The Clinical Heterogeneity of Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)-A Report of Three Cases, Including Twins.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320, ORPHA:98920) is a rare autosomal recessive congenital motor neuron disease. It is caused by variants in the IGHMBP2 gene. Clinically, it presents with respiratory failure due to diaphragmatic paralysis, progressive muscle weakness starting in the distal parts of the limbs, dysphagia, and damage to sensory and autonomic nerves. Unlike spinal muscular atrophy (SMA), SMARD1 has a distinct genetic etiology and is not detected in the population newborn screening programs. Most children with SMARD1 do not survive beyond the first year of life due to progressive respiratory failure. Artificial ventilation can prolong survival, but no specific treatment is available. Therapy focuses on mechanical ventilation and improving the patient's quality of life. Research into gene therapy is ongoing. We report three female patients with SMARD1, including twins from a triplet pregnancy. In twin sisters (patient no. 1 and patient no. 2), two heterozygous variants in the IGHMBP2 gene were identified: c.595G>C/p.Ala199Pro and c.1615_1623del/p.Ser539_Tyr541del. In patient no. 3, a variant c.1478C>T/p.Thr493Ile and a variant c.439C>T/p.Arg147* in the IGHMBP2 gene were detected. Our findings underscore the variability of clinical presentations, even among patients sharing the same pathogenic variants in the IGHMBP2 gene, and emphasize the importance of early genetic diagnosis in patients presenting with respiratory failure, with or without associated diaphragmatic muscle paralysis.

Regulação da Septina 9 na síndrome do desconforto respiratório agudo associado à malária / The role of Septin 9 in regulating vascular permeability in malarial respiratory distress syndrome

A malária é um problema mundial de saúde, com 249 milhões de casos de infecção, ocasionando 608 mil mortes no ano de 2022. Causada pelo gênero Plasmodium, são cinco principais espécies causadoras da malária no ser humano, o Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium vivax e Plasmodium falciparum sendo os dois últimos responsáveis pelo maior número de casos clínicos e mortes ao redor do mundo, transmitida pelo mosquito fêmea do gênero Anopheles durante o repasto sanguíneo. Sabe-se ainda que eritrócitos infectados por Plasmodium berghei ANKA causam alteração no citoesqueleto de actina, consequentemente levando a hiperpermeabiliade da barreira endotelial. Em experimentos in vitro, a imunofluorescência, foi observada alteração do citoesqueleto de actina em células estimuladas com eritrócitos parasitados por PbA (EP), em contrapartida, aquelas não estimuladas (NE) e estimuladas com eritrócitos não parasitados por PbA (EnP), não mostraram alterações no mesmo. Nos experimentos in vivo, ao observar dados coletados, sendo estes respiratórios (penh e frequência respiratória) e parasitemia coletados no 7º DPI, foi observado um mesmo padrão entre o experimento 1 e o experimento 2. Os animais infectados com 106 de eritrócitos infectados, foram alocados em dois grupos, sendo eles hiperparasitemia (HP) ou síndrome do desconforto respiratório agudo-associado a malária (SDRA/SDRA-MA) e comparados àqueles não infectados (NI). Os animais NI, não apresentam parasitemia, em contrapartida, os animais SDRA, tem maior parasitemia que os HP, visto que estes têm aumento em sua parasitemia após o 12º DPI, e assim seguem aumentando gradativamente até levar os animais a óbito.O penh tem o mesmo padrão que a parasitemia, os NI com penh mais baixa que os HPs e os SDRA, sendo dentre estes, o grupo SDRA o mais elevado. A frequência respiratória, por sua vez se apresenta mais elevada no grupo NI, sendo o grupo SDRAmenor que o HP, um achado tido como normal, visto que os pulmões de animais com SDRA sofrem maior dano que os HPs. Apesar de não apresentar um valor significativo, as imagens de gel SDS-PAGE (WB) mostram maior concentração da Septina 9 nos animais com SDRA em comparação com os HPs e com os NIs. O mesmo é observado na qRT-PCR, mesmo sem significância estatística, o valor mostrado nos gráficos temmaior concentração nos SDRA. Assim, a Septina 9 está presente nas CEPP, e, mesmo sem significância estatística, da mesma forma que está presente nas amostras de tecido pulmonar utilizadas no WB e qT-PCR. É hipotetizado ainda que esta proteína pode ser ativada e assim sofrer alteração em sua localização intracelular

Malaria is a global health problem, with 249 million cases of infection, causing 608 thousand deaths in the year 2022. Caused by the genus Plasmodium, there are five main species that cause malaria in humans, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium vivax and Plasmodium falciparum, the last two being responsible for the largest number of clinical cases and deaths around the world, transmitted by the female mosquito of the genus Anopheles during blood meal. It is also known that erythrocytes infected by Plasmodium berghei ANKA (PbA) cause changes in the actin cytoskeleton, consequently leading to hyperpermeability of the endothelial barrier. In in vitro experiments, immunofluorescence, changes in the actin cytoskeleton were observed in cells stimulated with erythrocytes parasitized by PbA (EP), in contrast, those not stimulated (NE) and stimulated with erythrocytes not parasitized by PbA (EnP), did not show changes the same. In the in vivo experiments, when observing collected data, these being respiratory (penh and respiratory frequency) and parasitemia collected on the 7th DPI, the same pattern was observed between experiment 1 and experiment 2. Animals infected with 106 infected erythrocytes were allocated into two groups, namely hyperparasitemia (HP) or malaria-associated acute respiratory distress syndrome (ARDS/ARDS-MA) and compared to those not infected (NI). NI animals do not present parasitemia, on the other hand, ARDS animals have greater parasitemia than HP animals, as the latter have an increase in their parasitemia after the 12th DPI, and thus continue to gradually increase until the animals die. the same pattern as parasitemia, NI with lower penh than HPs and ARDS, among these, the ARDS group being the highest. The respiratory rate, in turn, is higher in the NI group, with the ARDS group being lower than the HP, a finding considered normal, given that the lungs of animals with ARDS suffer greater damage than the HPs. Despite not showing a significant value, SDS-PAGE (WB) gel images show a higher concentration of Septin 9 in animals with ARDS compared to HPs and NIs. The same is observed in qRT-PCR, even without statistical significance, the value shown in the graphs has a higher concentration in ARDS. Thus, Septin 9 is present in CEPP, and, even without statistical significance, in the same way that it is present in lung tissue samples used in WB and qT-PCR. It is also hypothesized that this protein can be activated and thus undergo changes in its intracellular location

Increased circulating cytokeratin 19 fragment levels in preterm neonates receiving mechanical ventilation are associated with poor outcome.

Invasive mechanical ventilation and oxygen toxicity are postnatal contributors to chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Cyfra 21-1 is a soluble fragment of cytokeratin 19, which belongs to the cytoskeleton stabilizing epithelial intermediate filaments. As a biomarker of structural integrity, Cyfra 21-1 might be associated with airway injury and lung hypoplasia in neonates. Serum Cyfra 21-1 concentrations for 80 preterm and 80 healthy term newborns were measured within 48 h after birth. Preterm infants with the combined endpoint BPD/mortality had significantly higher Cyfra 21-1 levels compared with those without fulfilling BPD/mortality criteria (P = 0.01). Also, severe RDS (>grade III) was associated with higher Cyfra levels (P = 0.01). Total duration of oxygen therapy was more than five times longer in neonates with high Cyfra 21-1 levels (P = 0.01). Infants with higher Cyfra 21-1 values were more likely to receive mechanical ventilation (50% vs. 17.5%). However, the duration of mechanical ventilation was similar between groups. The median Cyfra value was 1.93 ng/mL (IQR: 1.68-2.53 ng/mL) in healthy term neonates and 8.5 ng/mL (IQR: 3.6-16.0 ng/mL) in preterm infants. Using ROC analysis, we calculated a Cyfra cutoff > 8.5 ng/mL to predict BPD/death with an AUC of 0.795 (P = 0.004), a sensitivity of 88.9%, and a specificity of 55%. Mortality was predicted with a cutoff > 17.4 ng/mL (AUC: 0.94; P = 0.001), a sensitivity of 100%, and a specificity of 84%. These findings suggest that Cyfra 21-1 concentration might be useful to predict poor outcome in premature infants.

The common ABCA3E292V variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.

ATP-binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing enhanced green fluorescent protein (EGFP)-tagged ABCA3 isoforms show a functional deficiency of the ABCA3E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3E292V demonstrate the presence of small electron-dense lamellar bodies, time-dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age-dependent inflammation and fibrillary collagen deposition in alveolar septa. Older ABCA3E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 cell autophagy.

Repercussões da ventilação não invasiva em recém-nascidos prematuros com síndrome do desconforto respiratório agudo: revisão integrativa / Repercussionsof non-invasive ventilation in premature newborns with acute respiratory discomfort syndrome: integrative review / Repercusionesde la ventilación no invasiva en recién nacidos prematuros con síndrome de malestar respiratorio agudo: revisión integrativa

Introdução: Neonatos pré-termos apresentam singularidades anátomo-fisiológicas predispondo-os a complicações respiratórias como a Síndrome do Desconforto Respiratório Aguda. Caracterizada pelo déficit de surfactante pulmonar e consequente insuficiência respiratória, aumentando a necessidade de suporte ventilatório invasivo e não invasivo.Objetivo: Analisar os efeitos da ventilação não invasiva em recém-nascidos prematuros com Síndrome do Desconforto Respiratório Aguda. Metodologia: Trata-se de uma revisão integrativa no qual utilizou-se das bases de dados: SciELO, LILACS, PEDro, MEDLINE e Bireme. Os critérios de inclusão foram estudos relacionadosatemática em portuguêseinglês completos e com publicação entre 2015 a 2020.Resultados:Nos seteestudos sintetizados houve a utilização dos sistemas de suporte ventilatório: pressão positiva em vias aéreas a dois níveis: cânulas nasais aquecidas, umidificadas e de alto fluxo; ventilação de pressão positiva nas vias aéreas nasal, e a ventilação por pressão positiva intermitente nasal. Dois estudos que utilizaram cânulas nasais apontaram efeitos menos benéficos; e um relatou desfechos semelhantes aos demais, além de provocar menor dano nasal. Conclusões: Aventilação não invasiva tevegrande redução do número de falhas de extubação dos pacientes, principalmente naqueles que receberam a ventilação pressão positiva nas vias aéreas nasaise a ventilação por pressão positiva intermitente nasal (AU).

Introduction:Pre-term neonates have anatomophysiologicalsingularities predisposing them to respiratory complications such as Acute Respiratory Discomfort Syndrome. It is characterized by a deficit in pulmonary surfactant and consequent respiratory failure, increasing the need for invasive and non-invasive ventilatory support.Objective:To analyze the effects of non-invasive ventilation in premature newborns with Acute Respiratory Discomfort Syndrome. Methodology:In this integrative review, we used the following databases: SciELO, LILACS, PEDro, MEDLINE, and Bireme. Inclusion criteria were studies wrote in Portuguese and English and published between 2015 and 2020. Results:In the seven synthesized studies, ventilatory support systems were used: positive airway pressure at two levels: heated, humidified, and high-flow nasal cannulas; positive pressure ventilation in the nasal airways; and intermittent positive pressure ventilation. Two studies that used nasal cannulas showed less beneficial effects, and one reported similar outcome to the others, in addition to causing less nasal damage. Conclusions:Non-invasive ventilation had a significant reduction in the number of extubation failures in patients, especially in those who received positive pressure ventilation in the nasal airways and ventilation by positive intermittent nasal pressure (AU).

Introducción:Los neonatos pretérmino presentan singularidades anatomofisiológicasque predisponen a complicaciones respiratorias como el Síndrome de Malestar Respiratorio Agudo. Se caracteriza por un déficit de surfactante pulmonar y la consiguiente insuficiencia respiratoria, aumentando la necesidad de soporte ventilatorio invasivo y no invasivo. Objetivo:Analizar los efectos de la ventilación no invasiva en recién nacidos prematuros con Síndrome de Malestar Respiratorio Agudo. Metodología:En esta revisión integradora se utilizaron las siguientes bases de datos: SciELO, LILACS, PEDro, MEDLINE y Bireme. Los criterios de inclusión fueron estudios escritos en portugués y en inglés y publicados entre 2015 y 2020.Resultados:En los siete estudios sintetizados se utilizaron sistemas de soporte ventilatorio: presión positiva en la vía aéreaen dos niveles: cánulas nasales calentadas, humidificadas y de alto flujo; ventilación con presión positiva en la vía aérea nasal; y ventilación con presión positiva intermitente. Dos estudios que utilizaron cánulas nasales mostraron efectos menos beneficiosos, y uno informó de un resultado similar al de los otros, además de causar menos daño nasal. Conclusiones:La ventilación no invasiva tuvo una reducción significativa en el número de fracasos de extubación en los pacientes, especialmente en aquellos que recibieron ventilación con presión positiva en las vías aéreas nasales y ventilación por presión nasal positiva intermitente (AU).

Timing of term elective cesarean section and adverse neonatal outcomes: A multi-center retrospective cohort study.

BACKGROUND: Rate of cesarean section (CS), including elective CS has globally increased. Studies have found that term elective CS before 39 weeks of gestation is associated with increased risk of adverse respiratory outcomes. OBJECTIVE: To determine the rate of elective CS and examine the association between timing of elective term CS and adverse neonatal outcomes in a large population of Lebanese women. METHODS: A Multi-Center Study was conducted using data from the National Collaborative Perinatal Neonatal Network database. Simple and multivariable logistic regression models were used to examine the association between timing of term elective CS and adverse neonatal outcomes. Some of the neonatal adverse outcomes we examined included respiratory distress syndrome, admission to the NICU, and a composite of respiratory outcomes. RESULTS: A total of 28,997 low risk mothers who delivered through primary and repeat elective CS were included in the study. Uncomplicated elective planned term CS constituted 25% of all CS deliveries in Lebanon. Primary and repeat CS at 37 weeks of gestation increased the odds of most of the studied adverse neonatal outcomes. There were few associations between CS and adverse neonatal outcomes at 38 weeks of gestation. CONCLUSIONS: Term primary and repeat cesarean delivery prior to 39 weeks of gestation is associated with respiratory and other adverse neonatal outcomes. Delaying birth 1-2 weeks till 39 weeks of gestation can prevent 64-77% of adverse respiratory outcomes.

Therapeutic effects and outcomes of rescue high-frequency oscillatory ventilation for premature infants with severe refractory respiratory failure.

Despite wide application of high frequency oscillatory ventilation (HFOV) in neonates with respiratory distress, little has been reported about its rescue use in preterm infants. We aimed to evaluate the therapeutic effects of HFOV in preterm neonates with refractory respiratory failure and investigate the independent risk factors of in-hospital mortality. We retrospectively analyzed data collected prospectively (January 2011-December 2018) in four neonatal intensive care units of two tertiary-level medical centers in Taiwan. All premature infants (gestational age 24-34 weeks) receiving HFOV as rescue therapy for refractory respiratory failure were included. A total of 668 preterm neonates with refractory respiratory failure were enrolled. The median (IQR) gestational age and birth weight were 27.3 (25.3-31.0) weeks and 915.0 (710.0-1380.0) g, respectively. Pre-HFOV use of cardiac inotropic agents and inhaled nitric oxide were 70.5% and 23.4%, respectively. The oxygenation index (OI), FiO2, and AaDO2 were markedly increased after HFOV initiation (all p < 0.001), and can be decreased within 24-48 h (all p < 0.001) after use of HFOV. 375 (56.1%) patients had a good response to HFOV within 3 days. The final in-hospital mortality rate was 34.7%. No association was found between specific primary pulmonary disease and survival in multivariate analysis. We found preterm neonates with gestational age < 28 weeks, occurrences of sepsis, severe hypotension, multiple organ dysfunctions, initial higher severity of respiratory failure and response to HFOV within the first 72 h were independently associated with final in-hospital mortality. The mortality rate of preterm neonates with severe respiratory failure remains high after rescue HFOV treatment. Aggressive therapeutic interventions to treat sepsis and prevent organ dysfunctions are the suggested strategies to optimize outcomes.

The Prediction of Bronchopulmonary Dysplasia in Very Low Birth Weight Infants through Clinical Indicators within 1 Hour of Delivery.

BACKGROUND: Despite the advances in neonatology, the incidence of bronchopulmonary dysplasia (BPD) is increasing. It is important to prevent the development of BPD in the first place. The online BPD outcome estimator from National Institute of Children Health and Human Development and Neonatal Research Network is available. However, it is not applicable for Asians. Moreover, limits are set for birth weight and gestational weeks excluding those who may still have BPD. The aim of this study was to develop a prediction model for BPD using first hour perinatal and neonatal factors in Korean very low birth weight infants (VLBWIs). METHODS: Data were collected for 8,022 VLBWIs with gestational age (GA) ≥ 22 weeks who were born between January 1, 2013 and December 31, 2016, and admitted to the neonatal intensive care units of the KNN. Multiple logistic regression models reanalyzed by stepwise selection with significant clinical indicators for BPD. PROC package was used to calculate the area under curve (AUC) and corresponding 95% confidence intervals. Moreover, it was used to search the best cut-off value. External validation was performed with the 2017 Korean neonatal network (KNN) data. RESULTS: After all missing data were excluded, 4,600 VLBWIs were included in the training dataset of the prediction model. Predictability of presence of BPD was 90.8% and prediction P value cut off was 0.550. Five-minute Apgar score, birth weight, GA, sex, surfactant use were significant indicators. Predictability of severe BPD was 81.5% and prediction P value cut off was 0.160. Five-minute Apgar score, birth weight, maternal PIH, chronic maternal hypertension, GA, sex, respiratory distress syndrome, need of resuscitation at birth were significant indicators. After external validation, sensitivity and specificity did not change significantly. CONCLUSION: From this study, high predictability was obtained using clinical parameters obtained within one hour of life. P value for prediction of each grade of BPD and equation for calculation was presented. It can be helpful for the early prediction of BPD in Korean VLBWI. This study will contribute to the prediction of BPD in Asians especially Korean VLBWIs, not currently included in the NICHD BPD online BPD predictor. In addition, the predictive power may be continuously increased with the cumulative data of KNN.

Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder.

Rab proteins coordinate inter-organellar vesicle-mediated transport, facilitating intracellular communication, protein recycling, and signaling processes. Dysfunction of Rab proteins or their direct interactors leads to a wide range of diseases with diverse manifestations. We describe seven individuals from four consanguineous Arab Muslim families with an infantile-lethal syndrome, including failure to thrive (FTT), chronic diarrhea, neonatal respiratory distress, variable pituitary dysfunction, and distal arthrogryposis. Exome sequencing analysis in the independent families, followed by an internal gene-matching process using a local exome database, identified a homozygous splice-site variant in MADD (c.2816 + 1 G > A) on a common haplotype. The variant segregated with the disease in all available family members. Determination of cDNA sequence verified single exon skipping, resulting in an out-of-frame deletion. MADD encodes a Rab guanine nucleotide exchange factor (GEF), which activates RAB3 and RAB27A/27B and is thus a crucial regulator of neuromuscular junctions and endocrine secretory granule release. Moreover, MADD protects cells from caspase-mediated TNF-α-induced apoptosis. The combined roles of MADD and its downstream effectors correlate with the phenotypic spectrum of disease, and call for additional studies to confirm the pathogenic mechanism and to investigate possible therapeutic avenues through modulation of TNF-α signaling.

Chronic Oxytocin treatment has long lasting therapeutic potential in a rat model of neonatal hypercapnic-hypoxia injury, through enhanced GABAergic signaling and by reducing hippocampal gliosis with its anti-inflammatory feature.

Previous studies have shown that, oxytocin has anticonvulsant and neuroprotective effects. One of the most important complications of Hypercapnic-hypoxia is drug resistance epilepsy. Effects of chronic intraperitoneal oxytocin treatment on gliosis, neuroinflammation and seizure activity was investigated in a model in which rats were exposed to hypoxia on postnatal day 1 and later challenged to the seizure-inducing pentylenetetrazol Forty pups were included in the study on their first day of birth. 16 pups were exposed to 100% CO2 for 5 minutes and other 16 pups for 10 minutes. The remaining 8 pups comprised the control group. Groups were classified according to oxytocin administration within the first 4 weeks. Pentylenetetrazol was administered 6 months after the oxytocin treatment. The Racine's Convulsion Scale and onset times of first myoclonic jerk (FMJ) were evaluated. To determine the mechanisms by which oxytocin exerted its effects on hypercapnic-anoxia exposed rats, we performed CA1 total neuron count & CA1 GFAP immunostaining, and measured brain levels of TNF-α and GAD-67. The Racine scale and TNF-α values were significantly lower in both groups that received oxytocin, while time-to-FMJ and GAD-67 level were significantly higher. The histopathological evaluations showed that oxytocin had significant ameliorative effects (especially regarding gliosis) on the hippocampus of hypoxic rats. Regarding the results of present study, it can be speculated that after acute hypercapnic-anoxia exposure, chronic Oxytocin treatment has long lasting therapeutic potential on rats, possibly by reducing the gliosis with its anti-inflammatory feature and by activating the GABA pathway.

Combined Genome Sequencing and RNA Analysis Reveals and Characterizes a Deep Intronic Variant in IGHMBP2 in a Patient With Spinal Muscular Atrophy With Respiratory Distress Type 1.

BACKGROUND: Pathogenic variants in the IGHMBP2 gene cause recessive spinal motor neuropathies of variable phenotype, including a predominantly distal motor impairment of Charcot-Marie-Tooth type 2S and the more severe condition of spinal muscular atrophy with respiratory distress type 1 in which infantile respiratory failure predominates. METHODS: We describe the first reported case of spinal muscular atrophy with respiratory distress type 1 caused by a novel deep intronic variant in IGHMBP2 (NM_002180c.712-610A>G). RESULTS: The variant was detected by whole genome sequencing. Reverse transcription-polymerase chain reaction and complimentary DNA sequencing were used to characterize the impact of the novel variant. CONCLUSIONS: This report illustrates the utility in clinical practice of genome sequencing and RNA analysis, compared with exome sequencing alone.

Lung CD103+dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection.

Premature infants, especially those with bronchopulmonary dysplasia (BPD), develop recurrent severe respiratory viral illnesses. We have shown that hyperoxic exposure of immature mice, a model of BPD, increases lung IL-12-producing Clec9a+ CD103+ dendritic cells (DCs), pro-inflammatory responses, and airway hyperreactivity following rhinovirus (RV) infection. However, the requirement for CD103+ DCs and Clec9a, a DAMP receptor that binds necrotic cell cytoskeletal filamentous actin (F-actin), for RV-induced inflammatory responses has not been demonstrated. To test this, 2-day-old C57BL/6J, CD103+ DC-deficient Batf3-/- or Clec9agfp-/- mice were exposed to normoxia or hyperoxia for 14 days. Also, selected mice were treated with neutralizing antibody against CD103. Immediately after hyperoxia, the mice were inoculated with RV intranasally. We found that compared with wild-type mice, hyperoxia-exposed Batf3-/- mice showed reduced levels of IL-12p40, IFN-γ, and TNF-α, fewer IFN-γ-producing CD4+ T cells, and decreased airway responsiveness following RV infection. Similar effects were observed in anti-CD103-treated and Clec9agfp-/- mice. Furthermore, hyperoxia increased airway dead cell number and extracellular F-actin levels. Finally, studies in preterm infants with respiratory distress syndrome showed that tracheal aspirate CLEC9A expression positively correlated with IL12B expression, consistent with the notion that CLEC9A+ cells are responsible for IL-12 production in humans as well as mice. We conclude that CD103+ DCs and Clec9a are required for hyperoxia-induced pro-inflammatory responses to RV infection. In premature infants, Clec9a-mediated activation of CD103+ DCs may promote pro-inflammatory responses to viral infection, thereby driving respiratory morbidity.

Novel homozygous missense mutation in ABCA3 protein leading to severe respiratory distress in term infant.

The term baby presented with respiratory distress with X-ray pictures consistent as hyaline membrane disease (HMD). Baby was ventilated and treated with surfactant. Because of the persistence of high ventilation needs with X-ray pictures consistent with HMD with a transient response to surfactant every time, the possibility of an inherited disorder of surfactant metabolism was kept. Whole-exome sequencing revealed a novel homozygous missense mutation in the gene for ATP binding cassette transporter protein A3. The baby died after 100 days of ventilation.

An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.

Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet-Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help "democratize" the diagnosis of PCD, which is currently limited to highly specialized centers.

Ibudilast, a Phosphodiesterase-4 Inhibitor, Ameliorates Acute Respiratory Distress Syndrome in Neonatal Mice by Alleviating Inflammation and Apoptosis.

BACKGROUND Acute respiratory distress syndrome (ARDS) is a sudden and serious disease with increasing morbidity and mortality rates. Phosphodiesterase 4 (PDE4) is a novel target for inflammatory disease, and ibudilast (IBU), a PDE4 inhibitor, inhibits inflammatory response. Our study investigated the effect of IBU on the pathogenesis of neonatal ARDS and the underlying mechanism related to it. MATERIAL AND METHODS Western blotting was performed to analyze the expression levels of PDE4, CXCR4, SDF-1, CXCR5, CXCL1, inflammatory cytokines, and proteins related to cell apoptosis. Hematoxylin-eosin staining was performed to observe the pathological morphology of lung tissue. Pulmonary edema score was used to assess the degree of lung water accumulation after pulmonary injury. Enzyme-linked immunosorbent assay (ELISA) was used to assess levels of inflammatory factors (TNF-alpha, IL-1ß, IL-6, and MCP-1) in serum. TUNEL assay was used to detect apoptotic cells. RESULTS Increased expression of PDE4 was observed in an LPS-induced neonatal ARDS mouse model, and IBU ameliorated LPS-induced pathological manifestations and pulmonary edema in lung tissue. In addition, IBU attenuated the secretion of inflammatory cytokines by inactivating the chemokine axis in the LPS-induced neonatal ARDS mouse model. Finally, IBU significantly reduced LPS-induced cell apoptosis in lung tissue. CONCLUSIONS IBU, a PDE4 inhibitor, protected against ARDS by interfering with pulmonary inflammation and apoptosis. Our findings provide a novel and promising strategy to regulate pulmonary inflammation in ARDS.

Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.

Semiquantitative Ultrasound Assessment of Lung Aeration Correlates With Lung Tissue Inflammation.

We studied the relationship between ultrasound-assessed lung aeration and inflammation in a particular population of ventilated preterm neonates with mild-to-moderate lung inflammation and no congenital heart defect. Lung aeration estimated by a semiquantitative lung ultrasound score significantly correlated with several inflammatory markers both at cellular (neutrophil count in bronchoalveolar lavage: ρ = 0.400, p = 0.018) and molecular level (total proteins: ρ = 0.524, p = 0.021; interleukine-8: ρ = 0.523, p = 0.021; granulocytes-macrophages colony stimulating factor: ρ = 0.493, p = 0.020; all measured in bronchoalveolar lavage and expressed as epithelial lining fluid concentrations). Lung ultrasound might detect changes in lung aeration attributable to mild-to-moderate local inflammation if cardiogenic lung edema is excluded. Thus, it is possible to describe some levels of lung inflammation with semiquantitative lung ultrasound.

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin µ-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.

Clostridium difficile causante de síndrome de distrés respiratorio agudo tras pancreatectomía total / Acute respiratory distress syndrome due to clostridium difficile after total pancreatectomy

La diarrea nosocomial, que es la adquirida en el ámbito hospitalario, suele ser producida por Clostridium difficile. Sin embargo, en raras ocasiones puede ocasionar un síndrome de distrés respiratorio. Por ello, el diagnóstico de dicha patología es difícil si no se sospecha. El tratamiento se basa en el uso de antibiótico vía oral. Se expone el caso de una paciente de 66 años con dicha patología tras la realización de pancreatectomía total.

Nosocomial (hospital-acquired) diarrhea is usually caused by Clostridium difficile. On rare occasions it can cause acute respiratory distress syndrome (ARDS). Therefore, this condition should be suspected in order to make a diagnosis. Treatment is based on oral antibiotics. We report the case of a 66-year-old female patient with ARDS secondary to Clostridium difficile colitis after total pancreatectomy.

MiR-200a improves respiratory distress syndrome in newborn rabbits via the Wnt/ß-catenin signaling pathway.

OBJECTIVE: The aim of this study was to investigate the effect of micro-ribonucleic acid (miR)-200a on respiratory distress syndrome (RDS) in newborn rabbits by regulating the Wnt/ß-catenin signaling pathway. MATERIALS AND METHODS: In this work, newborn rabbits aged three days were selected from our laboratory as research objects. The messenger RNA (mRNA) and protein expression levels of miR-200a, ß-catenin and interleukin-10 (IL-10) in blood samples of healthy newborn rabbits and newborn rabbits with RDS were determined by fluorescence quantitative Polymerase Chain Reaction (PCR) and Western blotting, respectively. Lentivirus-packaged plasmids containing miR-200a were then injected into newborn rabbits suffering from RDS. After 2 d, the mRNA and protein expression levels of miR-200a, ß-catenin and IL-10 in blood samples of newborn rabbits in different treatment groups were measured. Meanwhile, lung sections were collected from newborn rabbits in different treatment groups. After that, the sections were observed via hematoxylin and eosin (H&E) staining. At the same time, lung coefficient of newborn rabbits in different treatment groups was also measured. RESULTS: Compared with healthy newborn rabbits, the mRNA and protein expression levels of miR-200a and IL-10 in the blood of newborn rabbits with RDS decreased significantly (p<0.05), while ß-catenin increased markedly (p<0.05). The mRNA and protein expression levels of ß-catenin and IL-10 in newborn RDS rabbits with miR-200a over-expression and knockout were detected as well. The results revealed that lowly expressed miR-200a could remarkably promote the expression level of ß-catenin, whereas inhibiting the expression of IL-10. However, highly expressed miR-200a could significantly inhibit the expression level of ß-catenin and promote the expression level of IL-10. H&E staining results manifested that miR-200a knockout markedly promoted the increase of pulmonary alveoli with increased lung coefficients. However, the up-regulation of miR-200a could reduce lung coefficients and remarkably improve RDS. CONCLUSIONS: MiR-200a regulates RDS in newborn rabbits by regulating the Wnt/ß-catenin signaling pathway.