Syncytiotrophoblast Markers Are Downregulated in Placentas from Idiopathic Stillbirths.

The trophoblast cells are responsible for the transfer of nutrients between the mother and the foetus and play a major role in placental endocrine function by producing and releasing large amounts of hormones and growth factors. Syncytiotrophoblast cells (STB), formed by the fusion of mononuclear cytotrophoblasts (CTB), constitute the interface between the foetus and the mother and are essential for all of these functions. We performed transcriptome analysis of human placental samples from two control groups-live births (LB), and stillbirths (SB) with a clinically recognised cause-and from our study group, idiopathic stillbirths (iSB). We identified 1172 DEGs in iSB, when comparing with the LB group; however, when we compared iSB with the SB group, only 15 and 12 genes were down- and upregulated in iSB, respectively. An assessment of these DEGs identified 15 commonly downregulated genes in iSB. Among these, several syncytiotrophoblast markers, like genes from the PSG and CSH families, as well as ALPP, KISS1, and CRH, were significantly downregulated in placental samples from iSB. The transcriptome analysis revealed underlying differences at a molecular level involving the syncytiotrophoblast. This suggests that defects in the syncytial layer may underlie unexplained stillbirths, therefore offering insights to improve clinical obstetrics practice.

The role of DNA hydroxymethylation and TET enzymes in placental development and pregnancy outcome.

The placenta is a temporary organ that is essential for supporting mammalian embryo and fetal development. Understanding the molecular mechanisms underlying trophoblast differentiation and placental function may contribute to improving the diagnosis and treatment of obstetric complications. Epigenetics plays a significant role in the regulation of gene expression, particularly at imprinted genes, which are fundamental in the control of placental development. The Ten-Eleven-Translocation enzymes are part of the epigenetic machinery, converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). DNA hydroxymethylation is thought to act as an intermediate in the DNA demethylation mechanism and potentially be a stable and functionally relevant epigenetic mark on its own. The role of DNA hydroxymethylation during differentiation and development of the placenta is not fully understood but increasing knowledge in this field will help to evaluate its potential role in pregnancy complications. This review focuses on DNA hydroxymethylation and its epigenetic regulators in human and mouse placental development and function. Additionally, we address 5hmC in the context of genomic imprinting mechanism and in pregnancy complications, such as intrauterine growth restriction, preeclampsia and pregnancy loss. The cumulative findings show that DNA hydroxymethylation might be important for the control of gene expression in the placenta and suggest a dynamic role in the differentiation of trophoblast cell types during gestation.

Aripiprazole Offsets Mutant ATXN3-Induced Motor Dysfunction by Targeting Dopamine D2 and Serotonin 1A and 2A Receptors in C. elegans.

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado-Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole's cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

Influence of the PFNA screw position on the risk of cut-out in an unstable intertrochanteric fracture: a computational analysis.

The position of the lag screw in the femoral head is a key factor to cut-out, the most reported complication in the internal fixation of intertrochanteric fractures. Considering that the best position for the lag screw remains controversial, the aim of this study was to evaluate the influence of different lag screw positions on the risk of cut-out of an unstable intertrochanteric fracture fixed with a Proximal Femoral Nail Anti-Rotation (PFNA) implant. The relationship between cut-out and the tip-apex distance (TAD) or the calcar referenced tip-apex distance (CalTAD) was also investigated. Finite element models of one male and one female femur treated with a PFNA implant were developed considering the lag screw positioned centrally and inferiorly on the anteroposterior view, and for each of these, the screw tip at 4 discrete positions along its longitudinal axis. All 8 positions simulated for each femur considered the lag screw in a centre position on the lateral view. The risk of cut-out was evaluated for two loading conditions assuming it is related with high compressive strains. The bone region at the fracture line, near the tip of the missing medial fragment, was always the most concerning regarding high compressive strains. The inferior positioning of the lag screw reduced the volume of bone susceptible to yielding compared to the centre positioning. The deep placement of the screw tip improved the outcome for both centre and inferior positions. The results suggested the inferior and deep placement of the screw to be the best position to reduce the risk of cut-out. The volume of bone susceptible to yielding was found not to be correlated to TAD or CalTAD, suggesting that further investigation is necessary to identify other, more reliable, predictors of cut-out.

Deregulation of imprinted genes expression and epigenetic regulators in placental tissue from intrauterine growth restriction.

PURPOSE: Intrauterine growth restriction (IUGR) is a fetal growth complication that can be caused by ineffective nutrient transfer from the mother to the fetus via the placenta. Abnormal placental development and function have been correlated with abnormal expression of imprinted genes, which are regulated by epigenetic modifications at imprinting control regions (ICRs). In this study, we analyzed the expression of imprinted genes known to be involved in fetal growth and epigenetic regulators involved in DNA methylation, as well as DNA methylation at the KvDMR1 imprinting control region and global levels of DNA hydroxymethylation, in IUGR cases. METHODS: Expression levels of imprinted genes and epigenetic regulators were analyzed in term placental samples from 21 IUGR cases and 9 non-IUGR (control) samples, by RT-qPCR. Additionally, KvDMR1 methylation was analyzed by bisulfite sequencing and combined bisulfite restriction analysis (COBRA) techniques. Moreover, global DNA methylation and hydroxymethylation levels were also measured. RESULTS: We observed increased expression of PHLDA2, CDKN1C, and PEG10 imprinted genes and of DNMT1, DNMT3A, DNMT3B, and TET3 epigenetic regulators in IUGR placentas. No differences in methylation levels at the KvDMR1 were observed between the IUGR and control groups; similarly, no differences in global DNA methylation and hydromethylation were detected. CONCLUSION: Our study shows that deregulation of epigenetic mechanisms, namely increased expression of imprinted genes and epigenetic regulators, might be associated with IUGR etiology. Therefore, this study adds knowledge to the molecular mechanisms underlying IUGR, which may contribute to novel prediction tools and future therapeutic options for the management of IUGR pregnancies.

Oral and maxillofacial conditions, dietary aspects, and nutritional status of children with congenital Zika syndrome.

OBJECTIVE: The aim of this study was to investigate oral and maxillofacial outcomes in children with congenital Zika syndrome (CZS) and the presence of nonnutritive sucking habits, functional habits, and features related to breastfeeding and nutrition of these children. STUDY DESIGN: We conducted a cross-sectional study with 45 children with CZS and 50 healthy controls in Sergipe state, Brazil, from February 2018 to June 2018. Demographic and clinical data, including breastfeeding and feeding data, were obtained for each child. Additionally, oral and maxillofacial evaluation was performed. RESULTS: Low weight (prevalence rate [PR] 8.33; 95% confidence interval [CI] 2.02-34.45), nonexclusive breastfeeding up to 6 months (PR 1.56; 95% CI 1.18-2.08); mouth breathing (PR 3.46; 95% CI 1.83-6.52); difficulty in swallowing (PR 6.00; 95% CI 2.53-14.25); and excessive salivation (PR 4.81; 95% CI 2.18-10.62) were more frequent in children with CZS. Children with CZS were more likely to have abnormal insertion of the upper labial frenulum (PR 7.04; 95% CI 2.23-22.20); ogival palate (PR 3.70; 95% CI 1.63-8.40), dental enamel defects (PR 2.22; 95% CI 1.05-4.69); and delayed dental eruption (PR 8.89; 95% CI 1.16-68.32) compared with healthy children. CONCLUSIONS: Children with CZS had a higher frequency of problems related to breastfeeding, low weight, and oral and maxillofacial abnormalities compared with healthy children.

Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses.

Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.

Plectranthus amboinicus essential oil and carvacrol bioactive against planktonic and biofilm of oxacillin- and vancomycin-resistant Staphylococcus aureus.

BACKGROUND: The emergence of multidrug-resistant bacteria is a worldwide concern and in order to find an alternative to this problem, the occurrence of antimicrobial compounds in Plectranthus amboinicus essential oil was investigated. Thus, this study aims to determine susceptibility of Staphylococcus aureus isolated from food to antibiotics, P. amboinicus essential oil (PAEO) and carvacrol. METHODS: Leaves and stem of P. amboinicus were used for extraction of essential oil (PAEO) by hydrodistillation technique and EO chemical analysis was performed by gas chromatography coupled to a mass spectrometer. S. aureus strains (n = 35) isolated from food and S. aureus ATCC 6538 were used to evaluate the antimicrobial and antibiofilm activity of PAEO and carvacrol. All strains (n = 35) were submitted to antimicrobial susceptibility profile by disk diffusion method. Determination of MIC and MBC was performed by microdilution technique and antibiofilm activity was determined by microtiter-plate technique with crystal violet assay and counting viable cells in Colony Forming Units (CFU). RESULTS: Carvacrol (88.17%) was the major component in the PAEO. Antibiotic resistance was detected in 28 S. aureus strains (80%) and 12 strains (34.3%) were oxacillin and vancomycin-resistant (OVRSA). From the 28 resistant strains, 7 (25%) showed resistance plasmid of 12,000 bp. All strains (n = 35) were sensitive to PAEO and carvacrol, with inhibition zones ranging from 16 to 38 mm and 23 to 42 mm, respectively. The lowest MIC (0.25 mg mL-1) and MBC (0.5 mg mL-1) values were observed when carvacrol was used against OVRSA. When a 0.5 mg mL-1 concentration of PAEO and carvacrol was used, no viable cells were found on S. aureus biofilm. CONCLUSION: The antibacterial effect of carvacrol and PAEO proves to be a possible alternative against planktonic forms and staphylococcal biofilm.

Hiperplasia de glândula salivar sublingual: relato de caso / Hyperplasia of the sublingual salivary glands: a case report

A hiperplasia da glândula salivar sublingual é descrita como uma desordem benigna de envolvimento funcional. Apresenta um crescimento lento e progressivo, assintomático, uni ou bilateral da glândula sublingual, de etiologia incerta, em que muitos fatores causadores podem estar associados. O diagnóstico é clínico, complementado por exames de imagens. Seu tratamento pode ser conservador ou cirúrgico, dependendo do grau de comprometimento. O trabalho desenvolvido tem por objetivo relatar um caso de hiperplasia de glândula sublingual em uma paciente do gênero masculino de 39 anos, submetido a procedimento cirúrgico sob anestesia local.

Hyperplasia of the sublingual salivary gland is described as a benign disorder with functional compromise. It presents a slow, progressive and asymptomatic growth of one of or both the sublingual glands. Its etiology remains unspecified, and many factors may be involved. The diagnosis is mostly clinical, complemented by imaging studies. The treatment may be conservative or surgical, depending on the progression status of the disorder. This paper reports a case of sublingual gland hyperplasia in a 39-year-old male patient who was submitted to surgery under local anesthesia.

Displasia fibrosa: osteoplastia com acesso Weber-Ferguson. Relato de caso / Fibrous dysplasia: osteoplasty using the Weber-Ferguson approach. A case report

A displasia óssea é descrita como uma desordem benigna de desenvolvimento ósseo, caracterizada pela substituição de osso normal por uma proliferação excessiva de tecido conjuntivo fibroso. Essa condição pode estar presente em um único osso (Displasia Fibrosa Monostótica) ou em até 75% de todo o esqueleto (Displasia Fibrosa Poliostótica). Alterações cutâneas e endócrinas podem estar associadas à displasia fibrosa poliostótica, caracterizando a Síndrome de McCune-Albright. O diagnóstico baseia-se na história, apresentação clínica, nos exames radiográficos e, quando necessário, em exames histopatológicos. A transformação da displasia fibrosa em lesão maligna ou sarcomatosa é uma complicação rara. O trabalho desenvolvido tem como objetivo relatar um caso de displasia óssea poliostótica em um paciente do gênero masculino de 40 anos, que foi submetidoa procedimento cirúrgico para osteoplastia através do acesso de Weber-Ferguson...

Bone dysplasia is described as a benign disorder of bone development, characterized by the replacement of normal bone by an excessive proliferation of fibrous connective tissue. The condition may be present in a sinlge bone (monostotic fibrous dysplasia) or in up to 75% of the entire skeleton (polyostotic fibrous dysplasia). Cutaneous and endocrine changes may be associated with polyostotic dysplasia, characterizing the McCune-Albright syndrome. Diagnosis is based on the history, clinical presentation, radiographic examinations and, when necessary, on histopathological studies. The transformation of fibrous dysplasia into a malignant or sarcomatous lesion is a rare complication. The purpose of the present study is to report the case of polyostotic bone dysplasia in a 40-year-old male patient who was submitted to a osteoplasty using the Weber-Fergsun approach...