The Regulation of Rasd1 Expression by Glucocorticoids and Prolactin Controls Peripartum Maternal Insulin Secretion

The transition from gestation to lactation is characterized by a robust adaptation of maternal pancreatic beta-cells. Consistent with the loss of beta-cell mass, glucose-induced insulin secretion is down-regulated in the islets of early lactating dams. Extensive experimental evidence has demonstrated that the surge of prolactin is responsible for the morphofunctional remodeling of the maternal endocrine pancreas during pregnancy, but the precise molecular mechanisms by which this phenotype is rapidly reversed after delivery are not completely understood. This study investigated whether glucocorticoid-regulated expression of Rasd1/Dexras, a small inhibitoryGprotein, is involved in this physiological plasticity. Immunofluorescent staining demonstrated that Rasd1 is localized within pancreatic beta-cells. Rasd1 expression in insulin-secreting cells was increased by dexamethasone and decreased by prolactin. In vivo data confirmed that Rasd1 expression is decreased in islets from pregnant rats and increased in islets from lactating mothers. Knockdown of Rasd1 abolished the inhibitory effects of dexamethasone on insulin secretion and the protein kinase A, protein kinase C, and ERK1/2 pathways. Chromatin immunoprecipitation experiments revealed that glucocorticoid receptor (GR) and signal transducer and activator of transcription 5b (STAT5b) cooperatively mediate glucocorticoid-induced Rasd1 expression in islets. Prolactin inhibited the stimulatory effect of GR/STAT5b complex on Rasd1 transcription. Overall, our data indicate that the stimulation of Rasd1 expression by glucocorticoid at the end of pregnancy reverses the increased insulin secretion that occurs during pregnancy. Prolactin negatively regulates this pathway by inhibiting GR/STAT5b transcriptional activity on the Rasd1 gene. (Endocrinology 153: 3668-3678, 2012)

The impact of the CACNA1C risk allele on limbic structures and facial emotions recognition in bipolar disorder subjects and healthy controls

Introduction: Impairments in facial emotion recognition (PER) have been reported in bipolar disorder (BD) during all mood states. FER has been the focus of functional magnetic resonance imaging studies evaluating differential activation of limbic regions. Recently, the alpha 1-C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene has been described as a risk gene for BD and its Met allele found to increase CACNA1C mRNA expression. In healthy controls, the CACNA1C risk (Met) allele has been reported to increase limbic system activation during emotional stimuli and also to impact on cognitive function. The aim of this study was to investigate the impact of CACNA1C genotype on FER scores and limbic system morphology in subjects with BD and healthy controls. Material and methods: Thirty-nine euthymic BD I subjects and 40 healthy controls were submitted to a PER recognition test battery and genotyped for CACNA1C. Subjects were also examined with a 3D 3-Tesla structural imaging protocol. Results: The CACNA1C risk allele for BD was associated to FER impairment in BD, while in controls nothing was observed. The CACNA1C genotype did not impact on amygdala or hippocampus volume neither in BD nor controls. Limitations: Sample size. Conclusion: The present findings suggest that a polymorphism in calcium channels interferes FER phenotype exclusively in BD and doesn't interfere on limbic structures morphology. (C) 2012 Elsevier B.V. All rights reserved.

Optic Disc Margin Anatomy in Patients with Glaucoma and Normal Controls with Spectral Domain Optical Coherence Tomography

Objective: To characterize optic nerve head (ONH) anatomy related to the clinical optic disc margin with spectral domain-optical coherence tomography (SD-OCT). Design: Cross-sectional study. Participants: Patients with open-angle glaucoma with focal, diffuse, and sclerotic optic disc damage, and age-matched normal controls. Methods: High-resolution radial SD-OCT B-scans centered on the ONH were analyzed at each clock hour. For each scan, the border tissue of Elschnig was classified for obliqueness (internally oblique, externally oblique, or nonoblique) and the presence of Bruch's membrane overhanging the border tissue. Optic disc stereophotographs were co-localized to SD-OCT data with customized software. The frequency with which the disc margin identified in stereophotographs coincided with (1) Bruch's membrane opening (BMO), defined as the innermost edge of Bruch's membrane; (2) Bruch's membrane/border tissue, defined as any aspect of either outside BMO or border tissue; or (3) border tissue, defined as any aspect of border tissue alone, in the B-scans was computed at each clock hour. Main Outcome Measures: The SD-OCT structures coinciding with the disc margin in stereophotographs. Results: There were 30 patients (10 with each type of disc damage) and 10 controls, with a median (range) age of 68.1 (42-86) years and 63.5 (42-77) years, respectively. Although 28 patients (93%) had 2 or more border tissue configurations, the most predominant one was internally oblique, primarily superiorly and nasally, frequently with Bruch's membrane overhang. Externally oblique border tissue was less frequent, observed mostly inferiorly and temporally. In controls, there was predominantly internally oblique configuration around the disc. Although the configurations were not statistically different between patients and controls, they were among the 3 glaucoma groups. At most locations, the SD-OCT structure most frequently identified as the disc margin was some aspect of Bruch's membrane and border tissue external to BMO. Bruch's membrane overhang was regionally present in the majority of patients with glaucoma and controls; however, in most cases it was not visible as the disc margin. Conclusions: The clinically perceived disc margin is most likely not the innermost edge of Bruch's membrane detected by SD-OCT. These findings have important implications for the automated detection of the disc margin and estimates of the neuroretinal rim. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;119:738-747 (C) 2012 by the American Academy of Ophthalmology.

Comparison of the Neutrophil Proteome in Trauma Patients and Normal Controls

Background: Neutrophils have an impressive array of microbicidal weapons, and in the presence of a pathogen, progress from a quiescent state in the bloodstream to a completely activated state. Failure to regulate this activation, for example, when the blood is flooded with cytokines after severe trauma, causes inappropriate neutrophil activation that paradoxically, is associated with tissue and organ damage. Acidic proteomic maps of quiescent human neutrophils were analyzed and compared to those of activated neutrophils from severe trauma patients. The analysis revealed 114 spots whose measured volumes differed between activated and quiescent neutrophils, with 27 upregulated and 87 downregulated in trauma conditions. Among the identified proteins, grancalcin, S100-A9 and CACNB2 reinforce observed correlations between motility and ion flux, ANXA3, SNAP, FGD1 and Zfyve19 are involved in vesicular transport and exocytosis, and GSTP1, HSPA1 HSPA1L, MAOB, UCH-L5, and PPA1 presented evidence that activated neutrophils may have diminished protection against oxidative damage and are prone to apoptosis. These are discussed, along with proteins involved in cytoskeleton reorganization, reactive oxygen species production, and ion flux. Proteins such as Zfyve19, MAOB and albumin-like protein were described for the first time in the neutrophil. In this work we achieved the identification of several proteins potentially involved in inflammatory signaling after trauma, as well as proteins described for the first time in neutrophils.

Contrast Sensitivity Mediated by Inferred Magno- and Parvocellular Pathways in Type 2 Diabetics with and without Nonproliferative Retinopathy

PURPOSE. To evaluate achromatic contrast sensitivity (CS) with magnocellular-(M) and parvocellular-(P) probing stimuli in type 2 diabetics, with (DR) or without (NDR) nonproliferative retinopathy. METHODS. Inferred M-and P-dominated responses were assessed with a modified version of the steady-/pulsed-pedestal paradigm (SP/PP) applied in 26 NDR (11 male; mean age, 55 +/- 9 years; disease duration, 5 +/- 4 years); 19 DR (6 male; mean age, 58 +/- 7 years; disease duration = 9 +/- 6 years); and 18 controls (CTRL; 12 male; mean age, 55 +/- 10 years). Thresholds were measured with pedestals at 7, 12, and 19 cd/m(2), and increment durations of 17 and 133 ms. The thresholds from the two stimulus durations were used to estimate critical durations (Tc) for each data set. RESULTS. Both DR and NDR patients had significant reduction in CS in both SP and PP paradigms in relation to CTRL (Kruskal-Wallis, P < 0.01). Patients` critical duration estimates for either paradigm were not significantly different from CTRL. CONCLUSIONS. The significant reduction of CS in both paradigms is consistent with losses of CS in both M and P pathways. The CS losses were not accompanied by losses in temporal processing speed in either diabetic group. Significant CS loss in the group without retinopathy reinforces the notion that neural changes associated with the cellular and functional visual loss may play an important role in the etiology of diabetic visual impairment. In addition, the results show that the SP/PP paradigm provides an additional tool for detection and characterization of the early functional damage due to diabetes. (Invest Ophthalmol Vis Sci. 2011; 52:1151-1155) DOI:10.1167/iovs.09-3705

Public Speaking in Social Phobia: A Pilot Study of Self-Ratings and Observers' Ratings of Social Skills

Objectives: The aim of this pilot study was to investigate whether patients with social anxiety disorder (SAD) differ from controls in the quality of skill-related behaviors displayed during a speech and in overall behavioral adequacy as perceived by observers and by the patients themselves. Design: A total of 18 SAD patients and 18 controls were screened by a diagnostic interview and took part in a 3-minute speech of their own choosing. For each videotaped speech, observers rated the adequacy of the skill-related behaviors and overall performance adequacy. After the experiment, participants were asked to rate their own overall performance adequacy. Results: The results showed that SAD patients exhibited significantly worse voice intonation and fluency of the speech, however no differences were found in global self-ratings. Moreover, the performance evaluations of the SAD group were consistent with the observers, while the controls evaluated their performance lower than the observers. Conclusions: The results are inconsistent with the cognitive model, because patients with SAD did not underestimate their performance. Compared with spontaneous interactions, the clear rules established for such social situations as speeches may result in less cognitive distortion for SAD patients. (C) 2012 Wiley Periodicals, Inc. J. Clin. Psychol. 68:397-402, 2012.

Immune receptors and adhesion molecules in human pulmonary leptospirosis

Pulmonary involvement in leptospirosis has been increasingly reported in the last 20 years, being related to the severity and mortality of the disease. The pathogenesis of pulmonary hemorrhage in leptospirosis is not understood. Lung endothelial cells have been proposed as targets in the pathogenesis of lung involvement in leptospirosis through the activation of Toll-like receptor 2 or the complement system, which stimulates the release of cytokines that lead to the activation of adhesion molecules. The aim of this study was to investigate the involvement of immune pathways and of the intercellular and vascular cell adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule, respectively) in the lungs of patients with pulmonary involvement of leptospirosis. We studied the lungs of 18 patients who died of leptospirosis and compared them with 2 groups of controls: normal and noninfectious hemorrhagic lungs. Using immunohistochemistry and image analysis, we quantified the expression of the C3a anaphylatoxin receptor, intercellular adhesion molecule, vascular cell adhesion molecule, and Toll-like receptor 2 in small pulmonary vessels and in the alveolar septa. There was an increased expression of intercellular adhesion molecule (P <.03) and C3a anaphylatoxin receptor (P <.008) in alveolar septa in the leptospirosis group compared with the normal and hemorrhagic controls. In the vessels of the leptospirosis group, there was an increased expression of intercellular adhesion molecule (P=.004), vascular cell adhesion molecule (P=.030), and Toll-like receptor 2 (P=.042) compared with the normal group. Vascular cell adhesion molecule expression in vessels was higher in the leptospirosis group compared with the hemorrhagic group (P=.015). Our results indicate that immune receptors and adhesion molecules participate in the phenomena leading to pulmonary hemorrhage in leptospirosis. (C) 2012 Elsevier Inc. All rights reserved.

MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression

Aim Matrix metalloproteinases (MMPs) play a key role in the tissue destruction characteristic of chronic periodontitis. The purpose of this study was to investigate the association of MMP and TIMP polymorphisms with chronic periodontitis in two populations. Material and Methods A total of 34 polymorphisms spanning 12 MMP and 2 TIMP genes were genotyped in 401 individuals from Brazil (99 cases with chronic periodontitis and 302 controls), and 274 individuals from the US (70 cases and 204 controls). Individuals were considered cases if presenting at least three teeth exhibiting sites of clinical attachment loss =5 mm in two different quadrants. Controls were characterized by absence of clinical attachment loss and no sites with probing depth >3 mm. MMP3 and TIMP1 mRNA expression was evaluated in healthy and diseased periodontal tissues. Results TIMP1 showed association with chronic periodontitis in the Brazilian population (for rs5906435, p = 0.0004), whereas MMP3 showed association in the US population (for rs679620, p = 0.0003; and rs650108, p = 0.002) and in the Brazilian population (for rs639752, p = 0.005). MMP3 and TIMP1 mRNA expression was significantly higher in diseased tissues when compared to control tissues. Conclusions Our results further support a role for variations in MMP3 in chronic periodontitis and report a novel association with TIMP1. These genes may be considered additional candidate genes for chronic periodontitis.

Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample

Schizophrenia is a severe psychiatric disorder with frequent recurrent psychotic relapses and progressive functional impairment. It results from a poorly understood gene-environment interaction. The gene encoding catechol-O-methyltransferase (COMT) is a likely candidate for schizophrenia. Its rs165599 (A/G) polymorphism has been shown to be associated with alteration of COMT gene expression. Therefore, the present study aimed to investigate a possible association between schizophrenia and this polymorphism. The distribution of the alleles and genotypes of this polymorphism was investigated in a Brazilian sample of 245 patients and 834 controls. The genotypic frequencies were in Hardy-Weinberg equilibrium and no statistically significant differences were found between cases and controls when analyzed according to gender or schizophrenia subtypes. There was also no difference in homozygosis between cases and controls. Thus, in the sample studied, there was no evidence of any association between schizophrenia and rs165599 (A/G) polymorphism in the non-coding region 3' of the COMT gene.

Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study

Background. Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). Method. FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. Results. We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis x time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis x time interaction. Conclusions. Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis.

Long-Term Occupational Exposure to Organic Solvents Affects Color Vision, Contrast Sensitivity and Visual Fields

The purpose of this study was to evaluate the visual outcome of chronic occupational exposure to a mixture of organic solvents by measuring color discrimination, achromatic contrast sensitivity and visual fields in a group of gas station workers. We tested 25 workers (20 males) and 25 controls with no history of chronic exposure to solvents (10 males). All participants had normal ophthalmologic exams. Subjects had worked in gas stations on an average of 9.6 +/- 6.2 years. Color vision was evaluated with the Lanthony D15d and Cambridge Colour Test (CCT). Visual field assessment consisted of white-on-white 24-2 automatic perimetry (Humphrey II-750i). Contrast sensitivity was measured for sinusoidal gratings of 0.2, 0.5, 1.0, 2.0, 5.0, 10.0 and 20.0 cycles per degree (cpd). Results from both groups were compared using the Mann-Whitney U test. The number of errors in the D15d was higher for workers relative to controls (p<0.01). Their CCT color discrimination thresholds were elevated compared to the control group along the protan, deutan and tritan confusion axes (p<0.01), and their ellipse area and ellipticity were higher (p<0.01). Genetic analysis of subjects with very elevated color discrimination thresholds excluded congenital causes for the visual losses. Automated perimetry thresholds showed elevation in the 9 degrees, 15 degrees and 21 degrees of eccentricity (p<0.01) and in MD and PSD indexes (p<0.01). Contrast sensitivity losses were found for all spatial frequencies measured (p<0.01) except for 0.5 cpd. Significant correlation was found between previous working years and deutan axis thresholds (rho = 0.59; p<0.05), indexes of the Lanthony D15d (rho = 0.52; p<0.05), perimetry results in the fovea (rho = -0.51; p<0.05) and at 3, 9 and 15 degrees of eccentricity (rho = -0.46; p<0.05). Extensive and diffuse visual changes were found, suggesting that specific occupational limits should be created.

Quality of sleep and quality of life in adolescents infected with human immunodeficiency virus

Objectives: To assess sleep characteristics of adolescents infected by HIV, and to ascertain whether psychosocial aspects are associated to the quality of sleep. Methods: A cross-sectional study assessing 102 HIV-infected adolescents of both genders, aged between 10 and 20 years-old and 120 Controls. Data collection was performed by applying the Sleep Disturbance Scale for Children, the Epworth Sleepiness Scale, and the Pediatric Quality of Life Inventory. Results: A sleep disturbance prevalence of 77.4% was found in patients, and a 75% prevalence in controls, and there was correlation between quality of sleep and of life. HIV-infected adolescents scored higher for sleep breathing disorders and had higher prevalence of excessive daytime sleepiness. Conclusions: HIV-infected adolescents had similar quality of sleep compared to healthy adolescents. This may be explained by the steady improvements in daily living as a result of successful anti-retroviral therapy, and by the vulnerability that affects Brazilian adolescents living in major urban centers.

Frontal Plane Biomechanics in Males and Females with and without Patellofemoral Pain

NAKAGAWA, T. H., E. T. U. MORIYA, C. D. MACIEL, and F. V. SERRAO. Frontal Plane Biomechanics in Males and Females with and without Patellofemoral Pain. Med. Sci. Sports &ere., Vol. 44, No. 9, pp. 1747-1755, 2012. Purpose: The study's purpose was to compare trunk, pelvis, hip, and knee frontal plane biomechanics in males and females with and without patellofemoral pain syndrome (PFPS) during stepping. Methods: Eighty recreational athletes were equally divided into four groups: female PFPS, female controls, male PFPS, and male controls. Trunk, pelvis, hip, and knee frontal plane kinematics and activation of the gluteus medius were evaluated at 15 degrees, 30 degrees, 45 degrees, and 60 degrees of knee flexion during the downward and upward phases of the stepping task. Isometric hip abductor torque was also evaluated. Results: Females showed increased hip adduction and knee abduction at all knee flexion angles, greater ipsilateral trunk lean and contralateral pelvic drop from 60 degrees of knee flexion till the end of the stepping task (P = 0.027-0.001), diminished hip abductor torque (P < 0.001), and increased gluteus medius activation than males (P = 0.008-0.001). PFPS subjects presented increased knee abduction at all the angles evaluated; greater trunk, pelvis, and hip motion from 45 of knee flexion of the downward phase till the end of the maneuver; and diminished gluteus medius activation at 60 degrees of knee flexion, compared with controls (P = 0.034-0.001). Females with PFPS showed lower hip abductor torque compared with the other groups. Conclusions: Females presented with altered frontal plane biomechanics that may predispose them to knee injury. PFPS subjects showed frontal plane biomechanics that could increase the lateral patellofemoral joint stress at all the angles evaluated and could increase even more from 45 degrees of knee flexion in the downward phase untill the end of the maneuver. Hip abductor strengthening and motor control training should be considered when treating females with PFPS.

Burden of maternal bipolar disorder on at-risk offspring: A controlled study on family planning and maternal care

Introduction: Bipolar disorder (BD) is a highly incapacitating disease typically associated with high rates of familial dysfunction. Despite recent literature suggesting that maternal care is an important environmental factor in the development of behavioral disorders, it is unclear how much maternal care is dysfunctional in BD subjects. Objective: The objective of this study was to characterize maternal care in DSM-IV/SCID diagnosed BD type I subjects compared to healthy controls with (PD) and without (NPD) other psychiatric diagnoses. Materials and methods: Thirty-four BD mothers and 106 controls underwent an interview about family planning and maternal care, obstetrical complications, and mother-child interactions. K-SADS-PL questions about violence exposure were used to ascertain domestic violence and physical/sexual abuse. Results: BD mothers were less likely to have stable unions (45.5%; p < 0.01) or to live with the biological father of their children (33.3%; p < 0.01), but had higher educational level and higher rates of social security use/retirement. They also had fewer children and used less contraceptive methods than controls. Children of BD women had higher rates of neonatal anoxia, and reported more physical abuse (16.1%; p = 0.02) than offspring of NPD mothers. Due to BD mothers' symptoms, 33.3% of offspring suffered physical and/or psychological abuse. Limitations: Post hoc analysis, and the use of questions as a surrogate of symptoms as opposed to validated instruments. Conclusion: This is one of few reports confirming that maternal care given by BD women is dysfunctional. BD psychopathology can lead to poor maternal care and both should be considered important environmental risk factors in BD, suggesting that BD psychoeducation should include maternal care orientation. (C) 2012 Elsevier B.V. All rights reserved.

Trunk, Pelvis, Hip, and Knee Kinematics, Hip Strength, and Gluteal Muscle Activation During a Single-Leg Squat in Males and Females With and Without Patellofemoral Pain Syndrome

STUDY DESIGN: Controlled laboratory study using a cross-sectional design. OBJECTIVES: To determine whether there are any differences between the sexes in trunk, pelvis, hip, and knee kinematics, hip strength, and gluteal muscle activation during the performance of a single-leg squat in individuals with patellofemoral pain syndrome (PFPS) and control participants. BACKGROUND: Though there is a greater incidence of PFPS in females, PFPS is also quite common in males. Trunk kinematics may affect hip and knee function; however, there is a lack of studies of the influence of the trunk in individuals with PFPS. METHODS: Eighty subjects were distributed into 4 groups: females with PFPS, female controls, males with PFPS, and male controls. Trunk, pelvis, hip, and knee kinematics and gluteal muscle activation were evaluated during a single-leg squat. Hip abduction and external rotation eccentric strength was measured on an isokinetic dynamometer. Group differences were assessed using a 2-way multivariate analysis of variance (sex by PFPS status). RESULTS: Compared to controls, subjects with PFPS had greater ipsilateral trunk lean (mean +/- SD, 9.3 degrees +/- 5.30 degrees versus 6.7 degrees +/- 3.0 degrees; P = .012), contralateral pelvic drop (10.3 degrees +/- 4.7 degrees versus 7.4 degrees 3.8 degrees; P = .003), hip adduction (14.8 degrees +/- 7.8 degrees versus 10.8 degrees +/- 5.6 degrees; P<.0001), and knee abduction (9.2 degrees +/- 5.0 degrees versus 5.8 degrees +/- 3.4 degrees; P<.0001) when performing a single-leg squat. Subjects with PFPS also had 18% less hip abduction and 17% less hip external rotation strength. Compared to female controls, females with PFPS had more hip internal rotation (P<.05) and less muscle activation of the gluteus medius (P = .017) during the single-leg squat. CONCLUSION: Despite many similarities in findings for males and females with PFPS, there may be specific sex differences that warrant consideration in future studies and when clinically evaluating and treating females with PFPS. J Orthop Sports Phys Ther 2012;42(6):491-501, Epub 8 March 2012. doi:10.2519/jospt.2012.3987