Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient

Fitting a 3D Morphable Model to Edges: A Comparison Between Hard and Soft Correspondences

We propose a fully automatic method for fitting a 3D morphable model to single face images in arbitrary pose and lighting. Our approach relies on geometric features (edges and landmarks) and, inspired by the iterated closest point algorithm, is based on computing hard correspondences between model vertices and edge pixels. We demonstrate that this is superior to previous work that uses soft correspondences to form an edge-derived cost surface that is minimised by nonlinear optimisation.Comment: To appear in ACCV 2016 Workshop on Facial Informatic

Percentile reference values for anthropometric body composition indices in European children from the IDEFICS study

INTRODUCTION: To characterise the nutritional status in children with obesity or wasting conditions, European anthropometric reference values for body composition measures beyond the body mass index (BMI) are needed. Differentiated assessment of body composition in children has long been hampered by the lack of appropriate references. OBJECTIVES: The aim of our study is to provide percentiles for body composition indices in normal weight European children, based on the IDEFICS cohort (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS). METHODS: Overall 18 745 2.0-10.9-year-old children from eight countries participated in the study. Children classified as overweight/obese or underweight according to IOTF (N = 5915) were excluded from the analysis. Anthropometric measurements (BMI (N = 12 830); triceps, subscapular, fat mass and fat mass index (N = 11 845-11 901); biceps, suprailiac skinfolds, sum of skinfolds calculated from skinfold thicknesses (N = 8129-8205), neck circumference (N = 12 241); waist circumference and waist-to-height ratio (N = 12 381)) were analysed stratified by sex and smoothed 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile curves were calculated using GAMLSS. RESULTS: Percentile values of the most important anthropometric measures related to the degree of adiposity are depicted for European girls and boys. Age-and sex-specific differences were investigated for all measures. As an example, the 50th and 99th percentile values of waist circumference ranged from 50.7-59.2 cm and from 51.3-58.7 cm in 4.5-to < 5.0-year-old girls and boys, respectively, to 60.6-74.5 cm in girls and to 59.9-76.7 cm in boys at the age of 10.5-10.9 years. CONCLUSION: The presented percentile curves may aid a differentiated assessment of total and abdominal adiposity in European children

Understanding disease control: influence of epidemiological and economic factors

We present a local spread model of disease transmission on a regular network and compare different control options ranging from treating the whole population to local control in a well-defined neighborhood of an infectious individual. Comparison is based on a total cost of epidemic, including cost of palliative treatment of ill individuals and preventive cost aimed at vaccination or culling of susceptible individuals. Disease is characterized by pre- symptomatic phase which makes detection and control difficult. Three general strategies emerge, global preventive treatment, local treatment within a neighborhood of certain size and only palliative treatment with no prevention. The choice between the strategies depends on relative costs of palliative and preventive treatment. The details of the local strategy and in particular the size of the optimal treatment neighborhood weakly depends on disease infectivity but strongly depends on other epidemiological factors. The required extend of prevention is proportional to the size of the infection neighborhood, but this relationship depends on time till detection and time till treatment in a non-nonlinear (power) law. In addition, we show that the optimal size of control neighborhood is highly sensitive to the relative cost, particularly for inefficient detection and control application. These results have important consequences for design of prevention strategies aiming at emerging diseases for which parameters are not known in advance

Regulation of the Respiration Quotient Across Ocean Basins

A key uncertainty for predicting future ocean oxygen levels is the response and feedback of organic matter respiration demand. One poorly constrained component of the respiration demand is the oxygen-to-carbon remineralization ratio—the respiration quotient. Currently, multiple biological hypotheses can explain variation in the respiration quotient of organic matter produced in the surface ocean. To test these hypotheses, we directly quantified the particulate respiration quotient in 715 samples along a meridional section of the Atlantic Ocean and compared to previous Pacific Ocean observations. We demonstrate significant regional shifts in the respiration quotient and a two-basin average of 1.16. Possible diel oscillations were also observed in the respiration quotient. Basin and regional variation in the respiration quotient were positively linked to temperature, N versus P stress, and plankton size structure. These observations suggest a complex regulation of the respiration quotient with important implications for the regional coupling of carbon and oxygen cycling

Partial chemical and functional characterization of milk whey products obtained by different processes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Whey protein samples (S-1 to S-5) were tested in vivo and in vitro for nutritional properties and selected bioactivities. Weanling male Wistar rats fed modified AIN-93G (12 g protein. 100 g(-1)) diets for 21 days were used the in vivo studies. The nutritional parameters did not differ among the protein diets tested. Erythrocyte glutathione content was considered high and was higher for S-3, but liver glutathione was the same for all dietary groups. For S-3, cytokine secretion (IL-10 and TNF-alpha) by human peripheral blood mononuclear cells (in RPMI-1640 medium) was higher in the absence of antigen than in the presence of BCG antigen. Interleukin-4 secretion was repressed in all treatments. The IC50, whey protein concentration required to inhibit 50% of the melanoma cell proliferation, was 2.68 mg.mL(-1) of culture medium for the S-3 sample and 3.66 mg.mL(-1) for the S-2 sample. Based on these results, it was concluded that S-3 (whey protein concentrate enriched with TGF-beta and lactoferrin) produced better nutritional and immunological responses than the other products tested.3215664Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CIPED (Pediatrics Investigation Center of the University of Campinas)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

The First Korean Case of Cutaneous Lung Tissue Heterotopia

Cutaneous lung tissue heterotopia is a very rare disorder where mature lung tissues develop in the skin. This is only the second known report of cutaneous lung tissue heterotopia, with the first by Singer et al. in 1998. A newborn infant had a hemangioma-like, freely movable mass connected to the anterior aspect of the sternal manubrium. Pathologic findings showed mature lung tissues with bronchi, bronchioles, and alveoli through the dermis and subcutis, and it was diagnosed as cutaneous lung tissue heterotopia. Cutaneous lung tissue heterotopia is hypervascular, so grossly it looks like a hemangioma. It can be differentiated from pulmonary sequestration, teratoma, bronchogenic cyst, and branchial cleft cyst by histology and the location of the mass. We describe the clinical, radiologic, and pathologic findings of a cutaneous lung tissue heterotopia, the first reported in Korea

A Copine family member, Cpne8, is a candidate quantitative trait gene for prion disease incubation time in mouse

Prion disease incubation time in mice is determined by many factors including genetic background. The prion gene itself plays a major role in incubation time; however, other genes are also known to be important. Whilst quantitative trait loci (QTL) studies have identified multiple loci across the genome, these regions are often large, and with the exception of Hectd2 on Mmu19, no quantitative trait genes or nucleotides for prion disease incubation time have been demonstrated. In this study, we use the Northport heterogeneous stock of mice to reduce the size of a previously identified QTL on Mmu15 from approximately 25 to 1.2 cM. We further characterised the genes in this region and identify Cpne8, a member of the copine family, as the most promising candidate gene. We also show that Cpne8 mRNA is upregulated at the terminal stage of disease, supporting a role in prion disease. Applying these techniques to other loci will facilitate the identification of key pathways in prion disease pathogenesis

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

A

Abstract:&nbsp; Human Bocavirus-1/HBoV1 causes acute respiratory infections/ARI (bronchiolitis/pneumonia) mostly in young children. It was identified in 2005 and has not yet been incorporated into the routine virus screening in ARI. Symptoms of viral pneumonia in children less than 2 years old are often interpreted as of bacterial etiology, leading to unnecessary administration of antibiotics. Objective: to report the case of a previously healthy infant who developed HBoV1 pneumonia without complications, in order to consider HBoV1 as one of the possible agents involved. Clinical case. 19-month-old female, full-term/2780 grams. No relevant personal or familiar pathological history; complete vaccination. Reason for consultation: fever, cough, and shortness of breath. Antecedents: 3 days before, she started with rhinitis and dry cough. She had a fever peak of 38.7°C, so her pediatrician prescribed oral amoxicillin. On Apr/26/2021 she went to the emergency service due to persistent fever and worsening cough. Mild/moderate respiratory distress was observed; inhaled adrenergic drugs were administered, with good clinical response and outpatient follow-up (prior swabbing for COVID-19). The next day, she returned with food rejection and was hospitalized. Laboratory: hemoglobin 10.9g/dl, hematocrit 34%; leukocytes: 15,380 (69/15/15); platelets 299,000/ml; gases: 7.48/27.2/84.2/19.9/-2.1); ionogram Na 134/K 4/Cl 100; CRP: 17.8. Chest X-ray compatible with viral pneumonia. O2 saturation: 93%. Amoxicillin was suspended; hydration, oxygen by nasal cannula (3 liters/min) and inhaled salbutamol were administered. The complete panel of respiratory viruses was negative (RSV, Parainfluenza 1-3, Metapneumovirus, Influenza A/B and Adenovirus by IF; PCR for COVID-19: negative). HBoV1 detected in nasal secretions and serum (PCR with high viral load/&gt;1x106 c.gen/mL) was the only positive finding. Evolution: 48 hours after admission she was afebrile; O2 saturation 95%; supplementary oxygen therapy was suspended. Patient was discharged without complications. In the follow-up (10 days) she did not show relapses or respiratory symptoms, so aerosol therapy was suspended. Conclusions. A case of HBoV1 infection in an infant with no comorbidity is reported. Recognition of the viral etiology in hospitalized cases of pneumonia contributes to optimize the clinical management of patients with rational use of antibiotics. HBoV1 should be included in the standard screening for respiratory infections in hospitalized infants.Resumen:&nbsp; Bocavirus humano-1/HBoV1 es un parvovirus que causa infecciones respiratorias/IRA (bronquiolitis o neumonía) sobre todo en niños pequeños. Fue identificado en 2005 y aún no está incorporado a la pesquisa de virus habituales en IRA. Los cuadros de neumonía viral en menores de 2 años suelen interpretarse como de etiología bacteriana, administrándoles antibióticos innecesariamente. Objetivo: Reportar el caso de una lactante, sin comorbilidades previas, que desarrolla neumonía por HBoV1 sin complicaciones, a fin de considerar a este virus como uno más de los posibles agentes involucrados. Caso clínico. Paciente femenina de 19 meses de edad, nacida a término/2780gramos. Sin antecedentes patológicos, ni familiares relevantes; vacunación completa. MC: fiebre, tos y dificultad respiratoria. Antecedentes: 3 días previos inicia con rinitis y tos seca. Presenta un pico febril de 38,7°C por lo que su pediatra prescribió amoxicilina vía oral. El día 26/04/2021 concurre al servicio de emergencia por persistencia de la fiebre y empeoramiento de la tos. Se objetiva dificultad respiratoria leve/moderada; se administra adrenérgicos inhalados, con buena repuesta clínica y seguimiento ambulatorio (previo hisopado para COVID-19). Al día siguiente, ante el rechazo alimentario se decide internación. Laboratorio: Hemoglobina 10.9g/dl-Hto 34%; GB:15.380(69/15/15); plaquetas 299.000/ml; Gases:7.48/27.2/84.2/19.9/-2.1); Ionograma (Na134/K4/Cl100); PCR:17.8. Rx tórax compatible con neumonía viral. SatO2:93%. Se suspende amoxicilina, se administra hidratación, oxígeno por naricera-3litros/min y salbutamol inhalado. El panel completo de virus respiratorios resultó negativo (IFI para VRS, Parainfluenza 1,2,3, Metapneumovirus, Infuenza A y B y Adenovirus; PCR para COVID-19: negativo). Detección de HBoV1 en secreciones nasales y suero (PCR positiva con alta carga viral/&gt;1x10^6c.gen/mL) fue el único hallazgo positivo. Evolución: a las 48 hs. del ingreso estaba afebril; Sat 95%; se suspende oxigenoterapia. Alta sin complicaciones. El seguimiento (hasta 10 días) no mostró recaídas o sintomatología respiratoria por lo que se suspende aerosolterapia. Conclusiones. Se reporta un caso de infección por BoVH1 en lactante sin comorbilidad previa. El reconocimiento de la etiología viral en los cuadros hospitalizados por neumonía contribuye a optimizar el manejo clínico de estos pacientes con uso más racional de antibióticos. La detección de BoVH1 debería ser parte de la pesquisa estándar para infecciones respiratorias en lactantes hospitalizados