Clinical characteristics of headaches in an urban Mennonite group in South Brazil / Características clínicas das cefaleias em um grupo menonita urbano do sul do Brasil

Abstract Background Genetic variants play a pathophysiological role in headaches, especially in migraine. The Mennonite group (MG) has been geographically and genetically isolated throughout its history, harboring a distinctive distribution of diseases. Objective To determine the characteristics of headaches in a group with direct Mennonite ancestry contrasting with other urban community members (control group [CG]). Methods Subjects with headaches were asked to complete a questionnaire covering: the type of headache, presence of aura, frequency and duration of attacks, pain location and severity, analgesic consumption, premonitory and postdromic manifestations, Depressive Thoughts Scale, Epworth Sleepiness Scale (ESS), General Anxiety Disorder-7, Patient Health Questionnaire-9 (PHQ-9), Migraine Disability Assessment, and Composite Autonomic System Score. Results We included 103 participants (CG: 45, Mennonite group [MG]: 58). Migraine was the most common headache (CG: 91.1%; MG: 81.0%; p = 0.172), followed by tension-type headache (CG: 8.9%; MG: 15.5%; p = 0.381). Aura was identified by 44.4% and 39.7% in the CG and MG, respectively (p = 0.689). The groups differed only concerning the frequency of retro-orbital pain (CG: 55.6%; MG: 32.8%; p = 0.027), PHQ-9 (CG: median 7, range 0 to 22; MG: median 5, range 0 to 19; p = 0.031) and ESS (CG: median 0, range 0 to 270; MG: median 0, range 0 to 108; p = 0.048) scores. Conclusion There were no major differences in the prevalence and clinical characterization of headaches between the MG and the CG. However, the latter showed more diffuse pain, sleepiness, and depressive symptoms. Specific genetic or epigenetic variants in Mennonite descendants might account for these differences.

Resumo Antecedentes Variantes genéticas desempenham um papel fisiopatológico nas cefaleias, especialmente na migrânea. O grupo menonita (GM) tem estado geográfica e geneticamente isolado ao longo de sua história, abrigando uma distribuição distinta de doenças. Objetivo Determinar as características das cefaleias em um grupo com ascendência menonita direta, comparando-as com as de outros membros da comunidade urbana (grupo controle [GC]). Métodos Participantes com cefaleia foram convidados a preencher um questionário abrangendo: tipo de cefaleia; presença de aura; frequência e duração dos ataques; localização e gravidade da dor; consumo de analgésicos; manifestações premonitórias e posdrômicas; Escala de Pensamentos Depressivos; Escala de Sonolência de Epworth (ESS); Transtorno de Ansiedade Geral-7 (GAD-7); Questionário de Saúde do Paciente-9 (PHQ-9); Avaliação de Incapacidade da Migrânea (MIDAS) e Escore do Sistema Autônomo Composto (COMPASS-31). Resultados Incluímos 103 participantes (GC: 45, GM: 58). A migrânea foi a cefaleia mais frequente (GC: 91,1%; GM: 81,0%; p = 0,172), seguida pela cefaleia tensional (GC: 8,9%; GM: 15,5%; p = 0,381). Aura foi identificada por 44,4% e 39,7% nos GC e GM, respectivamente (p = 0,689). Os grupos diferiram apenas com relação à frequência de dor retro-orbitária (GC: 55,6%; GM: 32,8%; p = 0,027), PHQ-9 (GC: mediana 7, amplitude 0 a 22; GM: mediana 5, amplitude 0 a 19; p = 0,031) e ESS (GC: mediana 0, amplitude 0 a 270; GM: mediana 0, amplitude 0 a 108; p = 0,048). Conclusão Não houve diferenças significativas na prevalência e caracterização clínica das cefaleias nos GM e GC. Entretanto, o último grupo mostrou mais dor difusa, sonolência e sintomas depressivos. Variantes genéticas ou epigenéticas específicas em descendentes de menonitas podem justificar tais diferenças.

The Second Highest Prevalence of Celiac Disease Worldwide: Genetic and Metabolic Insights in Southern Brazilian Mennonites.

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16-5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57-2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56-94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10-6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10-6), and higher than in Euro-Brazilians (p = 6.5 × 10-6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis.

Inside the pocket: Critical elements of HLA-mediated susceptibility to cervical precancerous lesions.

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide-binding cleft in HPV-related cervical disease. Therefore, we aimed to investigate the association between HLA-B, HLA-C, and HLA-DRB1 polymorphism and amino acid residues composing the pockets of the peptide-binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR-SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct the p-value for multiple comparisons. HLA-DRB1*13:01 was associated with protection against CIN II/III, while HLA-C*03:04 was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA-C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA-DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA-C and HLA-DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.

Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population.

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.

Interaction of Long Noncoding RNAs and Notch Signaling: Implications for Tissue Homeostasis Loss.

The Notch signaling is a crucial pathway involved in cellular development, progression, and differentiation. Deregulation of Notch signaling pathway commonly impacts tissue homeostasis, being highly associated with proliferative disorders. The long noncoding RNAs (lncRNAs), which are transcripts with more than 200 nucleotides that do not code for proteins, were already described as Notch signaling pathway-interacting molecules. Many of them act as important transcriptional and posttranscriptional regulators, affecting gene expression and targeting other regulatory molecules, such as miRNAs. Due to their strong impact on function and gene expression of Notch-related molecules, lncRNAs influence susceptibility to cancer and other diseases, and can be regarded as potential biomarkers and therapeutic targets. Along this chapter, we summarize the cross talk between the Notch signaling pathway and their most important modulating lncRNAs, as well as the pathological consequences of these interactions, in different tissues.

Condemned or Not to Die? Gene Polymorphisms Associated With Cell Death in Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that occurs sporadically across the globe and is endemic in Brazil. Keratinocyte adhesion loss (acantholysis) is associated with high levels of anti-desmoglein 1 IgG autoantibodies, but the role of cell death is poorly understood in PF. Current evidence disqualifies apoptosis as the major cell death mechanism and no other process has yet been investigated. To approach the role of variation in genes responsible for cell death pathways in pemphigus susceptibility, we systematically investigated the frequencies of 1,167 polymorphisms from genes encoding products of all 12 well-established cell death cascades (intrinsic and extrinsic apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic, NETotic, lysosome-dependent, autophagy-dependent, and immunogenic). By multivariate logistic regression, we compared allelic and genotypic frequencies of 227 PF patients and 194 controls obtained by microarray hybridization. We found 10 variants associated with PF (p < 0.005), belonging to six cell death pathways: apoptosis (TNF, TRAF2, CD36, and PAK2), immunogenic cell death (EIF2AK3, CD47, and SIRPA), necroptosis (TNF and TRAF2), necrosis (RAPGEF3), parthanatos (HK1), and pyroptosis (PRKN). Five polymorphisms were associated with susceptibility: TNF rs1800630*A (OR = 1.9, p = 0.0003), CD36 rs4112274*T (OR = 2.14, p = 0.0015), CD47 rs12695175*G (OR = 1.77, p = 0.0043), SIRPA rs6075340*A/A (OR = 2.75, p = 0.0009), and HK1 rs7072268*T (OR = 1.48, p = 0.0045). Other five variants were associated with protection: TRAF2 rs10781522*G (OR = 0.64, p = 0.0014), PAK2 rs9325377*A/A (OR = 0.48, p = 0.0023), EIF2AK3 rs10167879*T (OR = 0.48, p = 0.0007), RAPGEF3 rs10747521*A/A (OR = 0.42, p = 0.0040), and PRKN rs9355950*C (OR = 0.57, p = 0.0004). Through functional annotation, we found that all associated alleles, with the exception of PRKN rs9355950*C, were previously associated with differential gene expression levels in healthy individuals (mostly in skin and peripheral blood). Further functional validation of these genetic associations may contribute to the understanding of PF etiology and to the development of new drugs and therapeutic regimens for the disease.

Wound healing using ionic silver dressing and nonocrystalline silver dressing in rats / Cicatrização de feridas em ratos utilizando curativos com prata iônica e nanocristalina

PURPOSE: To investigate the results of the healing process on surgical wounds in the back of Wistar rats using nanocristaline and ionic silver dressing. METHODS: Sixty rats Wistar were submitted to surgical wounds with punch of 8mm in diameter. In 30 animals (groups PN - nanocristaline and AD - control) two surgical wounds were done diametrically opposite on the upper back side. On the right side was used nanocristaline (PN) silver dressing and on the left side, distilled water dressing (AD). On the other group of 30 rats, only one wound was made with the punch, on the right side, and was used ionic silver dressing. So, the groups were divided into three subgroups, according to the day of death (7th, 14th and 21st day). In each of these days the wounds diameter were measured to evaluate the wound contraction. Microscopic data were analyzed using the H&E staining to verify the inflammatory process and neovascularization. The Masson trichrome staining was used to verify the fibrosis. RESULTS: Macroscopically only the subgroup of 21st day showed statistical significance; between the groups AD and PI inflammatory process appeared in the 7th day subgroup in 90% of the cases. In neovascularization there was statistical significance between the groups PN and AD in the subgroup of 7th day. Fibrosis did not show statistical significance in the studied groups. CONCLUSIONS: In relation to wound contraction, PN and PI groups showed better results than the AD group. In regard to histological analysis, H&E staining showed that there was presence of inflammation in all groups, and at the end, the control group (AD) on 7th day, was superior to PN and PI groups. In relationship to fibrosis, no differences were obtained among groups.

OBJETIVO: Investigar os resultados da cicatrização de feridas cirúrgicas em dorso de ratos, utilizando curativos de prata nanocristalina e iônica. MÉTODOS: Sessenta ratos Wistar foram submetidos à feridas cirúrgicas com punch de 8mm de diâmetro. Foram confeccionadas duas lesões diametralmente opostas nos animais dos grupos prata nanocristalina (PN) e controle água destilada (AD). Na lesão do lado direito foi utilizado curativo com prata nanocristalina e na do lado esquerdo curativo com água destilada. No outro grupo de 30 ratos, apenas foi realizada uma lesão com o punch no lado esquerdo e curativo com prata iônica. Os grupos foram divididos em subgrupos conforme o dia da morte (7º, 14º e 21º dias), o que caracterizou a existência de três subgrupos, nos quais foram tomadas as medidas do centro das lesões para estudar macroscopicamente a contração da ferida Microscopicamente foi utilizada a coloração H&E, através da qual foi observado o processo inflamatório e a neovascularização. Com a coloração Tricômio de Masson, foi estudada a fibrose. RESULTADOS: Macroscopicamente apenas o subgrupo 21 dias apresentou significância estatística entre os grupos AD e prata iônica (PI), porém quando comparados os dias de avaliação, dois a dois, dentro de cada tratamento, todos os subgrupos apresentaram significância estatística (p<0,05). A variável intensidade da inflamação apresentou-se de forma acentuada no subgrupo sete dias em 90% dos casos, entre os grupos AD e PI. Na variável neovascularização houve significância estatística entre os grupos PN e AD no subgrupo sete dias. A variável fibrose não apresentou significância estatística nos subgrupos estudados. CONCLUSÕES: Em relação à contração da ferida, os grupos PN e PI apresentaram resultados superiores ao grupo AD. Com relação à análise histológica, na coloração H&E observou-se que houve presença de processo inflamatório nos grupos estudados sendo que, ao final, o grupo controle (AD) no 7º dia mostrou-se superior aos grupos PN e PI. Com relação à variável fibrose, não houve diferenças entre os grupos.