Immunohistochemical Expression of HLA-DR in the Conjunctiva of Patients Under Topical Prostaglandin Analogs Treatment

Purpose: Subclinical inflammation may be observed in patients, using topical antiglaucomatous drugs. The objective,e of this study was to investigate inflammation in conjunctiva of glaucoma patients using prostaglandin analogs, by the detection of a immunogenetic marker (HLA-DR) and compare the effect of 3 different drugs: latanoprost, bimatoprost, and travoprost in the induction of this inflammation. Subjects and Methods: Thirty-three patients with primary open-angle glaucoma were evaluated without and with prostaglandin analogs topical therapy. Imprints of conjunctival cells were obtained, fixed on glass slides. and Prepared for immunohistochemical analysis. Results: Before the use of prostaglandin analogs, 4 of the 33 patients evaluated presented expression (of HLA-DR in the conjunctiva (mild). After 1 month oil prostaglandin analog treatment, all but 1 patient presented HLA-DR staining. HLA-DR expression of these 32 patients was scored as mild (19 patients), medium (11 patients), or intense (2 patients). The differences were statistically significant both when the presence and the increased expression of HLA-DR were considered (P<0.001). When the 3 different groups were analyzed (latanoprost, bimatoprost, and travoprost) no statistically significant difference was round (P 0.27). Conclusions: The use of prostaglandin analogs eye drops provokes, a reaction, observed by HLA-DR subclinical inflammatory expression, even after a short period of treatment, independently of the class of the prostaglandin analogs used.

Association of Interferon-gamma gene polymorphism (+874 T/A) with systemic sclerosis

Aperfeicoamento de Pessoal de Nivel Superior (CAPES)

Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians

Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the 0 allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations. (C) 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

The effects of systemic stress on orthodontic tooth movement

Objectives: To determine if systemic stress affects the biological reactions occurring during orthodontic tooth movement. Methods: Four groups of male 10 week-old Wistar rats were used. Group A animals (N=10) were restrained for one hour per day for 40 days; Group B animals (N=10) were restrained for one hour per day for three days; Group C (N=10) and Group D (N=8) animals were unrestrained. The upper left first molars in the rats in Groups A (long-term stress), B (short-term stress) and C (control) were moved mesially during the last 14 days of the experiment. The animals in Group D (N=8) were used for body weight and hormonal dosage comparisons only. They were not subjected to any stress and did not have appliances fitted. All animals were killed at 18 weeks of age and blood collected for measurement of plasma corticosterone. Tooth movement was measured with an electronic caliper. The right and left hemi-maxillae of five rats from each group were removed and the number of tartrate-resistant acid phosphatase (TRAP) positive cells, defined as osteoclasts, adjacent to the mesial roots of the upper first molars counted. The contralateral side in each animal served as the control (split-mouth design). Results: Corticosterone levels were significantly higher in the stressed groups (Groups A and B) than in the control group (Group C). Tooth movement was significantly greater in Group A (long-term stress) compared with Group B (short-term stress) and Group C (control), which did not differ from each other. There were significantly more osteoclasts in the long-term stress group than in the short-term stress and control groups. Conclusion: Persistent systemic stress increases bone resorption during orthodontic tooth movement. Systemic stress may affect the rate of tooth movement during orthodontic treatment.

Effects of acute magnesium loading on pulmonary function of stable COPD patients

Background: Magnesium (Mg) use has the potential to promote bronchodilatation and to improve lung function in obstructive diseases. IV administration of Mg during exacerbations of chronic obstructive pulmonary disease (COPD) has led to improved peak flow. This study aimed to investigate the effects of acute IV Mg loading on respiratory parameters of stable COPD patients. Material/Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-two male COPD patients (64 +/- 6 years old, FEV1: 49 +/- 20%) received an IV infusion of 2 g of magnesium sulfate or placebo on two distinct occasions. Spirometry and mouth maximal respiratory pressures were obtained before and 45 minutes after the infusions. Results: Mg use led to significant changes in functional respiratory capacity (-0.48 1,95% CI: -0.96, -0.01), inspiratory capacity (0.21 1,95% CI: 0.04, 0.37). The treatment was also associated with a marginally significant decrease in residual volume (-0.47 1,95% CI: -0.96, 0.02, p=0.06). Conclusions: Acute IV Mg loading in stable COPD patients was associated with a reduction in lung hyperinflation and improvement of respiratory muscle strength. The clinical potential for chronic magnesium supplementation in COPD deserves further investigation.

Inflammatory and functional effects of increasing asthma treatment with formoterol or double dose budesonide

Adding a long-acting beta(2)-agonist to inhaled corticosteroids (ICS) for asthma treatment is better than increasing ICS dose in improving clinical status, although there is no consensus about the impact of this regimen on inflammation. In this double-blind, randomized, parallel group study, asthmatics with moderate to severe disease used budesonide (400 mcg/day) for 5 weeks (run-in period); then they were randomized to use budesonide (800 mcg/day - BUD group) or budesonide plus formoterol (400 mcg and 24 mcg/day, respectively - FORMO group) for 9 weeks (treatment period). Home PEF measurements, symptom daily reporting, spirometry, sputum induction (for differential cell counts and sputum cell cultures), and hypertonic saline bronchial challenge test were performed before and after treatments. TNF-alpha, IL-4 and eotaxin-2 levels in the sputum and cell culture supernatants were determined. Morning and night PEF values increased in the FORMO group during the treatment period (p < 0.01), from 435 +/- 162 to 489 +/- 169 and 428 +/- 160 to 496 +/- 173 L/min, respectively. The rate of exacerbations in the FORMO group was lower than in the BUD group (p < 0.05). Neutrophil counts in sputum increased in both groups (p < 0.05) and leukocyte viability after 48 h-culture increased in the FORMO group (p < 0.05). No other parameter changed significantly in either group. This study showed that adding formoterol to budesonide improved home PEF and provided protection from exacerbations, although increase of leukocyte viability in cell culture may be a matter of concern and needs further investigation. (C) 2008 Elsevier Ltd. All rights reserved.

Leprosy-specific oral lesions: A report of three cases

Leprosy is a chronic infection caused by Mycobacterium leprae, a bacillus that presents a peculiar tropism for the skin and peripheral nerves. The clinical spectrum of leprosy ranges from the tuberculoid form (TT) to the disseminative and progressive lepromatous form (LL). Oral lesions are rare but, when present, occur in the lepromatous form. This article describes the clinical and microscopic findings of three cases of LL with oral manifestations. All patients had the lepromatous form and their leprosy-specific oral lesions occurred in the palate. The diagnosis was based on clinical, serological and histopathological findings, and multidrug therapy for multibacillary leprosy was started and continued for 24 months. All patients completed treatment, but developed reaction episodes which were treated with prednisone and/or thalidomide. The authors emphasize the importance of oral mucosa evaluation by a dental health professional during patient care since oral lesions may act as a source of infection.

Bronchial responsiveness during esophageal acid infusion

Among the possible mechanisms explaining the worsening of asthma due to gastroesophageal reflux disease (GERD) is the increase in bronchial hyperresponsiveness. The effects of GERD on bronchial hyperresponsiveness in patients with bronchial asthma have yet to be studied in significant detail. The aim of this study was to determine the effects of esophageal acid perfusion on bronchial responsiveness to bradykinin in patients with both asthma and GERD. In 20 patients with asthma and GERD disease, esophageal pH was monitored with a pH meter and bronchial responsiveness was evaluated by aerosol inhalation of bradykinin during esophageal acid perfusion and, 24 h earlier or later the patients were submitted to another bronchial provocation test without acid infusion. No significant changes were observed in FEV1, FEF25-75%, FVC, or PEF during acid perfusion. The response to the bronchial provocation test did not differ between the control day and the day of acid infusion (p = 0.61). The concentration provoking a 20% fall in FEV1 (geometric mean +/- geometric SD) was 1.09 +/- 5.84 on the day of acid infusion and 0.98 +/- 5.52 on the control day. There is no evidence that acid infusion changes bronchial responsiveness to bradykinin. These findings strongly question the significance of acid infusion as a model to study the pathogenesis of GERD-induced asthma.

Estimates of Interethnic Admixture in the Brazilian Population Using a Panel of 24 X-Linked Insertion/Deletion Markers

Objectives. In this study, we aimed to identify ancestry informative haplotypes and make interethnic admixture estimates using X-chromosome markers. Methods. A significant sample (461 individuals) of European, African, and Native American populations was analyzed, and four linkage groups were identified. The data obtained were used to describe the ancestral contribution of populations from four different geographical regions of Brazil (745 individuals). Results. The global interethnic admixture estimates of the four mixed populations under investigation were calculated applying all the 24 insertion/deletion (INDEL) markers. In the North region, a larger Native Americans ancestry was observed (42%). The Northeast and Southeast regions had smaller Native American contribution (27% in both of them). In the South region, there was a large European contribution (46%). Conclusions. The estimates obtained are compatible with expectations for a colonization model with biased admixture between European men (one X chromosome) and Native American and African women (two X chromosomes), so the 24 X-INDEL panel described here can be a useful to make admixture interethnic estimates in Brazilian populations. Am. J. Hum. Biol. 22:849-852,2010. (C) 2010 Wiley-Liss, Inc.

Human leukocyte antigen (HLA) and single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-alpha-238 and-308 as genetic markers of susceptibility to psoriasis and severity of the disease in a long-term follow-up Brazilian study

Background The strongest genetic marker for psoriasis is Cw*06. Polymorphisms in the tumor necrosis factor (TNF)-alpha promoter region, especially replacement of guanine with adenine in positions -238 and -308 are related to higher TNF-alpha production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We performed a case-control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10-years of follow-up in mild or severe disease and determined HLA class I, II, and TNF single nucleotide polymorphisms (SNPs) -238 and -308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians. Methods Polymorphisms were identified using PCR/SSP. Alleles, genotypes, and haplotypes frequencies were compared using Fisher`s test. Results More severe disease was found in male patients. It may be suggested that alleles B*37, Cw*06, Cw*12, and DRB1*07 were associated with severe disease course, while B*57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF-238 G/G genotype frequency (OR: 3.21; CI: 1.06-9.71; P = 0.04) in the group with severe disease. Conclusions Polymorphisms in the TNF-alpha SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients, but these markers may be related to clinical manifestations.

Assessing Individual Interethnic Admixture and Population Substructure Using a 48-Insertion-Deletion (INSEL) Ancestry-Informative Marker (AIM) Panel

Estimating the proportions of different ancestries in admixed populations is very important in population genetics studies, and it is particularly important for detecting population substructure effects in case-control association studies. In this work, a set of 48 ancestry, informative insertion, deletion polymorphisms (INDELs) were selected with the goal of efficiently measuring the proportions of three different ancestries (sub-Saharan African, European, and Native American) in mixed populations. All selected markers can be easily analyzed via multiplex PCR and detected with standard capillary electrophoresis. A total of 593 unrelated individuals representative of European, African, and Native American parental populations were typed, as were 380 individuals from three Brazilian populations with known admixture patterns. As expected, the interethnic admixture estimates show that individuals from southern Brazil present an almost exclusively European ancestry; Afro-descendant communities in the Amazon region, apart from the major African contribution, present some degree of admixture with Europeans and Native Americans; and a sample from Belem, in the northeastern Amazon, shows a significant contribution of the three ethnic groups, although with a greater European proportion. In summary, a panel of ancestry-informative INDELs was optimized and proven to be a variable tool for estimating individual and global ancestry proportions in admixed populations. The ability to accurately infer interethnic admixtures highlights the usefulness of this marker set for assessing population substructure in association studies, particularly those conducted in Brazilian and other Latin American populations sharing trihybrid ancestry patterns. Hum Mutat 31:184-190, 2010. (C) 2009 Wiley-Liss, Inc.

Obstructive Sleep Apnea Is Frequent in Patients with Hypertensive Intracerebral Hemorrhage and Is Related to Perihematoma Edema

Background: Obstructive sleep apnea (OSA) is related to increased systemic inflammation and arterial hypertension. We hypothesize that OSA is frequent in patients with acute hypertensive intracerebral hemorrhage (ICH) and is related to the perihematoma edema. Methods: Thirty-two non-comatose patients with a hypertensive ICH underwent polysomnography in the acute phase. Perihematoma edema volume was measured on CT scans at admission, after 24 h (early control) and after 4-5 days (late control). The Spearman coefficient (r(s)) was used for correlations. Results: OSA occurred in 19 (59.4%) patients. The apnea-hypopnea index was correlated with relative edema at admission CT (r(s) = 0.40; p = 0.031), early CT (r(s) = 0.46; p = 0.011) and at late CT (r(s) = 0.59; p = 0.006). Conclusions: OSA is highly frequent during the acute phase of hypertensive ICH and is related to perihematoma edema. Copyright (C) 2009 S. Karger AG, Basel

Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis

Patients with sepsis have a marked defect in neutrophil migration. Here we identify a key role of Toll-like receptor 2 (TLR2) in the regulation of neutrophil migration and resistance during polymicrobial sepsis. We found that the expression of the chemokine receptor CXCR2 was dramatically down-regulated in circulating neutrophils from WT mice with severe sepsis, which correlates with reduced chemotaxis to CXCL2 in vitro and impaired migration into an infectious focus in vivo. TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration. Moreover, TLR2(-/-) mice exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival rate during severe sepsis compared with WT mice. In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2. Moreover, neutrophils activated ex vivo by LTA and adoptively transferred into naive WT recipient mice displayed a significantly reduced competence to migrate toward thioglycolate-induced peritonitis. Finally, LTA enhanced the expression of G protein-coupled receptor kinases 2 (GRK2) in neutrophils; increased expression of GRK2 was seen in blood neutrophils from WT mice, but not TLR2(-/-) mice, with severe sepsis. Our findings identify an unexpected detrimental role of TLR2 in polymicrobial sepsis and suggest that inhibition of TLR2 signaling may improve survival from sepsis.

IL-4 regulates susceptibility to intestinal inflammation in murine food allergy

Cardoso CR, Provinciatto PR, Godoi DF, Ferreira BR, Teixeira G, Rossi MA, Cunha FQ, Silva JS. IL-4 regulates susceptibility to intestinal inflammation in murine food allergy. Am J Physiol Gastrointest Liver Physiol 296: G593-G600, 2009. First published January 8, 2009; doi:10.1152/ajpgi.90431.2008.-Allergies involve a state of immediate hypersensitivity to antigens, including food proteins. The mechanism underlying the initiation and development of allergic responses involves IL-4 that directly induces the differentiation of committed effector Th2 lymphocytes. Although it is clear that Th2 responses play a pivotal role in the development of allergic responses, it remains unclear which mechanisms are involved in the development of the intestinal damages observed in food allergy. Accordingly, this work aimed to study the role of Th2/IL-4-dependent responses in the development of food allergy and intestinal pathology. C57BL/6 wild-type (WT) and IL-4(-/-) mice were sensitized with peanut proteins, challenged with peanut seeds, and followed for the development of food allergy and intestinal inflammation. Results demonstrated that exposure to peanut seeds led to weight loss in WT but not in IL-4(-/-) mice that preserved gut integrity with no signs of mucosal inflammation. These animals presented increased levels of IgG2a in sera, suggesting a role for allergic antibodies in the pathogenesis of WT animals. Most importantly, results also showed that lack of IL-4 modulated gut mucosal response in food allergy through diminished expression of TNF-alpha mRNA, increased Th1 IFN-gamma, IL-12p40, regulatory cytokines, and Foxp3, demonstrating their relevance in the control of allergic inflammatory processes, especially in the intestine. Finally, this study highlighted some of the complex mechanisms involved in the pathogenesis of allergic responses to food antigens in the gut, thereby providing valuable tools for directing novel therapeutic or preventive strategies to the control of allergic enteropathy.

Cellular prion protein modulates defensive attention and innate fear-induced behaviour evoked in transgenic mice submitted to an agonistic encounter with the tropical coral snake Oxyrhopus guibei

The cellular prion protein (PrPC) is a neuronal anchored glycoprotein that has been associated with distinct functions in the CNS, such as cellular adhesion and differentiation, synaptic plasticity and cognition. Here we investigated the putative involvement of the PrPC in the innate fear-induced behavioural reactions in wild-type (WT), PrPC knockout (Prnp(0/0)) and the PrPC overexpressing Tg-20 mice evoked in a prey versus predator paradigm. The behavioural performance of these mouse strains in olfactory discrimination tasks was also investigated. When confronted with coral snakes, mice from both Prnp(0/0) and Tg-20 strains presented a significant decrease in frequency and duration of defensive attention and risk assessment, compared to WT mice. Tg-20 mice presented decreased frequency of escape responses, increased exploratory behaviour, and enhancement of interaction with the snake, suggesting a robust fearlessness caused by PrPC overexpression. Interestingly, there was also a discrete decrease in the attentional defensive response (decreased frequency of defensive alertness) in Prnp(0/0) mice in the presence of coral snakes. Moreover, Tg-20 mice presented an increased exploration of novel environment and odors. The present findings indicate that the PrPC overexpression causes hyperactivity, fearlessness, and increased preference for visual, tactile and olfactory stimuli-associated novelty, and that the PrPC deficiency might lead to attention deficits. These results suggest that PrPC exerts an important role in the modulation of innate fear and novelty-induced exploration. (C) 2008 Published by Elsevier B.V.