RESUMO
BACKGROUND: Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non-verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent-report screening measure. PARTICIPANTS AND METHODS: A total of 25 parents of children/adults with a molecularly-confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent-screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. RESULTS: On average, parent ratings on the Math (mean Z = -3.08, SD = 0.87) and Spatial scales (mean Z = -2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = -1.31, SD = 1.46) (Wilcoxon sign rank test Z < -3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. CONCLUSIONS: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis.
Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Criança , Humanos , Anormalidades Múltiplas/genética , Cognição , Transtornos do Crescimento , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Pré-Escolar , AdolescenteRESUMO
BACKGROUND: There is limited information on the frequency of idiosyncratic drug-liver injury (DILI) among cancer patients. The aim of the study was to evaluate the frequency of DILI due to cancer treatment in a population-based setting. MATERIAL AND METHODS: All patients diagnosed with genitourinary cancer, breast cancer or metastatic malignant melanoma in 2007-2018 were matched with a database containing laboratory results for all major hospitals in Iceland. Medical chart review was performed for cases with ALT/AST ≥5× upper limit of normal (ULN), ALP ≥2× ULN or bilirubin ≥2× ULN. Patients with liver-, and/or bone metastases and isolated elevations of ALP and patients with other etiologies of liver enzyme elevations were excluded. Cases with a RUCAM score of probable or highly probable were included. RESULTS: Among 4956 patients, 840 patients had liver enzyme elevations. Overall, nine (0.2%) cases of DILI were identified, seven women (78%), median age 59 years (IQR 52-66). Four patients had kidney cancer, four breast cancer and one metastatic prostate cancer. In eight cases, a single agent was implicated: Pazopanib (n = 3), axitinib, docetaxel, gemcitabine, letrozole and paclitaxel. In all cases, the treatment was interrupted or discontinued due to the liver injury. No patient developed jaundice or liver failure and no death was linked to DILI. Time to normalization of liver enzymes was 17 days (IQR 25-120). CONCLUSION: DILI was found to be rare and no cases of severe liver injury occurred. However, approximately 90% of patients switched to another treatment which might have affected prognosis.
Assuntos
Neoplasias da Mama , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Hepáticas , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Estudos de Coortes , Feminino , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Kabuki (Niikawa-Kuroki) syndrome (KS) is caused by disease-causing variants in either of two components (KMT2D and KDM6A) of the histone methylation machinery. Nearly all individuals with KS have cognitive difficulties, and most have intellectual disability. Recent studies on a mouse model of KS suggest disruption of normal adult neurogenesis in the granule cell layer of the dentate gyrus of the hippocampus. These mutant mice also demonstrate hippocampal memory defects compared with littermates, but this phenotype is rescued postnatally with agents that target the epigenetic machinery. If these findings are relevant to humans with KS, we would expect significant and disproportionate disruption of visuospatial functioning in these individuals. METHODS: To test this hypothesis, we have compiled a battery to robustly explore visuospatial function. We prospectively recruited 22 patients with molecularly confirmed KS and 22 IQ-matched patients with intellectual disability. RESULTS: We observed significant deficiencies in visual motor, visual perception and visual motor memory in the KS group compared with the IQ-matched group on several measures. In contrast, language function appeared to be marginally better in the KS group compared with the IQ-matched group in a sentence comprehension task. CONCLUSIONS: Together, our data suggest specific disruption of visuospatial function, likely linked to the dentate gyrus, in individuals with KS and provide the groundwork for a novel and specific outcome measure for a clinical trial in a KS population.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Face/anormalidades , Doenças Hematológicas/genética , Doenças Hematológicas/fisiopatologia , Deficiência Intelectual/fisiopatologia , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia , Doenças Vestibulares/genética , Doenças Vestibulares/fisiopatologia , Percepção Visual/fisiologia , Adolescente , Adulto , Criança , Disfunção Cognitiva/etiologia , Giro Denteado/fisiopatologia , Face/fisiopatologia , Feminino , Doenças Hematológicas/complicações , Humanos , Deficiência Intelectual/etiologia , Masculino , Estudos Prospectivos , Doenças Vestibulares/complicações , Adulto JovemRESUMO
Drug-induced liver injury (DILI) is an important but rare adverse event which can range from mild liver enzyme elevations to liver failure, transplantation or death. A large proportion of commonly used medications, in addition to herbal and dietary supplements, can cause liver injury. DILI has been categorized as direct or idiosyncratic but indirect liver injury has emerged as a third type of drug-induced liver injury. These types of liver injury may warrant different clinical approach and treatment. Associations of HLA genotypes and risk of DILI have highlighted the importance of the immune system in the pathogenesis of DILI. Furthermore, novel agents affecting the immune response can lead to liver injury, often associated with autoimmune features in serologic tests and liver biopsies. Overall, the diagnosis of DILI remains a challenge as it is requires detailed case evaluation in addition to reviewing the hepatotoxic potentials and clinical signatures of the implicated agents. Biochemical profiles vary between agents and although individual drugs tend to portray a consistent clinicopathologic signature, many drugs have multiple signatures. Thanks to multicenter prospective studies on DILI and websites in the public domain such as LiverTox, physicians are provided with tools to investigate suspected DILI cases to increase the likelihood of establishing adiagnosis. The pathogenesis of DILI, epidemiology and current challenges in the diagnosis and management of the disease are reviewed in the paper.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Fígado/patologia , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Fatores de RiscoRESUMO
AIMS: Moritella viscosa is a Gram-negative psychrophilic bacterium that causes winter ulcer disease in farmed fish. The aim of the study was to describe an outer membrane protein of roughly 20 kDa in pathogenic M. viscosa and to compare the coincident protein of strains isolated from different fish species and geographical locations. METHODS AND RESULTS: The protein was isolated from a pathogenic strain of M. viscosa. An oligopeptide sequence obtained with MS/MS analysis showed homology to Escherichia coli OmpA and Neisseria surface protein A. The protein was named Moritella viscosa outer membrane protein 1 (MvOmp1), and sequence analysis confirmed that it is an integral membrane protein consisting of eight antiparallel ß-strands, three short periplasmic turns and four long hydrophilic extracellular loops. The encoding gene, mvomp1, was fully sequenced in nine strains representing different serotypes and phenotypes. The results revealed some differences in the extracellular loops between strains. The mvomp1 gene was cloned and expressed in E. coli, and the recombinant product was recognized by anti-M. viscosa polyclonal antisera. CONCLUSIONS: The results indicate that MvOmp1 is a major protective antigen of M. viscosa. SIGNIFICANCE AND IMPACT OF THE STUDY: The results open up possibilities for use of the protein as a part of a subunit vaccine in the future.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Moritella/imunologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/genética , Doenças dos Peixes/imunologia , Doenças dos Peixes/patologia , Peixes , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/patologia , Dados de Sequência Molecular , Alinhamento de SequênciaAssuntos
Angiotensinogênio/genética , Pré-Eclâmpsia/genética , Alelos , Sequência de Bases , Feminino , Predisposição Genética para Doença , Humanos , Islândia , Dados de Sequência Molecular , Polimorfismo Genético , Pré-Eclâmpsia/classificação , Pré-Eclâmpsia/etnologia , Pré-Eclâmpsia/urina , Gravidez , Estudos Prospectivos , Proteinúria/etiologia , Sequências Repetitivas de Ácido Nucleico , EscóciaRESUMO
The long term results of Silastic Scaphoid implants are presented in two groups of patients, with osteoarthritis of the radioscaphoid joint without known history of trauma or established pseudarthrosis of the scaphoid bone. The patients in the former group all became satisfied with the operative result whereas in the latter group only half of the patients were satisfied with the result.
Assuntos
Prótese Articular , Osteoartrite/cirurgia , Elastômeros de Silicone , Articulação do Punho , Adulto , Síndrome do Túnel Carpal/etiologia , Comportamento do Consumidor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/etiologia , Complicações Pós-Operatórias , Pseudoartrose/complicações , Inquéritos e QuestionáriosRESUMO
Fluorescein angiography (FA) was performed on 83 patients (68 diabetics) with foot ulcer or gangrene. Densitometric measurements were made on the FA images, and different FA parameters were defined. These parameters, as well as systolic ankle and toe blood pressures, were evaluated for predicting the future course, i.e., whether healing would occur or whether major amputation below or above the knee had to be performed. The toe slope (i.e., the rate of increase of fluorescence on the big toe during the first 10 seconds after its appearance on the toe) predicted healing correctly in 0.83 and major amputation in 0.88. The ankle and toe pressures had only slightly lower predictive value. The combination of ankle pressure and toe slope predicted healing correctly in 0.91 and major amputation in 0.88. When ankle pressure cannot be measured, FA is the method of choice. Further, FA provides information on regional blood flow unobtainable by any other method.
Assuntos
Angiofluoresceinografia , Doenças do Pé/diagnóstico , Úlcera Cutânea/diagnóstico , Adulto , Idoso , Amputação Cirúrgica , Tornozelo/irrigação sanguínea , Pressão Sanguínea , Feminino , Doenças do Pé/fisiopatologia , Doenças do Pé/cirurgia , Gangrena/diagnóstico , Gangrena/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Cutânea/fisiopatologia , Úlcera Cutânea/cirurgia , Dedos do Pé/irrigação sanguínea , CicatrizaçãoRESUMO
Familial predisposition and patterns of genetic inheritance of eclampsia and pre-eclampsia were investigated through three or four generations in 94 families from the homogenous island population of Iceland. The families descended from index women delivered in the years 1931-47 and who had either eclampsia (n = 38) or severe pre-eclampsia (n = 69). Inheritance was followed both through sons and daughters. The prevalence of pre-eclampsia and eclampsia in daughters was significantly higher (23%) than that in daughters-in-law (10%). No difference was noted in the prevalence of these diseases by whether the daughter was born of an eclamptic or pre-eclamptic mother or whether she was a first or later born daughter. There was a non-significantly higher occurrence of pre-eclampsia among grand-daughters than in grand-daughters-in-law. No difference was seen by whether grand-daughters descended through sons or daughters. With increasing numbers of affected daughters or grand-daughters the probability rose of finding more affected women in a family. Hypotheses of single recessive and dominant gene inheritance were compared and maximum likelihood estimates for gene frequency obtained. For a single recessive gene model this was 0.31 reflecting a population prevalence of 9.6%, whereas a dominant model with incomplete penetrance gave 0.14 at 48% gene penetrance, corresponding to a population prevalence of 0.9% homozygous expression of severe disease and 11% heterozygous expression of milder disease. Either genetic model could fit the data.