Expanding the genetic landscape of oral-facial-digital syndrome with two novel genes.

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.

Human amniotic membrane for the treatment of large and refractory macular holes: a retrospective, multicentric, interventional study.

BACKGROUND: The purpose of the current study is to report the anatomical and functional results of off-label human amniotic membrane graft as primary intervention to repair large to giant macular holes and in reoperations when wide internal limiting membrane peeling was unsuccessful. METHODS: Retrospective chart review was carried out in five different centers to identify all cases that had undergone off-label human amniotic membrane graft for the treatment of large or failed macular holes (MH). Data collected included age, gender, other concomitant diagnosis, symptoms duration, lens status, number of previous surgeries, macular hole measurements (minimum and base linear diameters), mean post-operative follow-up (months), and pre- and post-operative best corrected visual acuity (BCVA). Main outcome measures were anatomical MH closure rates and final BCVA (in logMAR). Nonparametric Wilcoxon rank-sum test was used because the data was not normally distributed, a P values < 0.05 were considered statistically significant. RESULTS: Nineteen eyes of 19 patients were identified and included in the study. Mean age was 66.21 ± 14.96 years and predominantly females (84%). All eyes had successfully closed MH with a single intervention with no recurrences during a mean of 9 ± 3.87 months follow-up. The median BCVA in logMAR preoperative was 1.30 ± 0.44 (0.80-2.0), approximately 20/400 on Snellen chart and the median BCVA in logMAR postoperative was 1.0 ± 0.72 (0.4-3.0) approximately 20/200 (p < 0.0001) with median of three lines of visual improvement. CONCLUSION: The use of human amniotic membrane graft seems to be a viable and effective alternative for the treatment of large and persistent macular holes. However, further larger prospective controlled studies are necessary to confirm our preliminary results of this new surgical technique.

Epidemiologia das urgências e emergências oftalmológicas em um Hospital Universitário Terciário / Epidemiologic profile of ophthalmic emergencies in a Tertiary University Hospital

Resumo O estudo buscou analisar e estudar a prevalência e as circunstâncias de urgências e emergências oftalmológicas no Pronto Socorro do Hospital de Clínicas de Uberlândia da Universidade Federal de Uberlândia (HCU-UFU) e no Ambulatório Amélio Marques no período de agosto de 2016 a agosto de 2017. Faz-se necessário tal estudo, pois emergências oftalmológicas são importantes causas de morbidades na sociedade(1). Ademais, através dele políticas de prevenção poderão ser feitas, além de maior capacitação de profissionais a partir do conhecimento das principais causas de atendimento. A metodologia proposta incluiu a coleta de dados do prontuário, sendo colhidas as informações sexo, idade e ocupação/profissão. Trata-se de um estudo epidemiológico exploratório observacional predominantemente descritivo do tipo transversal. O trabalho evidenciou que o sexo masculino foi o mais acometido e a faixa etária mais incidente foi entre 19 e 45 anos. Das causas de procura pelo pronto-atendimento oftalmológico, o trauma ocular por corpo estranho é a mais comum havendo uma estreita relação com as atividades laborais (mecânicos e ferragistas). Dessa forma, os dados serão um recurso importante para o auxiliar na compreensão do perfil epidemiológico do pronto-atendimento oftalmológico visando otimizar a administração do mesmo e para estimular a adoção de políticas públicas de prevenção no âmbito da saúde do trabalhador.

Abstract The study aimed to analyze and study the prevalence and circumstances of ophthalmic emergencies and urgencies in the Emergency Room of the Hospital de Clínicas de Uberlândia and the Central Ambulatory (Amélio Marques) of the Federal University of Uberlândia (HCU-UFU) from August 2016 to August 2017. This is a necessary study since ophthalmic emergencies are important causes of morbidities in society(1). In addition, this study will help to develop prevention policies and to make greater training of professionals based on knowledge of the main causes of eye emergencies. The proposed methodology included the collection of data from the medical record, with the information of sex, age and occupation/profession being collected. This is an observational, descriptive, transversal, exploratory epidemiological study. The study showed that males were the most affected and the most incident age group was between 19 and 45 years old. Eye trauma due to a foreign body is the most common cause of demand for ophthalmologic emergency care with a close relationship with work activities (mechanics and ironmongers). In this way, the data will be an important resource to assist in understanding the epidemiological profile of the ophthalmology emergency room in order to optimize its administration and to encourage the adoption of public prevention policies within the scope of occupational health.

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy.

BACKGROUND: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also known as Wolman disease. We sought to determine the outcomes and clinical needs of infants diagnosed with LAL-D, treated with enzyme replacement therapy (ERT). METHODS: A chart review was conducted on two infantile-onset LAL-D patients to determine clinical outcomes based on laboratory results, abdominal imaging, growth and dietary records, cardiology, endocrinology, ophthalmology, hematology, and neurocognitive evaluations. RESULTS: Two patients, both diagnosed and treated before 6 months old, demonstrated clinical improvement following weekly ERT. They required dosage increases to optimize growth and symptomatology. Both received a formula low in long chain triglycerides and high in medium chain triglycerides, an intervention that allowed significant catch-up growth. Patient 1 required treatment for partial adrenal insufficiency and hypothyroidism. Both patients demonstrated reduction in liver and spleen size and varying degrees of improved liver function. Neither experienced serious adverse reactions to ERT. CONCLUSION: ERT has led to longer and healthier survival of affected infants. It is imperative that dietary interventions and systemic clinical care become integral to the management. Continued evidence of survival and clinical improvement in this population, coupled with available mass spectrometry enzyme assay from dried blood spots, raises the question of this rare and possibly underdiagnosed disorder's candidacy for newborn screening.

A Case of Reversible Infantile Respiratory Chain Deficiency Presenting With Hypotonia, Hyperammonemia, and Failure to Thrive.

Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation. After several tests, a distinct genetic syndrome could not be identified and she continued to deteriorate. A muscle biopsy was performed and demonstrated severe mitochondrial myopathy with abundant COX-negative fibers. Ultrastructural abnormalities of the mitochondria, diagnostic of mitochondrial myopathy, were identified on electron microscopy. Molecular studies revealed the classic homoplasmic disease causing mutation, m.14674 T>C in the MT-TE gene, associated with reversible COX deficiency. Although hyperammonemia is an unusual presentation for mitochondrial myopathies, specifically reversible infantile respiratory chain deficiency, it should be included in the list of possible presenting symptoms for this condition.

De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects.

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

Biotinidase deficiency: novel mutations and their biochemical and clinical correlates.

Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder. Two nonsense mutations, eight single missense mutations, three allelic double missense mutations, and two are polymorphisms were identified in the biotinidase gene (BTD). One of the missense mutations, c.734G>A (p. C245Y), is the first to be reported that alters the cysteine in the putative location crucial for ester formation and binding of the biotinyl-moiety in the active site of the enzyme. These mutations add to the growing list of mutations that are helping to delineate structure/function relationships of the enzyme.

Padronizaçäo do método polarográfico no tumor de Walker em ratos Wistar / Standardization of polarography in Walker tumor inoculated in Wistar rats

Estudo polarográfico foi realizado em 15 ratos Wistar inoculados com tumor de Walker 256, implantando-se eletrodos de platina no tumor e no músculo, com o objetivo de padronizaçäo da polarografia no tumor de Walker 256. Os níveis de oxigênio foram sempre menores no tumor do que no músculo, tanto em condiçöes basais como após a oxigenaçäo. A resposta à oxigenaçäo foi mais lenta no tumor do que no músculo

Action of diclofenac sodium on the small intenstine of the rat after interruption of fecal peritonitis. Study of breaking strenth and of tissue collagen concentration

The objective of the present study was to investigate the biomechanical changes of the small intestinal wall occurring in fecal peritonitis associated with diclofenac sodium (DS). Wistar rats were divided at random into the following groups: Group 1 (DS), 60 animals that received an intramuscular injection of diclofenac sodium at the dose of 2 mg/kg body weight; Group 2 (Per), 60 animals that received an intraperitoneal injection of a suspension of human feces, with interruption of peritonitis after 6 hours; Group 3 (Per+DS), 60 animals that received an intraperitoneal injection of a suspension of human feces and DS according to the same scheme as used for Groups 1 and 2; Control Group, 12 animals injected intramusculary. The animals in Groups 1, 2 and 3 were successively sacrificed on the 2nd, 7th and 14th days after the interruption of peritonitis and/or the beginning of treatment, when breaking strength was determined and tissue hydroxyproline was measured. No deaths occured among DS animals, two deaths occurred in the Per group and six the Per+DS group between the 2nd and 12th postoperative day. The breaking strength of the DS group returned to normal levels on the 14th day of treatment, whereas in the Per and Per+DS groups the breaking strength continued to be below normal levels. On the basis of the experimental conditions and methods used, we conclude that diclofenac sodium and peritonitis decrease the breaking strenght and the tissue collagen of the small intestine. When peritonitis was associated with diclofenac sodium there was a summation of the deleterious effects observed separately in the Per and DS groups.

Estudo polarográfico da isquemia renal no cäo: açäo do manitol / Polarographic study of renal ischaemia in dog: manitol effect

Um estudo polarográfico do oxigênio renal, no córtex e na medula, antes e após isquemia renal foi realizado em 27 caes anestesiados, implantando-se 2 eletrodos de platino no rim esquerdo. A pesquisa teve como objetivo o estudo do fenômeno "no-reflow" após 2 e 3 horas de isquemia renal sob proteçao do manitol. A polarografia detectou o fenômeno "no-reflow" e demonstrou o efeito protetor do manitol na isquemia renal.

Estudo polarográfico do oxigênio renal no cäo: açäo do manitol / Polarographic study of renal oxygen in dog: mannitol action

Um estudo polarográfico do oxigênio renal, no córtex e na medula, foi efetuado em 19 cäes anestesiados, implantando-se 2 eletrodos de platina no rim esquerdo. A pesquisa teve como objetivos o estudo do método polarográfico e da açäo do manitol. Foram estudados os atributos: intensidade basal (ib), intensidade máxima (imax) e intervalo (I). A pesqusia constou de 2 grupos: grupo 1 (controle) e grupo 2 (administraçäo endovenosa de manitol). Os valores de ib e imax encontrados no córtex foram menores do que os da medula. Näo houve diferença significante nos atributos estudados entre o início e o fim da experiência (grupo 1). No grupo 2 o manitol determinou uma diminuiçäo de ib e um aumento de I

Avaliacao do PH esofagico durante 24 horas e seu emprego no diagnostico do refluxo gastro-esofagico em criancas / Evaluation of the PH esophagic during 24 hours and its use in diagnosis of the gastroesophageal reflux in childreens

O estudo do PH esofagico durante 24 horas foi realizado em 50 criancas divididas em 2 grupos: grupo I - portadoras de sintomas de refluxogastroesofagico (n=41) e grupo II - sem sintomas de refluxo gastroesofagico (n=9). As criancas sintomaticas foram divididas em 3 subgrupos IA - sintomas digestivos; grupo IB - sintomas respiratorios, e grupo IC sintomas digestivos e respiratorios. Nas criancas do grupo IA o indice de positividade do exame foi de 90%, enquanto que nos grupos IB e IC os indices foram de 30% e 72%, respectivamente. Os parametros mais importantes no diagnostico do refluxo gastroesofagico foram oNER com duracao superior a 5 e 15 minutos e a porcentagem do tempo em que o ph esofagico se apresentou foi inferior a 4 unidades. O estudo do ph esofagico durante 24 horas mostrou-se util no diagnostico do refluxo gastroesofagico em criancas.

Efeito de antiácido e bloqueadores dos aceptores H2 sobre a secreçäo gástrica do cäo / Effect of antiacid and H2 blockers on gastric secretion of the dog

Em dez cäes machos, foi estudado o efeito do hidróxido de alumínio, cimetidine e ranitidine sobre a secreçäo gástrica. Ocorreu elevaçäo do PH do estômago após o uso de cimetidine e ranitidine; após a ingestäo do hidróxido de alumínio näo foi observada nenhuma alteraçäo

Does the oxygen tension of coronary sinus blood reflect myocardial oxygen tension?

Coronary sinus blood oxygen tension (CSpO2) and myocardial oxygen tension (MpO2) were measured sismsultaneously during cardiac ischemia and reperfusion. Oxygen tension was measured using a decrease (56.5) ñ 10.1%; P < 0.001) in MpO2. Reperfusin induced a rapid but transient increase (35.9 ñ 4.3%; P < 0.001) in CSpO2 above the basal state while MpO2 returned gradually to the basal state. These results indicate that CSpO2 is of little value for the detection of changes in myocardial oxuigen metabolism during the initial phase (seconds) of cardiac reperfusin

Estudo comparativo de anastomoses no intestino delgado de cäo: estudos da força de ruptura, hidroxiprolina tecidual e anatomo patológico / Comparative study of smale bowel anastomosis in dogs: breapina strenght; hidroxyproline concentration; and hystopathologic study

Este trabalho tem como objetivo estudar a avaliaçäo da cicatrizaçäo de 3 tipos de anastomoses no intestino delgado do cäo: Sutura em plano único extramucosa com pontos separados ou contínua e a sutura contínua em dois planos. O estudo comparativo foi realizado através da medida da força de ruptura, dosagem de hidroxiprolina tecidual e o estudo anatomopatológico da cicatriz. Foram utilizados 32 cäes, distribuídos em 4 grupos experimentais, constituídos de 8 animais qur foram estudados no 3§, 7§, 14§ e 21§ dias de pós-operatório. No intestino delgado de cada cäo foram realizados os 3 tipos de anastomoses preconizados tendo como referência o ligamento de Treitz. Em relaçäo as suturas em plano único, näo observamos diferenças quanto a força de ruptura e concentraçäo de hidroxiprolina. O exame histológico evidenciou que a sutura com pontos separados oferece melhores condiçöes para a coaptaçäo da ferida cirúrgica. A sutura contínua em 2 planos näo ofereceu resistência as anastomoses, quando comparadas as suturas em plano único. A integridade desta anastomose é mantida apenas pela sutura sero-muscular, por ocorrer necrose precoce, do tecido englobado pela sutura perfurante tortal. Näo observamos correlaçäo entre as força de ruptura das anastomoses e a concentraçäo de hidroxiprolina tecidual

Influência da vagotomia gástrica proximal sobre a zona de alta pressäo esofagogástrica do cäo / Influence of parietal cell vagotomy on esophagogastric high pressure zone in dog

Em 30 cäes foi estudada a influência da vagotomia gástrica proximal (VGP) sobre a zona de alta pressäo (ZAP) esofagogástrica (pressäo e comprimento). Os animais foram divididos em três grupos: grupo 1, dez cäes submetidos a VGP com desnervaçäo gástrica até a transiçäo eosfagogástrica (TEG); grupo 2, dez cäes submetidos a VGP com desnervaçäo gástrica até a TEG e esofágica, interessando os 3 cm distais, e grupo 3 (controle), dez cäes submetidos apenas à laparotomia, sem realizaçäo de VGP. No período pós-operatório (imediato e tardio), näo foi observada qualquer alteraçäo da pressäo e comprimento da ZAP esofagogástrica no três grupos estudados

Efeito de antiácido e bloqueadores H2 sobre a zona de alta pressao esofagogástrica do cäo / Effect of antiacido and H2 blockers on high pressure zone of esophagogastric funciton in dog

Em dez cäes machos, foi estudado o efeito da administraçäo oral de antiácido (hidróxido de alumínio) e bloqueadores H2 (cimetidina e ranitidina) sobre a zona de alta pressäo esofagogástrica (amplitude de pressäo e comprimento). Näo foram observadas modificaçöes na pressäo e comprimento na zona de alta pressäo esofagogástrica após a administraçäo das três drogas

Estudo da resistência (força de ruptura) das anastomoses intestinais em plano único e em dois planos / Study on the resistance (breaking strength) of intestinal anastomoses in on and two layer's suture

A força de ruptura de três técnicas de anastomose realizadas no intestino delgado do cäo foi avaliada através de um instrumento de medida especialmente construído para este fim: sutura contínua em dois planos e sutura contínua e com pontos separados em plano único. Os resultados obtidos näo permitiram observar diferenças entre as três suturas estudads, no 3§, 7§, 14§, 21§ dias de pós-operatório. Conclui-se que, apesar da impressäo de segurança da anastomose com sutura contínua em dois planos, esta näo lhe confere maior resistência mecânica

Changes in myocardial and coronary sinus blood oxygen tension induced by asphysia and reoxygenation

This study analyzes variations of oxygen tension induced by asphyxia in the myocardium (MpO2) and coronary sinus blood (CSpO2) of the anesthetized open-chest dog. Oxygen tension was measured polarographically and arterial blood pressure and coronary blood flow were recorded simultaneously. Asphyxia increased arterial pressure and coronary blood flow but decreased both MpO2 and CSpO2. During the reoxygenation phase, arterial pressure and coronary flow decreased gradually. Reoxygenation induced a rapid but transient increase in CSpO2 above control levels. In contrast, MpO2 returned gradually to the basal state. The mechanisms(s) involved in the differential effects of asphyxia followed by reoxygenation on MpO2 and CSpO2 remain to be elucidated