Evidence for a genetic contribution to the ossification of spinal ligaments in Ossification of Posterior Longitudinal Ligament and Diffuse idiopathic skeletal hyperostosis: A narrative review.

Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Ossification of the Posterior Longitudinal Ligament (OPLL) are common disorders characterized by the ossification of spinal ligaments. The cause for this ossification is currently unknown but a genetic contribution has been hypothesized. Over the last decade, many studies on the genetics of ectopic calcification disorders have been performed, mainly on OPLL. Most of these studies were based on linkage analysis and case control association studies. Animal models have provided some clues but so far, the involvement of the identified genes has not been confirmed in human cases. In the last few years, many common variants in several genes have been associated with OPLL. However, these associations have not been at definitive levels of significance and evidence of functional significance is generally modest. The current evidence suggests a multifactorial aetiopathogenesis for DISH and OPLL with a subset of cases showing a stronger genetic component.

Telemedicine in post-molar follow-up: is it a useful tool?

BACKGROUND: Telemonitoring is an alternative to in-person appointments and overcomes geographic distance barriers. OBJECTIVE: The primary objective of this study was to evaluate adherence to post-molar follow-up using both WhatsApp and in-person appointments compared with standard care. The secondary objective was to evaluate the rate of completion of post-molar follow-up of complete moles, considering 6 and 3 months of duration. METHODS: This retrospective cohort study was conducted at the Gestational Trophoblastic Disease Center, São Paulo Hospital. Patients with complete or partial mole treatment between January 1, 2009 and December 31, 2018 were included in two groups: group 1 (patients from 2009 to 2013) and group 2 (from 2014 to 2018), before and after telemonitoring implementation, respectively. Complete follow-up was considered if after the first normal human chorionic gonadotropin (hCG) level (<5 mIU/mL), the patient was followed up for an additional 30 days (partial mole) or 180 days (complete mole). Loss to post-molar follow-up with positive hCG was also evaluated. Statistical analysis was performed using Pearson's Χ2 test, 5% significance level (p=0.05), and R version 4.0.2. RESULTS: A total of 308 patients were included in the study, 92 of them were assessed in group 1 and 216 patients in group 2. There was no difference between the rates of complete follow-up after telemonitoring implementation (complete mole: 42/72=58.3% group 1 vs 85/163=52.1% group 2; p=0.38; partial mole: 16/20=80% group 1 vs 37/53=69.8 group 2; p=0.3), and no increase of loss to post-molar follow-up with positive hCG (8/92=8.7% group 1 vs 14/216=6.5% group 2; p=0.49). The shortening of follow-up of complete moles to 90 days increased the rate of complete post-molar follow-up (from 127/235=54.0% to 189/235=80.4%, p<0.001). CONCLUSIONS: The association of telemonitoring with in-person appointments could have had an advantage in post-molar follow-up since it did not reduce adherence to hormonal surveillance. Shortening post-molar follow-up after complete mole to 90 days after the first normal hCG level increased the rate of complete post-molar follow-up.

Whole exome sequencing of patients with diffuse idiopathic skeletal hyperostosis and calcium pyrophosphate crystal chondrocalcinosis.

OBJECTIVES: DISH/CC is a poorly understood phenotype characterised by peripheral and axial enthesopathic calcifications, frequently fulfilling the radiological criteria for Diffuse Idiopathic Skeletal Hyperostosis (DISH, MIM 106400), and in some cases associated with Calcium Pyrophosphate Dihydrate (CPPD) Chondrocalcinosis (CC). The concurrence of DISH and CC suggests a shared pathogenic mechanism. In order to identify genetic variants for susceptibility we performed whole exome sequencing in four patients showing this phenotype. MATERIALS AND METHODS: Exome data were filtered in order to find a variant or a group of variants that could be associated with the DISH/CC phenotype. Variants of interest were subsequently confirmed by Sanger sequencing. Selected variants were screened in a cohort of 65 DISH/CC patients vs 118 controls from Azores. The statistical analysis was performed using PLINK V1.07. RESULTS: We identified 21 genetic variants in 17 genes that were directly or indirectly related to mineralization, several are predicted to have a strong effect at a protein level. Phylogenetic analysis of altered amino acids indicates that these are either highly conserved in vertebrates or conserved in mammals. In case-control analyses, variant rs34473884 in PPP2R2D was significantly associated with the DISH/CC phenotype (p=0.028; OR=1.789, 95% CI= 1.060 - 3.021)). CONCLUSION: The results of the present and preceding studies with the DISH/CC families suggests that the phenotype has a polygenic basis. The PPP2R2D gene could be involved in this phenotype in an as yet unknown way.

Persistence of the ABCC6 genes and the emergence of the bony skeleton in vertebrates.

The ATP-binding cassette transporter 6 (ABCC6) gene encodes a cellular transmembrane protein transporter (MRP6) that is involved in the regulation of tissue calcification in mammals. Mutations in ABCC6 are associated with human ectopic calcification disorders. To gain insight into its evolution and involvement in tissue calcification we conducted a comparative analysis of the ABCC6 gene and the related gene ABCC1 from invertebrates to vertebrates where a bony endoskeleton first evolved. Taking into consideration the role of ABCC6 in ectopic calcification of human skin we analysed the involvement of both genes in the regeneration of scales, mineralized structures that develop in fish skin. The ABCC6 gene was only found in bony vertebrate genomes and was absent from Elasmobranchs, Agnatha and from invertebrates. In teleost fish the abcc6 gene duplicated but the two genes persisted only in some teleost genomes. Six disease causing amino acid mutations in human MRP6 are a normal feature of abcc6 in fish, suggesting they do not have a deleterious effect on the protein. After scale removal the abcc6 (5 and 10 days) and abcc1 (10 days) gene expression was up-regulated relative to the intact control skin and this coincided with a time of intense scale mineralization.

Combined approach for finding susceptibility genes in DISH/chondrocalcinosis families: whole-genome-wide linkage and IBS/IBD studies.

Twelve families with exuberant and early-onset calcium pyrophosphate dehydrate chondrocalcinosis (CC) and diffuse idiopathic skeletal hyperostosis (DISH), hereafter designated DISH/CC, were identified in Terceira Island, the Azores, Portugal. Ninety-two (92) individuals from these families were selected for whole-genome-wide linkage analysis. An identity-by-descent (IBD) analysis was performed in 10 individuals from 5 of the investigated pedigrees. The chromosome area with the maximal logarithm of the odds score (1.32; P=0.007) was not identified using the IBD/identity-by-state (IBS) analysis; therefore, it was not investigated further. From the IBD/IBS analysis, two candidate genes, LEMD3 and RSPO4, were identified and sequenced. Nine genetic variants were identified in the RSPO4 gene; one regulatory variant (rs146447064) was significantly more frequent in control individuals than in DISH/CC patients (P=0.03). Four variants were identified in LEMD3, and the rs201930700 variant was further investigated using segregation analysis. None of the genetic variants in RSPO4 or LEMD3 segregated within the studied families. Therefore, although a major genetic effect was shown to determine DISH/CC occurrence within these families, the specific genetic variants involved were not identified.

Efficacy of topiramate in the treatment of crack cocaine dependence: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: We performed a double-blind, randomized, placebo-controlled trial to assess the efficacy of topiramate in the treatment of crack cocaine dependence. METHOD: Sixty men who were dependent on cocaine (DSM-IV) (exclusive use of crack cocaine) were selected. The subjects were randomly assigned to either a topiramate group (subjects received 50-200 mg of topiramate per day for 12 weeks) or a control group (subjects received placebo). The initial daily treatment dose was 50 mg, and this dose was increased weekly at increments of 25 to 50 mg, based on the subject's tolerability, to a maximum of 200 mg. All of the subjects also participated in motivational interviews and group therapy. The primary outcome measures were detection of benzoylecgonine in the urine, study retention, frequency of cocaine smoking, amount of cocaine use, and mean amount of money spent on cocaine per week. The study was conducted from February 2013 to February 2014. RESULTS: Twenty-nine subjects in the topiramate group and 29 subjects in the control group completed the study. Longitudinal assessment revealed that retention was not significant (odds ratio [OR] = 1.072, P = .908) between the 2 groups. Negative results from a urine test for benzoylecgonine (a cocaine metabolite), which is a measure of cocaine abstinence, were more frequently obtained from the topiramate group (OR = 8.687, P < .001). Topiramate reduced the quantity of cocaine used (mean reduction = -3.108 g, P < .001), the frequency of cocaine use (mean = -0.784 times per week, P = .005), and the amount of money spent on cocaine (mean [US dollars] = -$25.38, P = .015; this variable did not achieve statistical significance after Bonferroni correction) compared with the placebo during the 12 weeks (or 84 days) of the assessment. However, the differences in reductions between the 2 groups in the quantity of cocaine used, the frequency of cocaine use, and money spent on cocaine over time (time × group interaction) were present only during the first 4 weeks, and none of these variables by 12 weeks. The studied groups did not differ with regard to secondary end points, such as study dropout and the number of subjects who reported side effects. CONCLUSIONS: The present findings indicate that topiramate is effective and safe and thus reinforce previous data suggesting that topiramate is a potentially useful treatment for crack cocaine dependence. However, we found that topiramate is only useful as an adjunctive treatment during the first 4 weeks of the treatment. Future studies with larger samples are needed to confirm these results. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-3vwfjs and UTN: U1111-1131-4443.

Há relação entre internações hospitalares por doenças respiratórias, mudanças climáticas e focos de queimadas numa população pediátrica? / Is there relationship between hospital admissions for respiratory diseases, climate changes and fire outbreaks in the pediatric population?

Introdução: Considerando que o Tocantins está entre os Estados brasileiros com maior número de ocorrência de incêndios florestais, os focos de queimadas nessa região assumem importância como fator causal, no que se refere ao aumento de internações por doenças respiratórias. Objetivo: Determinar a relação entre focos de calor (queimadas), índices pluviométricos, umidade relativa do ar e média de temperatura mensal com o número de internações hospitalares por doenças respiratórias no Hospital Infantil Público de Palmas (HIPP). Método: Foi realizado estudo transversal que comparou o número de focos de calor (queimadas), índices pluviométricos e umidade relativa do ar com o número de internações hospitalares por doenças respiratórias em um hospital infantil de Palmas - TO, no ano de 2012. Resultados: Do total de internações no HIPP por diversas causas, 42,24% foram decorrentes de doenças respiratórias. O índice pluviométrico chegou a 0 mm no terceiro trimestre, 54,9±42,6 mm no segundo, seguido por 194,8±149,9 mm no quarto e, finalmente, 249,2±128,9 mm no primeiro (p<0,04). Com relação à umidade, variou de 41,7±4,7% no terceiro trimestre para 65,6±7,9 % no segundo, 69,0±11,9% no quarto e 81,9±2,7% no primeiro (p<0,04). Aparentemente, a diferença no número de focos de incêndio não foi estatisticamente significativa. Foi observada correlação negativa entre o índice pluviométrico e o número de internações por doenças respiratórias, no total (R=-0,606; p<0,03) e por pneumonia (R=-0,735; p<0,01). Conclusão: Os fatores ambientais têm importância causal com o aumento de internações por doenças respiratórias; portanto, devem ser implementadas ações voltadas à saúde para melhora dos atendimentos dos pacientes nos períodos de seca.