Assessing the utility of autofluorescence-based pulmonary optical endomicroscopy to predict the malignant potential of solitary pulmonary nodules in humans

Solitary pulmonary nodules are common, often incidental findings on chest CT scans. The investigation of pulmonary nodules is time-consuming and often leads to protracted follow-up with ongoing radiological surveillance, however, clinical calculators that assess the risk of the nodule being malignant exist to help in the stratification of patients. Furthermore recent advances in interventional pulmonology include the ability to both navigate to nodules and also to perform autofluorescence endomicroscopy. In this study we assessed the efficacy of incorporating additional information from label-free fibre-based optical endomicrosopy of the nodule on assessing risk of malignancy. Using image analysis and machine learning approaches, we find that this information does not yield any gain in predictive performance in a cohort of patients. Further advances with pulmonary endomicroscopy will require the addition of molecular tracers to improve information from this procedure

LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Symptomatic hypopituitarism revealing a primary empty sella turcica

A 64-year-old nulliparous women presented with clinical signs of thyroid and adrenocortical insufficiency. Subsequent hormonal investigations demonstrated a failure of all anterior pituitary functions. Pneumotomo-encephalography revealed a large arachnoid herniation, leading to the diagnosis of primary empty sella turcica syndrome with secondary panhypopituitarism. This unusual observation emphasizes the necessity of ruling out an empty sella turcica syndrome in patients with pituitary insufficiency.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Análise de cargas acidentais em pavimentos de garagem

O trabalho tem como foco a análise das cargas acidentais utilizadas para pavimentos de garagem, considerando as recomendações de normas nacionais e internacionais para a definição do valor das cargas a serem aplicadas nas lajes nervuradas. A norma brasileira NBR 6120/1980 [1], que trata do assunto, não especifica nada em relação a cargas concentradas, enquanto normas internacionais como Euro Code [2] e IBC [3], recomendam considerar cargas distribuídas e concentradas. Atualmente, as lajes nervuradas são utilizadas amplamente em pavimentos de garagem. Neste contexto, considerando os padrões de veículos mais utilizados no país, será que os valores de cargas distribuídas das normas são adequados para o dimensionamento das lajes nervuradas? Ou é necessário fazer uma correção destas cargas para levar em consideração as cargas concentradas da ordem de 8,5 kN por pneu correspondente a um veículo utilitário. O objetivo deste trabalho é procurar as respostas para estas duas perguntas através de uma análise paramétrica envolvendo os principais parâmetros de uma laje nervurada, que são: a relação (lambda) entre os lados, a distância entre as nervuras principais e o esquema de apoio da laje (uni ou bidirecional). De uma forma geral o conjunto das simulações mostra que as cargas recomendadas pelas normas citadas precisariam de correção quando utilizadas em pavimento de garagem para reproduzir o efeito das cargas concentradas das rodas de veículos tipo utilitário

Immediate and delayed alterations of adrenocorticotropin and cortisol nyctohemeral profiles after corticotropin-releasing factor in normal man.

Intravenous injections of 50 micrograms corticotropin-releasing factor (CRF) to four normal men at 0900 and 2300 h were followed by significant plasma ACTH and cortisol elevations, without changes in GH and PRL concentrations. The responses were more easily assessed late in the evening than in the morning, when they were superimposed upon the spontaneous hormonal variations. The initial hormonal response was always followed by a period of decreased hormonal values compared to control patterns. The normal pituitary-adrenal response to CRF was blunted or abolished by prior administration of dexamethasone. These data suggest that exogenous administration or CRF-induced endogenous production of glucocorticoids modulates the sensitivity of corticotropic cells to the action of CRF. Since normal ACTH and cortisol secretory episodes are likely to obscure the effects of CRF, stimulation tests for clinical purposes should be performed during the quiescent period, i.e. late in the evening.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

A hypomorphic BMPR1B

Background: Grebe dysplasia, Hunter-Thompson dysplasia, and du Pan dysplasia constitute a spectrum of skeletal dysplasias inherited as an autosomal recessive trait characterized by short stature, severe acromesomelic shortening of the limbs, and normal axial skeleton. The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5. In single instances, Grebe dysplasia and a Grebe dysplasia-like phenotype with genital anomalies have been shown to be caused by mutations in BMPR1B, encoding a GDF5 receptor. Methods: We clinically and radiologically characterised an acromesomelic chondrodysplasia in an adult woman born to consanguineous parents. We sequenced GDF5 and BMPR1B on DNA of the proposita. We performed 3D structural analysis and luciferase reporter assays to functionally investigate the identified BMPR1B mutation. Results: We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation. We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia. Conclusions: The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B