64 research outputs found
PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.
PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation
Lung epithelial stem cells and their niches : Fgf10 takes center stage
Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)
Convergence, divergence and hybridity: a regulatory governance perspective on health technology assessment HTA) in England and Germany
Countries adopt different methods and processes to evaluate the benefits and costs of health technologies. It is important to identify and analyse the factors that influence the uptake and use of these methods and processes across countries. In this paper, we introduce a regulatory governance approach to the analysis of convergence, divergence and hybridity in HTA methods, discussing and critically analysing national processes for HTA in two major European Union (EU) Member States: England and Germany. We argue that any reasonably sophisticated account of national approaches to HTA must recognise that globalisation and the emergence of advanced industrial society involves the potential for widely varying processes, methods and evidential requirements. We suggest that this potentiality also confronts health policy analysts with the challenge of constructing analytical frameworks capable of identifying the diverse institutional, domestic and other factors that shape national approaches to HTA
Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency
This is the final version. Available on open access from Elsevier via the DOI in this recordData Availability:
The variants listed in this paper have been deposited in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) with accessions SCV001572828 - SCV001572838.PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants. RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein. CONCLUSION: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition
Multi-messenger observations of a binary neutron star merger
On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta
7000 years of turnover: historical contingency and human niche construction shape the Caribbean's Anthropocene biota
A Critical Appraisal of the Pain Associated with Iatrogenic Adult Spinal Deformity, and Treatment by Spinal Cord Stimulation. A Case Report and Review of the Literature
Padrão de acometimento da coluna cervical na artrite reumatoide: seguimento de 6 anos Cuadro de afectación de la columna cervical en la artritis reumatoidea: seguimiento de 6 años Pattern of involvement of the cervical column in rheumatoid arthritis: a 6 year follow up
OBJETIVOS: Foi avaliado o padrão de acometimento cervical em pacientes com diagnóstico de artrite reumatoide, correlacionando-se os achados de imagem com quadro neurológico, medicação utilizada, tempo de evolução da doença, idade de início da doença, exames laboratoriais e quadro clínico. MÉTODOS: Esse mesmo grupo de pacientes tinha sido estudado há 6 anos, e esses dados foram comparados para avaliar se houve piora do padrão de acometimento ao longo do tempo. Foram feitas radiografias simples da coluna cervical, nas incidências ântero-posterior, perfil neutro e dinâmico. A classificação de Ranawat foi utilizada para avaliar a sintomatologia dolorosa e o envolvimento neurológico. Foram utilizados os testes de regressão logística univariada (p < 0,05). RESULTADOS: Foram avaliados 24 dos 35 pacientes que compuseram a amostra anterior, havendo perda de seguimento de 7. Encontramos algumas correlações estatisticamente significativas: reflexo bicciptal (p = 0,049) e método de Ranawat (p = 0,023, no raio-x em extensão e p = 0,034, no raio-x neutro) com coluna estável, erosão do dente do áxis (p = 0,048) e subluxação lateral (p = 0,022) com instabilidade atlanto-axial e sinal de Lhermithé (p = 0,025) com invaginação basilar. Instabilidade cervical foi encontrada em 66,6% (16/24), havendo um aumento estatisticamente significante da instabilidade subaxial nos últimos 6 anos (p = 0,032). CONCLUSÕES: Em ordem decrescente, as instabilidades foram: subluxação atlanto-axial com 50%, subluxação subaxial com 41,6% e invaginação basilar com 16,6%. Houve um aumento no número de pacientes com instabilidade subaxial, não se observando correlação com a faixa etária de acometimento. Também não se observou correlação do reflexo biciptal com qualquer tipo de instabilidade e sim com a coluna cervical estável, resultado diferente do encontrado anteriormente.<br>OBJETIVOS: Fue evaluado el cuadrode afectación cervical en pacientes con diagnóstico de artritis reumatoidea, correlacionando los hallazgos de imagen con cuadro neurológico, medicación utilizada, tiempo de evolución de la enfermedad, edad del paciente alinicio de la enfermedad, exámenes de laboratorio y cuadro clínico. MÉTODOS: Ese mismo grupo de pacientes había sido estudiado 6 años antes, y esos datos recolectados fueron comparados para evaluar si hubo un empeoramiento del cuadrode afectacióna lo largo del tiempo. Se hicieron radiografías simples de la columna cervical, en las incidencias antero posterior, perfil neutro y dinámico. La clasificación de Ranawat fue utilizada para evaluar la sintomatología dolorosa y la involucración neurológica. Se utilizaron las pruebas de regresión logística univariada (p<0,05). RESULTADOS: Evaluados 24 de los 35 pacientes que formaron parte de la muestra anterior, habiendo pérdida de seguimiento de 7. Encontramos algunas correlaciones estadísticamente significativas: reflejo bicipital (p=0,049) y método de Ranawat (p=0,023, en el Rayo X en extensión a p=0,034, en el Rayo X neutro) con columna estable, erosión del odontoide (p=0,048) y subluxación lateral (p=0,022) con inestabilidad atlanto-axial y señal de Lhermithé (p=0,025) con invaginación basilar. Se ha encontrado inestabilidad cervical en un 66,6% (16/24), habiendo un aumento significativamente estadístico de la inestabilidad subaxial en los últimos 6 años p=0,032). CONCLUSIONES: En orden decreciente, las inestabilidades han sido estas: subluxación atlantoaxial con un 50%, subluxación subaxial, con un 41,6% e invaginación basilar, con un 16,6%. Hubo un aumento en el número de pacientes con inestabilidad subaxial, aunque no se ha observado correlación de ese tipo de inestabilidad con el nivel de edad de afectación. Tampoco se ha observado correlación del reflejo bicipital con cualquier tipo de inestabilidad, sino con la columna cervical estable, resultado distinto del que había sido encontrado en la serie anterior.<br>OBJECTIVE: The long-term pattern of cervical involvement in patients with a diagnosis of rheumatoid arthritis was investigated, correlating the imaging findings with neurological symptoms, medication used, duration of the disease, age of onset, laboratory tests and clinical picture. METHODS: This same group of patients had already been studied for some time, and data were compared to verify if there was a worsening of the involvement pattern throughout time. Plain X-rays were obtained from the cervical column, in anteroposterior and neutral and dynamic lateral views. The Ranawat classification was used to evaluate pain symptoms and neurological involvement. For the analysis, the authors used the univariate logistic regression tests (p<0.05). RESULTS: Twenty-four of the 35 patients from the previous sample were evaluated and seven were lost to follow up. The authors found some statistically significant correlations: bicipital reflex (p=0.049) and the Ranawat method (p=0.023 with extension X-ray and p=0.034 with a neutral X-ray) with a stable column, erosion of the dens axis (p=0.048) and lateral subluxation (p=0.22) with atlanto-axial instability and the Lhermitte signal (p=0.025) with basilar invagination. Cervical instability was found in 66.6% (16/24) of the patients, and there was a significant statistical increase of the subaxial instability for the past 6 years (p=0.032). CONCLUSIONS: In a decreasing order of occurrence, the authors were able to verify the following types of instability: atlanto-axial subluxation, 50%; subaxial subluxation, 41.6%; and basilar invagination, 16.6%. An increase in the number of patients with subaxial instability was verified, and no correlation was observed regarding the age of onset. Additionally, no correlation was found between the bicipital reflex and any type of instability but rather with a stable column, and this result is different from what the authors obtained in the previous series
Dengue epidemics in the Caribbean-temperature indices to gauge the potential for onset of dengue
Caribbean dengue epidemics, Climate variability, Correlations, Disease onset, Heat build up, Lapse and lead time, Mosquito breeding environments, Moving average temperature, Statistical lag,
- …