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BACKGROUND AND AIMS: We have previously shown in a model of hepatic ischaemia/reperfusion injury that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) restores reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an inverse modulator of metalloproteases (MMPs) and inhibitor of the sheddases ADAM10 and ADAM17 involved in inflammation and fibrogenesis. Here, the effects of FXR agonists OCA and INT-787 on hepatic levels of RECK, MMPs, ADAM10 and ADAM17 were compared in a diet-induced ob/ob mouse model of non-alcoholic steatohepatitis (NASH). METHODS: Lep ob/ob NASH mice fed a high-fat diet (HFD) or control diet (CD) for 9 weeks (wks) were treated with OCA or INT-787 0.05% dosed via HFD admixture (30 mg/kg/day) or HFD for further 12 wks. Serum alanine transaminase (ALT) and inflammatory cytokines, liver RECK, MMP-2 and MMP-9 activity as well as ADAM10, ADAM17, collagen deposition (Sirius red), hepatic stellate cell activation (α-SMA) and pCK+ reactive biliary cells were quantified. RESULTS: Only INT-787 significantly reduced serum ALT, IL-1ß and TGF-ß. A downregulation of RECK expression and protein levels observed in HFD groups (at 9 and 21 wks) was counteracted by both OCA and INT-787. HFD induced a significant increase in liver MMP-2 and MMP-9; OCA administration reduced both MMP-2 and MMP-9 while INT-787 markedly reduced MMP-2 expression. OCA and INT-787 reduced both ADAM10 and ADAM17 expression and number of pCK+ cells. INT-787 was superior to OCA in decreasing collagen deposition and α-SMA levels. CONCLUSION: INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Fígado/metabolismo , Ácido Quenodesoxicólico/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Dieta Hiperlipídica/efeitos adversos , Colágeno/metabolismo , Colágeno/farmacologiaRESUMO
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
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Comunicação Interventricular , Humanos , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Comunicação Interventricular/genética , Mutação , Fatores de Transcrição/genéticaRESUMO
Necroptosis is a form of regulated necrosis and is executed by MLKL when MLKL is engaged in triggering the rupture of cell plasma membrane. MLKL activation also leads to the protease, ADAMs-mediated ectodomain shedding of cell surface proteins of necroptotic cells. Tumor necroptosis often happens in advanced solid tumors, and blocking necroptosis by MLKL deletion in breast cancer dramatically reduces tumor metastasis. It has been suggested that tumor necroptosis affects tumor progression through modulating the tumor microenvironment. However, the exact mechanism by which tumor necroptosis promotes tumor metastasis remains elusive. Here, we report that the ectodomain shedding of cell surface proteins of necroptotic cells is critical for the promoting effect of tumor necroptosis in tumor metastasis through inhibiting the anti-tumor activity of T cells. We found that blocking tumor necroptosis by MLKL deletion led to the dramatic reduction of tumor metastasis and significantly elevated anti-tumor activity of tumor-infiltrating and peripheral blood T cells. Importantly, the increased anti-tumor activity of T cells is a key cause for the reduced metastasis as the depletion of CD8+ T cells completely restored the level of metastasis in the Mlkl KO mice. Interestingly, the levels of some soluble cell surface proteins including sE-cadherin that are known to promote metastasis are also dramatically reduced in MLKL null tumors/mice. Administration of ADAMs pan inhibitor reduces the levels of soluble cell surface proteins in WT tumors/mice and leads to the dramatic decrease in metastasis. Finally, we showed the sE-cadherin/KLRG1 inhibitory receptor is the major pathway for necroptosis-mediated suppression of the anti-tumor activity of T cells and the promotion of metastasis. Hence, our study reveals a novel mechanism of tumor necroptosis-mediated promotion of metastasis and suggests that tumor necroptosis and necroptosis-activated ADAMs are potential targets for controlling metastasis.
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Neoplasias da Mama , Proteínas de Membrana , Necroptose , Metástase Neoplásica , Animais , Camundongos , Caderinas , Proteínas de Membrana/metabolismo , Camundongos Knockout , Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/farmacologia , Microambiente Tumoral , Neoplasias da Mama/patologiaRESUMO
The Notch proteins play key roles in cell fate determination during development. Germline pathogenic variants in NOTCH1 predispose to a spectrum of cardiovascular malformations including Adams-Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C-terminus of the single-pass transmembrane receptor encoded by NOTCH1 contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a NOTCH1-mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss-of-function protein that acts as an antimorph through competition with wild-type NOTCH1.
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Displasia Ectodérmica , Deformidades Congênitas dos Membros , Dermatoses do Couro Cabeludo , Humanos , Receptor Notch1/genética , Displasia Ectodérmica/genética , Dermatoses do Couro Cabeludo/congênito , Deformidades Congênitas dos Membros/genéticaRESUMO
BACKGROUND: Adams-Oliver syndrome (AOS) (#614,219) is a multiple malformation disorder characterized by the presence of aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). METHODS AND RESULTS: We describe a confirmed case of AOS with a novel pathogenic variation in Dedicator Of Cytokinesis 6 (DOCK6) gene, with neurological abnormalities, characterized by the presence of a multiple malformation entity with extensive cardiological and neurological abnormalities. CONCLUSIONS: In AOS, genotype-phenotype correlations have been described. DOCK6 mutations appear to be related with congenital cardiac and central nervous system malformations associated with intellectual disability, as illustrated in the present case.
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Displasia Ectodérmica , Humanos , Citocinese , Displasia Ectodérmica/genética , Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/genética , Feminino , CriançaRESUMO
Development of a functional gonad includes migration of primordial germ cells (PGCs), differentiations of somatic and germ cells, formation of primary follicles or spermatogenic cysts with somatic gonadal cells, development and maturation of gametes, and subsequent releasing of mature germ cells. These processes require extensive cellular and tissue remodeling, as well as broad alterations of the surrounding extracellular matrix (ECM). Metalloproteases, including MMPs (matrix metalloproteases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), are suggested to have critical roles in the remodeling of the ECM during gonad development. However, few research articles and reviews are available on the functions and mechanisms of metalloproteases in remodeling gonadal ECM, gonadal development, or gonadal differentiation. Moreover, most studies focused on the roles of transcription and growth factors in early gonad development and primary sex determination, leaving a significant knowledge gap on how differentially expressed metalloproteases exert effects on the ECM, cell migration, development, and survival of germ cells during the development and differentiation of ovaries or testes. We will review gonad development with focus on the evidence of metalloprotease involvements, and with an emphasis on zebrafish as a model for studying gonadal sex differentiation and metalloprotease functions.
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Desintegrinas , Peixe-Zebra , Animais , Gônadas , Diferenciação Sexual , Células Germinativas , MetaloproteasesRESUMO
ARKRAY ADAMS A1c HA-8190V is a fully automated high-pressure liquid chromatography (HPLC) system for the measurement of HbA1c. The runtime is 58 s per sample in the Variant mode and 24 s per sample in the Fast mode. We evaluated the analytical performance of this analyzer in the Variant mode, to verify the quality of analysis, according to the consensus criteria established for this measurand. Reproducibility, trueness, carry-over, linearity, interferences and comparison with ARKRAY ADAMS A1c HA-8180V and HA-8180T analyzers were evaluated. Total CVs were 0.76% (IFCC units) 0.55 (NGSP units) at low HbA1c concentration and 0.85% (IFCC units) 0.68 (NGSP units) at high HbA1c concentration. Mean difference with the target values was -1.25 mmol/mol (-0.119%) and total error at medium level was 2.83% (IFCC units), 2.46% (NGSP units) Carry-over was 0%. Linearity was shown in the range 27-122 mmol/mol (4.6-13.3%). The results were not affected in the range of total Hb 59-199 g/L, labile fraction up to 5.5%, carbamylated up to Hb 6.3% nor acetylated Hb up to 5.3%. Method comparison demonstrated good concordance between the methods. The analyzer demonstrated a high analytical performance adequate for routine clinical use in laboratories with high workloads.
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Hemoglobinas Glicadas , Humanos , Reprodutibilidade dos Testes , Cromatografia Líquida de Alta Pressão/métodosRESUMO
INTRODUCTION: ARKRAY ADAMS A1c Lite HA-8380V is a fully automated high- performance liquid chromatography system for the measurement of HbA1c. We aimed to evaluate its analytical performance using the Variant Mode. METHODS: Carry-over, linearity, imprecision, trueness, interferences and comparison against ARKRAY ADAMS A1c HA-8180V and HA-8180T analyzers were studied. RESULTS: Total CVs 0.93% (IFCC units), 0.63% (NGSP units) at low concentration and 1.01% (IFCC) 0.74% (NGSP), at high concentration. Mean difference with the target values was -0.44 mmol/mol (IFCC) -0.04% (NGSP). Carry-over, linearity and method comparison were excellent.The results were not affected in the range of total Hb 39-199 g/L, labile fraction 5.7%, carbamylated Hb 9.1% nor acetylated Hb 7.8%, effect of common variants was negligible. CONCLUSIONS: the analyzer demonstrated very good analytical performances, according to the consensus criteria established for HbA1c; it is adequate for laboratories with medium-low workloads.
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Hemoglobinas Glicadas , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND/OBJECTIVES: Cutis marmorata telangiectatica congenita (CMTC) is a capillary malformation characterized by congenital, reticulated, well-demarcated dark blue, red-purple, or violaceous macules or plaques, with a coarse fixed livedo pattern. Nearly always, contiguous areas of skin atrophy and/or ulceration are present. CMTC is usually localized but may rarely be generalized. Such generalized cases may be a feature of Adams-Oliver syndrome (AOS). The nosologic confusion surrounding the term CMTC and uncertainty about the risk of associated abnormalities hinders the appropriate workup of patients and prognostic counseling for families. We hypothesized that the risk of associated anomalies in children with localized CMTC is very low. METHODS: We performed a literature review and retrospective review of patients with CMTC to propose a more precise clinical definition and ascertain the risk of associated anomalies. RESULTS: We included 78 patients determined to have a diagnosis of CMTC based on consensus. The majority of patients had localized CMTC. Most patients with generalized CMTC met the criteria for the diagnosis of AOS. The associations found in patients with localized CMTC were mostly dermatological, with atrophy, ulcerations, or erosions present in 71%. Extracutaneous findings were present in 34.4% of patients and consisted mainly of extremity asymmetry (24.5%) that improved over time. CONCLUSION: Our study showed a very low frequency of extracutaneous anomalies among patients with localized CTMC, ipsilateral limb discrepancy being the most common. We did not find a strong association with any other visceral anomalies that would justify routine evaluation in patients with localized CMTC.
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We discuss the current state of knowledge of stable homotopy groups of spheres. We describe a computational method using motivic homotopy theory, viewed as a deformation of classical homotopy theory. This yields a streamlined computation of the first 61 stable homotopy groups and gives information about the stable homotopy groups in dimensions 62 through 90. As an application, we determine the groups of homotopy spheres that classify smooth structures on spheres through dimension 90, except for dimension 4. The method relies more heavily on machine computations than previous methods and is therefore less prone to error. The main mathematical tool is the Adams spectral sequence.
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PURPOSE: The calcar femorale (femoral calcar) is used in the English literature to designate the thickened medial cortex of the femoral neck. This term is, however, incorrect, as the calcar femorale is actually quite another structure. METHODS: Searching was performed in original and historic publication. RESULTS: The importance of the thickened medial cortex of the proximal femur in femoral neck fractures was discussed already by Robert Adams in 1834-1836. Therefore, the German surgeon C.W. Streubel, in 1847, called it Adamscher Knochenbogen (Adams' arch). Due to misspelling, this term was gradually changed to Adambogen, and at the turn of twentieth century, it was commonly used primarily in the German literature. Then, it fell into oblivion and its "renaissance" came as late as during the 1960s, again in the German literature, in connection with operative treatment of trochanteric fractures. CONCLUSIONS: However, under the influence of the English literature, it has been replaced by the term calcar femorale (femoral calcar), used ever since. The term Adams' arch should be reserved for the thickened medial cortex of the proximal femur, while the term calcar femorale (femoral calcar) should be used for the vertical plate arising from the medial cortex close below the lesser trochanter.
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Colo do Fêmur , Fêmur , Humanos , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Extremidade Inferior , Placas ÓsseasRESUMO
The reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein, negatively regulates various membrane proteins involved in the tissue governing extracellular matrix (ECM) remodeling such as metalloproteases (MMPs) and the sheddases ADAM10 and ADAM17. The significance of the present review is to summarize the current understanding of the pathophysiological role of RECK, a newly discovered signaling pathway associated with different liver injuries. Specifically, this review analyzes published data on the downregulation of RECK expression in hepatic ischemia/reperfusion (I/R) injury, liver-related cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), as well as in the progression of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). In addition, this review discusses the regulation of RECK by inducers, such as FXR agonists. The RECK protein has also been suggested as a potential diagnostic and prognostic marker for liver injury or as a biomarker with predictive value for drug treatment efficacy.
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Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Cisteína , Motivos Kazal , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismoRESUMO
To achieve the aim of immediately halting spread of COVID-19 it is essential to know the dynamic behavior of the virus of intensive level of replication. Simply analyzing experimental data to learn about this disease consumes a lot of effort and cost. Mathematical models may be able to assist in this regard. Through integrating the mathematical frameworks with the accessible disease data it will be useful and outlay to comprehend the primary components involved in the spreading of COVID-19. There are so many techniques to formulate the impact of disease on the population mathematically, including deterministic modeling, stochastic modeling or fractional order modeling etc. Fractional derivative modeling is one of the essential techniques for analyzing real-world issues and making accurate assessments of situations. In this paper, a fractional order epidemic model that represents the transmission of COVID-19 using seven compartments of population susceptible, exposed, infective, recovered, the quarantine population, recovered-exposed, and dead population is provided. The fractional order derivative is considered in the Caputo sense. In order to determine the epidemic forecast and persistence, we calculate the reproduction number R 0 . Applying fixed point theory, the existence and uniqueness of the solutions of fractional order derivative have been studied . Moreover, we implement the generalized Adams-Bashforth-Moulton method to get an approximate solution of the fractional-order COVID-19 model. Finally, numerical result and an outstanding graphic simulation are presented.
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Background. Adams-Oliver syndrome is a congenital disease whose main findings are aplasia cutis congenita of the scalp and terminal transverse limb defects. The pathogenesis is unknown, but it is postulated that ischemic events in susceptible tissues cause the lesions in the embryonic period.Case report. We present a newborn with a severe phenotype of Adams-Oliver syndrome. The infant's mother had a SARS-CoV-2 infection in the first trimester of pregnancy. Prenatal ultrasound indicates a probable worsening of the disease after the first trimester.Conclusion. This study shows a previously unpublished severe AOS phenotype in a term newborn. There are some signs that the disease could have progressed beyond the first trimester, either spontaneously or by the inflammatory mechanisms of SARS-CoV-2.
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COVID-19 , Displasia Ectodérmica , Deformidades Congênitas dos Membros , Humanos , SARS-CoV-2 , COVID-19/complicações , Displasia Ectodérmica/complicações , Deformidades Congênitas dos Membros/diagnóstico , Couro Cabeludo/anormalidadesRESUMO
At present, most of the research on hip exoskeleton robots adopts the method of decoupling analysis of hip joint motion, decoupling the ball pair motion of hip joint into rotational motion on sagittal plane, coronal plane and cross section, and designing it into series mechanism. Aiming at the problems of error accumulation and man-machine coupling in series mechanism, a parallel hip rehabilitation exoskeleton structure is proposed based on the bionic analysis of human hip joint. The structure model is established and the kinematics analysis is carried out. Through the OpenSim software, the curve of hip flexion and extension, adduction and abduction angle in a gait cycle is obtained. The inverse solution of the structure is obtained by the D-H coordinate system method. The gait data points are selected and compared with the inverse solution obtained by ADAMS software simulation. The results show that the inverse solution expression is correct. The parallel hip exoskeleton structure can meet the requirements of the rotation angle of the hip joint of the human body, and can basically achieve the movement of the hip joint, which is helpful to improve the human-computer interaction performance of the exoskeleton.
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Exoesqueleto Energizado , Humanos , Articulação do Quadril , Marcha , Fenômenos Biomecânicos , Simulação por ComputadorRESUMO
Leprosy is a granulomatous infection caused by infection with Mycobacterium leprae or M. lepromatosis. We evaluated skin biopsy and slit skin smear samples from 92 leprosy patients in Colombia by quantitative PCR. Five (5.4%) patients tested positive for M. lepromatosis, providing evidence of the presence of this pathogen in Colombia.
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Hanseníase , Mycobacterium , Colômbia/epidemiologia , Humanos , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Hanseníase/microbiologia , Mycobacterium leprae/genéticaRESUMO
PURPOSE: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex. METHODS: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability. RESULTS: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed. CONCLUSION: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.
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Transtorno do Espectro Autista , Displasia Ectodérmica , Transtornos do Neurodesenvolvimento , Humanos , Couro Cabeludo/anormalidades , Couro Cabeludo/metabolismo , Transtorno do Espectro Autista/genética , Células HEK293 , Fator de Transcrição AP-1/genética , Éxons/genética , Displasia Ectodérmica/genética , Transtornos do Neurodesenvolvimento/genética , RNA Mensageiro , Antígeno 2 Relacionado a Fos/genéticaRESUMO
Aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) are the characteristic findings of Adams-Oliver syndrome (AOS). The variable clinical spectrum further includes cardiac, neurologic, renal, and ophthalmological findings. Associated genes in AOS are in the Notch and the CDC42/Rac1 signaling pathways. Both autosomal-dominant and autosomal-recessive inheritances have been reported, the latter with pathogenic variants in DOCK6 or EOGT. The EOGT-associated recessive type of AOS has been postulated to present a more favorable prognosis. We here report a 12-year-old girl from a refugee family of Iraq with consanguineous parents. She was born with a severe phenotype of AOS presenting a large ACC of the scalp with an underlying skull defect, which was often infected and inflamed. Afterward, additional ulceration developed. Furthermore, the girl showed microcephaly, TTLD on both hands and feet, and neurological findings: spastic paresis, epilepsy and suspicion of intellectual deficit. Molecular genetic analysis (next-generation sequencing) revealed a novel frameshift mutation in the EOGT gene in Exon 13 in homozygous constellation: c.1013dupA p.(Asn338Lysfs*24). A biopsy within an ulceration at the scalp ACC showed a cutaneous squamous cell carcinoma (cSCC) with local invasive growth into the dura, the meninges, and the cortex. Treatment including surgical resection and focal irradiation was not curative and the girl deceased 6 months after initial diagnosis. This report on a patient with AOS and an autosomal-recessive EOGT gene variant dying of a local aggressive cSCC at an ACC lesion shows that close monitoring of ACC is essential.
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Carcinoma de Células Escamosas , Displasia Ectodérmica , Deformidades Congênitas dos Membros , Dermatoses do Couro Cabeludo , Neoplasias Cutâneas , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Feminino , Mutação da Fase de Leitura , Humanos , Deformidades Congênitas dos Membros/genética , Mutação , N-Acetilglucosaminiltransferases/genética , Couro Cabeludo/patologia , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Crânio/patologiaRESUMO
Adams-Oliver syndrome (AOS), a rare inherited disorder, is characterized by scalp and terminal limb defects. Several genes associated with Notch pathway mutations have led to AOS. Here, we report a Thai male newborn presenting with aplasia cutis congenita and absence of a right pulmonary artery, which is suggestive of AOS. This was confirmed by the identification of a novel missense mutation in DLL4, a heterozygous one base pair change at nucleotide 82 (c.82G>C, p.Gly28Arg), which is in N-terminal domain. This is the first DLL4-related AOS case with arterial defect.
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Displasia Ectodérmica , Deformidades Congênitas dos Membros , Dermatoses do Couro Cabeludo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação ao Cálcio/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Masculino , Mutação , Artéria Pulmonar , Couro Cabeludo , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genéticaRESUMO
INTRODUCTION: The three dimensional deformation of the spine in scoliosis is specific for a given child with regard to the number and length of curvatures, their degree of rotation and the size of the curvature angle. Early diagnosis of scoliosis in a clinical examination according to the Adams test depends on the correlation between the angle of trunk inclination (ATI) and the Cobb angle and the adopted diagnosis criterion. The aim of the study was to demonstrate the need to adopt different diagnostic criteria for ATI depending on the age and location of scoliosis. Moreover, the observed differences in the ATI/Cobb correlation became the basis for the proposal to introduce the concept of low, medium and high-rotated of curvature to the clinical description of scoliosis. MATERIALS AND METHODS: The group consisted of 229 children who were first examined, aged 6 to 17 years, with an average age of -11.57 years (SD ± 3.26), with symptoms of idiopathic scoliosis. The correlation of the criteria for the diagnosis of scoliosis in the ATI 7° clinical trial with a Cobb angle of 10° three dimensional in the X-ray image was used to distinguish three types of curvature/scoliosis, i.e., low, medium and high rotation. The frequencies of each type were compiled for three age groups and three scoliosis locations. Moreover, the degree of vertebral rotation according to the Perdriolli (AVR) of curvature was correlated with the Cobb angle and ATI. A one-way logistic regression model was used to assess the effectiveness of scoliosis detection in children based on the measurement of the ATI angle alone and the measurement of both ATI and Cobb angles. RESULTS: Low-rotated curves were most often found in the age groups of 6-9 and 10-12 years in 65.6% and 71.4% of patients, respectively (p < 0.05). Medium-rotated curvatures were most common in the age group of 13-17 years - 51.6%. With regard to the localization of scoliosis, the low-rotated curvatures were significantly more frequently (p < 0.05) found in the lumbar and thoracolumbar spine. Moreover, the univariate regression model for ATI showed that we could detect scoliosis best by taking the cut-off point of 5° and the mathematically determined Cobb angle was 9.5°. Patients with ATI ≥ 7° had significantly higher AVR values ââthan those with ATI < 7°, and the ATI/AVR correlation was of average strength. CONCLUSION: The specific morphology of the scoliotic curvature of the child's spine may be manifested by the difference in the ATI/Cobb correlation depending on the location of the scoliosis and change with age. The curvatures of the scoliosis that form can be low, medium and high-rotated, and the low-rotated curvatures were most often found in the 6-9- and 10-12-year-old groups and in the lumbar and thoracolumbar section. To increase the rate of early diagnosis of scoliosis, the results suggest the need to adopt two ATI criteria for the diagnosis of scoliosis at screening, 5° for age of 6-12 years, and when asymmetry affects the lumbar and thoracolumbar section, and 7° for the remaining children.