Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA-G (103.7 copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis

Rationale Sepsis is defined as a systemic inflammatory response to infection, which in its severe form is associated with multiple organ dysfunction syndrome (MODS). The precise mechanisms by Which MODS develops remain unclear. Neutrophils have a pivotal role in the defense against infections; however, overwhelming activation of neutrophils is known to elicit tissue damage. Objectives: We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis. Methods: Sepsis was induced in wild-type mice treated with CCR2 antagonist (RS504393) or CCR2(-/-) mice by cecal ligation and puncture (CLP) model. Neutrophil infiltration into the organs was measured by myeloperoxidase activity and fluorescence-activated cell sorter. CCR2 expression and chemotaxis were determined in neutrophils stimulated with Toll-like receptor agonists or isolated from septic mice and patients. Measurements and Main Results: CCR2 expression and responsiveness to its ligands was induced in circulating neutrophils during CLP-induced sepsis by a mechanism dependent on Toll-like receptor/nuclear factor-kappa B pathway. Genetic or pharmacologic inhibition of CCR2 protected mice from CLP-induced mortality. This protection was associated with lower infiltration of neutrophils into the lungs, heart, and kidneys and reduced serum biochemical indicators of organ injury and dysfunction. Importantly, neutrophils from septic patients express high levels of CCR2, and the severity of patient illness correlated positively with increasing neutrophil chemotaxis to CCR2 ligands. Conclusions: Collectively, these data identify CCR2 as a key receptor that drives the inappropriate infiltration of neutrophils into remote organs during sepsis. Therefore, CCR2 blockade is a novel potential therapeutic target for treatment of sepsis-induced MODS.

Identification of genetic alterations by multiple ligation-dependent probe amplification (MLPA) analysis in oligodendrogliomas

Concurrent deletion at 1p/19q is a common signature of oligodendrogliomas, and it may, be identified in low-grade tumours (grade II) suggesting it represents an early event in the development of these brain neoplasms. Additional non-random changes primarily involve CDKN2A, PTEN and EGFR. Identification of all of these genetic changes has become an additional parameter in the evaluation of the clinical patients` prognosis, including good response to conventional chemotherapy. Multiple ligation-dependent probe amplification (MLPA) analysis is a new methodology that allows an easy identification of the oligodendrogliomas` abnormalities in a single step. No need of the respective constitutional DNA from each patient is another advantage of this method. We used MLPA kits P088 and P105 to determine the molecular characteristics of a series of 40 oligodendrogliomas. Deletions at I p and 19q were identified in 45% and 65% of cases, respectively. Alterations of EGFR, CDKN2A, ERBB2, PTEN and TP53 were also identified in variable frequencies among 7% to 35% of tumours. These findings demonstrate that MLPA is a reliable technique to the detection of molecular genetic changes in oligodendrogliomas.

Further psychometric study of the Beck Anxiety Inventory including factorial analysis and social anxiety disorder screening

Objective. To analyze the psychometric properties of the Brazilian Portuguese version of the Beck Anxiety Inventory (BAI) in terms of its internal consistency, scores distribution, concurrent and discriminant validity, and factorial analysis in a sample of university students and social anxiety disorder (SAD) cases and non-cases. Methods. A sample of Brazilian university students from the general population (N = 2314) and a sample of university students identified as cases (N = 88) and non-cases (N = 90) of SAD were assessed, using as a parameter the Structured Clinical Interview for the DSM-IV. The different instruments were completed individually in the presence of an experienced rater. Results. The BAI showed adequate internal consistency (0.88-0.92) and discriminant validity, with 0.74 sensitivity and 0.71 specificity for a cut-off score of 10. The factorial analysis suggested a three-factor solution to be the most adequate. Conclusions. The version of the BAI studied is quite adequate to be used in the context of Brazilian university students, identifying the presence of anxiety indicators. However, its usefulness to screen for SAD seems limited.

Altered gray matter morphometry and resting-state functional and structural connectivity in social anxiety disorder

In social anxiety disorder (SAD), impairments in limbic/paralimbic structures are associated with emotional dysregulation and inhibition of the medial prefrontal cortex (MPFq. Little is known, however, about alterations in limbic and frontal regions associated with the integrated morphometric, functional, and structural architecture of SAD. Whether altered gray matter volume is associated with altered functional and structural connectivity in SAD. Three techniques were used with 18 SAD patients and 18 healthy controls: voxel-based morphometry; resting-state functional connectivity analysis; and diffusion tensor imaging tractography. SAD patients exhibited significantly decreased gray matter volumes in the right posterior inferior temporal gyrus (ITG) and right parahippocampal/hippocampal gyrus (PHG/HIP). Gray matter volumes in these two regions negatively correlated with the fear factor of the Liebowitz Social Anxiety Scale. In addition, we found increased functional connectivity in SAD patients between the right posterior ITG and the left inferior occipital gyrus, and between the right PHF/HIP and left middle temporal gyms. SAD patients had increased right MPFC volume, along with enhanced structural connectivity in the genu of the corpus callosum. Reduced limbic/paralimbic volume, together with increased resting-state functional connectivity, suggests the existence of a compensatory mechanism in SAD. Increased MPFC volume, consonant with enhanced structural connectivity, suggests a long-time overgeneralization of structural connectivity and a role of this area in the mediation of clinical severity. Overall, our results may provide a valuable basis for future studies combining morphometric, functional and anatomical data in the search for a comprehensive understanding of the neural circuitry underlying SAD. (C) 2011 Elsevier B.V. All rights reserved.

Social anxiety disorder: studies of instrument validation for the Brazilian context

Social anxiety disorder (SAD) is a highly prevalent condition even though its recognition and diagnosis are underestimated by both patients and clinicians. In view of the importance of assessment scales for systematic diagnosis in psychiatry, the objective of this investigation was to present studies of validation for the Brazilian population of three instruments for the assessment of different aspects of SAD. The following psychometric studies were carried out: a) discriminative validity of the Mini Social Phobia Inventory (Mini-SPIN-MS), a reduced instrument for the screening of SAD; b) reliability and discriminative validity of the Brief Social Phobia Scale (BSPS), a hetero-applied instrument for the assessment of different aspects of SAD, and c) discriminative validity of the items and subscales of the Self-Statements during Public Speaking Scale (SSPS), an instrument for the assessment of cognitive aspects related to public speaking. All instruments showed excellent psychometric qualities, especially indicators of discrimination between persons with and without SAD, with diagnostic confirmation by the Structured Clinical Interview for DSM-IV (SCID-IV). It was concluded that this set of instruments, with specificity regarding their objectives, could be of great clinical usefulness, especially for the Brazilian population that, until recently, had no such resources for the measurement and assessment of the different aspects of SAD. New multicenter and intercultural studies may provide further information about cultural influences on SAD.

Social anxiety disorder women easily recognize fearfull, sad and happy faces: The influence of gender

Background: It has been suggested that individuals with social anxiety disorder (SAD) are exaggeratedly concerned about approval and disapproval by others. Therefore, we assessed the recognition of facial expressions by individuals with SAD, in an attempt to overcome the limitations of previous studies. Methods: The sample was formed by 231 individuals (78 SAD patients and 153 healthy controls). All individuals were treatment naive, aged 18-30 years and with similar socioeconomic level. Participants judged which emotion (happiness, sadness, disgust, anger, fear, and surprise) was presented in the facial expression of stimuli displayed on a computer screen. The stimuli were manipulated in order to depict different emotional intensities, with the initial image being a neutral face (0%) and, as the individual moved on across images, the expressions increased their emotional intensity until reaching the total emotion (100%). The time, accuracy, and intensity necessary to perform judgments were evaluated. Results: The groups did not show statistically significant differences in respect to the number of correct judgments or to the time necessary to respond. However, women with SAD required less emotional intensity to recognize faces displaying fear (p = 0.002), sadness (p = 0.033) and happiness (p = 0.002), with no significant differences for the other emotions or men with SAD. Conclusions: The findings suggest that women with SAD are hypersensitive to threat-related and approval-related social cues. Future studies investigating the neural basis of the impaired processing of facial emotion in SAD using functional neuroimaging would be desirable and opportune. (C) 2009 Elsevier Ltd. All rights reserved.

Headache and Symptoms of Temporomandibular Disorder: An Epidemiological Study

Objectives.-A population-based cross-sectional study was conducted to estimate the prevalence of migraine, episodic tension-type headaches (ETTH), and chronic daily headaches (CDH), as well as the presence of symptoms of temporomandibular disorders (TMD) in the adult population. Background.-The potential comorbidity of headache syndromes and TMD has been established mostly based on clinic-based studies. Methods.-A representative sample of 1230 inhabitants (51.5% women) was interviewed by a validated phone survey. TMD symptoms were assessed through 5 questions, as recommended by the American Academy of Orofacial Pain, in an attempt to classify possible TMD. Primary headaches were diagnosed based on the International Classification of Headache Disorders. Results.-When at least 1 TMD symptom was reported, any headache happened in 56.5% vs 31.9% (P < .0001) in those with no symptoms. For 2 symptoms, figures were 65.1% vs 36.3% (P < .0001); for 3 or more symptoms, the difference was even more pronounced: 72.8% vs 37.9%. (P < .0001). Taking individuals without headache as the reference, the prevalence of at least 1 TMD symptom was increased in ETTH (prevalence ratio = 1.48, 95% confidence interval = 1.20-1.79), migraine (2.10, 1.80-2.47) and CDH (2.41, 1.84-3.17). At least 2 TMD symptoms also happened more frequently in migraine (4.4, 3.0-6.3), CDH (3.4; 1.5-7.6), and ETTH (2.1; 1.3-3.2), relative to individuals with no headaches. Finally, 3 or more TMD symptoms were also more common in migraine (6.2; 3.8-10.2) than in no headaches. Differences were significant for ETTH (2.7 1.5-4.8), and were numerically but not significant for CDH (2.3; 0.66-8.04). Conclusions.-Temporomandibular disorder symptoms are more common in migraine, ETTH, and CDH relative to individuals without headache. Magnitude of association is higher for migraine. Future studies should clarify the nature of the relationship.

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG

Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P = 0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for a ll patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P = 0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens. Bone Marrow Transplantation (2010) 45, 239-248; doi:10.1038/bmt.2009.127; published online 6 July 2009

Cannabidiol was ineffective for manic episode of bipolar affective disorder

The pharmacological profile of cannabidiol (CBD) has several characteristics in common with drugs known to benefit bipolar affective disorder (BAD), leading to the hypothesis that CBD may have therapeutic properties in BAD. Therefore, the aim of the present report was to directly investigate for the first time the efficacy and safety of CBD in two patients with BAD. Both patients met DSM IV criteria for bipolar I disorder experiencing a manic episode without comorbid conditions. This was an inpatient study, and the efficacy, tolerability and side effects were assessed. Both patients received placebo for the initial 5 days and CBD from the 6th to 30th day (initial oral dose of 600 mg reaching 1200 mg/day). From the 6th to the 20th day, the first patient (a 34-year-old woman) received adjunctive olanzapine (oral dose of 10-15 mg). On day 31, CBD treatment was discontinued and replaced by placebo for 5 days. The first patient showed symptoms improvement while on olanzapine plus CBD, but showed no additional improvement during CBD monotherapy. The second patient (a 36-year-old woman) had no symptoms improvement with any dose of CBD during the trial. Both patients tolerated CBD very well and no side-effects were reported. These preliminary data suggest that CBD may not be effective for the manic episode of BAD.

HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis

Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95% CI: 1.07-9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95% CI: 3.51-71.85; p<0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.

Matrix metalloproteinase-9 genotypes and haplotypes are associated with multiple sclerosis and with the degree of disability of the disease

Multiple sclerosis (MS) is an autoimmune disease causing severe neurological disability. This study was carried out in order to determine whether the MMP-9 C(-1562)T and (CA)(13-25) polymorphisms are associated with MS. A total of 165 patients (92 whites/73 mulattos) and 191 controls (96 whites/95 mulattos) were enrolled in the study. While no difference in C(-1562)T polymorphism was observed between MS and healthy subjects, (CA)(n) genotypes and alleles were associated with MS. Moreover, the haplotypes are not associated with MS but seem to be relevant to the clinical status of MS. Thus the (CA)(n) polymorphism may contribute to MS susceptibility, but C(-1562)T and (CA)(n) haplotypes may modulate disease severity. (c) 2009 Elsevier B.V. All rights reserved.

Comparability between telephone and face-to-face Structured Clinical Interview for DSM-IV in assessing social anxiety disorder

PURPOSE. This article evaluates the comparability of the telephone and in-person Structured Clinical Interview for DSM-IV (SCID) interviews in assessing patients with social anxiety disorder (SAD) as an independent anxiety diagnosis. DESIGN AND METHODS. One hundred subjects were randomly selected and interviewed with the SCID, once by telephone and once in person (1-3 months later). FINDINGS. The prevalence of SAD assessed with the telephone interviews was 56%, whereas the in-person prevalence was 52%, with no statistically significant difference. The test-retest kappa for the 200 interviews was .84, indication of excellent agreement. PRACTICE IMPLICATIONS. These findings, along with the existing evidence of their validity, should encourage the use of SCID by telephone for SAD diagnostic interviews.