significantly related to DAVD at follow-up. Furthermore, age, baseline status of smoking, and total cholesterol level were significant predictors of a smaller AVA at follow-up study. In contrast, hypertension and obesity had no detectable relationship with long-term changes of aortic valve structure. In the general population we observed a high prevalence of DAVD that is associated with long-term exposure to elevated cholesterol levels and active smoking. These findings strengthen the notion that smoking cessation and cholesterol lowering are promising treatment targets for prevention of DAVD.

High frequency of lipoprotein risk levels for cardiovascular disease in Takayasu arteritis

The objective of this study is to characterize the lipoprotein risk levels in Takayasu arteritis (TA) patients and its possible association with disease activity and glucocorticoid use. Twenty-five female TA patients were consecutively included and compared with 30 age-, gender-, and body mass index-matched healthy controls. Demographic features and the lipid profile were determined and cardiovascular risk levels were evaluated according to NCEP/ATPIII. Total cholesterol (TC), LDL-c, HDL-c, and triglycerides were determined after a 12-h overnight fast. Exclusion criteria were conditions that interfere in the lipid profile. The disease duration was 6.6 +/- 7.4 years; 30% had clinical activity and 80% had laboratory activity. Regarding NCEP/ATPIII risk levels, TA patients presented higher frequency of lipid risk compared to controls: high TC (48% vs. 20%, p = 0.04), low HDL-c (20% vs. 0%, p = 0.015), and high triglycerides (36% vs. 10%, p = 0.026). No difference was observed related to LDL-c risk levels between both groups (40% vs. 20%, p = 0.14). Remarkably, 60% of the patients had at least one lipid risk factor for cardiovascular disease. No difference in the lipids was observed between patients with and without clinical activity; however, those with laboratory activity showed lower levels of HDL-c (1.37 +/- 0.42 vs. 2.00 +/- 0.63 mmol/L, p = 0.012) than patients without this activity. A negative correlation was found between HDL-c and CRP levels (r = -0.42, p = 0.04). Lipids were similar in patients under glucocorticoid compared to those without this therapy. This is the first study to identify that TA, an inflammatory disease, has a proatherogenic lipid profile which is associated to laboratory disease activity.

Genetic association and cellular function of MC1R variant alleles in human pigmentation

We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.

Optimizing Medical Therapy of Acromegaly: Beneficial Effects of Cabergoline in Patients Uncontrolled with Long-Acting Release Octreotide

Background: Previous data indicate a beneficial effect of cabergoline (CAB) association to somatostatin analogs (SA) in acromegalics resistant to SA monotherapy. Objective: To assess the efficacy of CAB association on acromegalics with high IGF-I on stable long-acting release octreotide (OCT-LAR) (30 mg/28 days). Design, Subjects and Methods: 34 patients (17 male, 25-85 years, 33 macroadenomas) were enrolled in this prospective study. OCT-LAR was administered as primary (n = 4) and as secondary (n = 30) treatment: after surgery (n = 16), after surgery + radiotherapy (RT) (n = 11), and after RT only (n = 3). Duration of OCT-LAR therapy prior to CAB was 24 8 12 months. The immunohistochemical features of the tumors disclosed GH/PRL co-secretion in 11/21 patients. 13 patients had high PRL levels prior to CAB. The initial CAB dose was 1.5 mg/week. No IGF-I normalization led to a dose increase to 3.5 mg/week. The OCT-LAR dose was kept stable during treatment. IGF-I, GH and PRL levels were compared before and after CAB association. OCT-LAR was withdrawn in patients who achieved IGF-I normalization, in order to assess the influence of CAB. Results: Comparing OCT-LAR to OCT-LAR/CAB treatment, there was a significant decrease in mean GH, IGF-I, %ULNR- IGF-I and PRL levels. During OCT-LAR/CAB treatment, IGF-I normalized in 19 patients (56%). IGF-I normalization was correlated to lowest IGF-I levels on OCT-LAR monotherapy, but not to baseline PRL levels or GH/PRL co-expression. OCT-LAR withdrawn in all who had achieved IGF-I normalization on combined therapy resulted in IGF-I elevation to abnormal levels in all patients. Gastro intestinal symptoms were reported by 12 patients. Conclusion: OCT-LAR and CAB association has been shown to be an effective alternative therapy for those acromegalics who still have active acromegaly despite monotherapy with SA, mainly for those with lower pretreatment IGF-I concentrations. According to previous studies, the beneficial effects of CAB occur even when pretreatment PRL is normal and/or there is no tumor GH/PRL co-expression. Copyright (C) 2009 S. Karger AG, Basel

Emotions at multiple levels: An integration

Weiss and Isen have provided many supportive comments about the multi-level perspective, but also found limitations. Isen noted the importance of integrating affect, cognition, and motivation. Weiss commented similarly that the model lacked an integrating “thread.” He suggested that, to be truly multilevel, each level should constrain processes at other levels, and also provide guidance for the development of new concepts. Weiss also noted that the focus on biological processes was a strength of the model. I respond by suggesting that these very biological processes may constitute the “missing” thread. To illustrate this, I discuss some of the recent research on emotions in organizational settings, and argue that biology both constrains and guides theory at each level of the model. Based on this proposition, I revisit each of the five levels in the model, to demonstrate how this integration can be accomplished in this fashion. Finally, I address two additional points: aggregation bias, and the possibility of extending the model to include higher levels of industry and region.

Influence of Single-Nucleotide Polymorphisms on C-Reactive Protein Levels in Chronic Kidney Disease Before and After Kidney Transplantation

Introduction. We sought to evaluate 2 sing] e-nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene promoter region for their effects on CRP levels in chronic kidney disease (CKD) patients before and after a successful kidney transplantation. Methods. Fifty CKD patients were evaluated before and at the first and second years after the graft. Two SNPs were studied, a bi-allelic (G -> A) at the -409 and a tri-allelic (C -> T -> A) variation at the -390 position in the CRP gene. Results. All patients presented the -409GG genotype. At the -390 position, the ""A"" allele was not found; there were 15 ""CC"" patients, 11 ""TT"" patients, and 24 ""CT"" patients. CRP levels were different among patients with various genotypes (P < .019). Also the presence of the allele ""T"" was sufficient to determine differences in CRP levels both in pretransplantation (P = .045) and at 1 year posttransplantation (P = .011), but not at the second year (P = .448). Conclusion. SNPs at the -390 position of the CRP gene promoter region influence CRP basal levels in such a way that the ""C"" allele correlated with the lowest and the ""T"" with the highest. We did not observe this influence in our patients at the second year posttransplantation.

Effects of ambient levels of air pollution generated by traffic on birth and placental weights in mice

Objective: To examine whether there is an association between fetal and/or placental weight and exposure to ambient levels of air pollution in mice. Design: Chronic experiments on mice that were exposed to polluted vs. clean air. Setting: Environmental exposure to atmospheric pollution. Animal(S): Female Swiss mice (n = 70) were maintained at different stages of gestation in an exposure chamber located at an intersection with heavy traffic in a major city in Brazil. Control mice were maintained in a similar chamber, located adjacent to the exposure chamber but equipped with filters for particles and reactive gases. Intervention(s): Animals were divided into six groups as follows: no exposure, exposure to a polluted chamber throughout gestation, exposure to a polluted chamber during the 1st week of pregnancy, exposure to a polluted chamber during the 2nd and 3rd weeks, exposure to a polluted chamber during the 1st and 2nd week, and exposure to a polluted chamber during the 3rd week. Main Outcome Measure(S): At the end of the gestational period, the determination of fetal and placental weight was performed after cesarean section. Result(s): Exposure to air pollution during the 1st week of pregnancy promoted a significant reduction in fetal weight. Mice exposed to polluted air, in any phase of gestation, presented with lower placental weight in comparison to mice maintained in clean chambers. Conclusion(s): Exposure to ambient levels of traffic pollution at early phases of gestation is a determinant for decreased final fetal weight. Placental weight is reduced with exposure to air pollution at any phase of gestation. (Fertil Steril (R) 2008;90:1921-4. (C)2008 by American Society for Reproductive Medicine.)

Chronic exposure to ambient levels of urban particles affects mouse lung development

Rationale- Chronic exposure to air pollution has been associated with adverse effects on children`s lung growth. Objectives: We analyzed the effects of chronic exposure to urban levels of particulate matter (PM) on selected phases of mouse lung development. Methods: The exposure occurred in two open-top chambers (filtered and nonfiltered) placed 20 m from a street with heavy traffic in Sao Paulo, 24 hours/day for 8 months. There was a significant reduction of the levels of PM(2.5) inside the filtered chamber (filtered = 2.9 +/- 3.0 mu g/m(3), nonfiltered = 16.8 +/- 8.3 mu g/m(3); P = 0.001). At this exposure site, vehicular sources are the major components of PM(2.5) (PM <= 2.5 mu m). Exposure of the parental generation in the two chambers occurred from the 10th to the 120th days of life. After mating and birth of offspring, a crossover of mothers and pups occurred within the chambers, resulting in four groups of pups: nonexposed, prenatal, postnatal, and pre+postnatal. Offspring were killed at the age of 15 (n = 42) and 90 (n = 35) days; lungs were analyzed by morphometry for surface to volume ratio (as an estimator of alveolization). Pressure-volume curves were performed in the older groups, using a 20-ml plethysmograph. Measurements and Main Results: Mice exposed to PM(2.5) pre+postnatally presented a smaller surface to volume ratio when compared with nonexposed animals (P = 0.036). The pre+postnatal group presented reduced inspiratory and expiratory volumes at higher levels of transpulmonary pressure (P = 0.001). There were no differences among prenatal and postnatal exposure and nonexposed animals. Conclusions: Our data provide anatomical and functional support to the concept that chronic exposure to urban PM affects lung growth.

The role of BPH, lower urinary tract symptoms, and PSA levels on erectile function of Brazilian men who undergo prostate cancer screening

Introduction. Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are common problems in middle-aged and older men. Recently, epidemiologic studies have shown significant associations between severity of LUTS and male sexual dysfunction. Aim. We analyzed the role of prostate enlargement, LUTS, and prostate specific antigen (PSA) levels in the erectile function of Brazilian men who underwent prostate cancer (PCa) screening. Method. We analyzed data from 1,008 consecutive patients enrolled in a PCa screening program. Benign prostatic hyperplasia (BPH) was defined as a prostate weight greater than 30 g as defined by digital rectal examination. For statistical analysis, we used the chi-squared and analysis of variance tests. The odds ratios (OR) for correlation of ED with prostate volume LUTS and PSA were estimated using logistic regression models. Main Outcome Measure. The American Urological Association (AUA) symptom score for LUTS and the International Index of Erectile Function. Results. Mean patient age was 61.2 years (45-87) and median PSA value was 1.9 ng/mL. BPH was identified in 48.5% of patients. Mild, moderate, and severe LUTS were found in 52.3%, 30.9%, and 16.8% of cases, respectively. ED was classified as absent, mild, mild to moderate, moderate, and severe in 18.6%, 23.1%, 18.6%, 15.2%, and 24.5%, respectively. While only 5.4% of the patients with no ED presented severe LUTS, this finding was observed in 27.1% of patients with severe ED (P<0.001). Univariate logistic regression analysis demonstrated that age, prostate volume, AUA symptom score, and PSA levels were significant predictors of ED. However, when controlled for patient age, only LUTS remained as an independent predictor of ED. Conclusions. Controlling for patient age, LUTS are independent risk factors for the development of ED among Brazilian men who undergo PCa screening.