Comparative single-cell transcriptomic profile of hybrid immunity induced by adenovirus vector-based COVID-19 vaccines.

In this study, antibody response and a single-cell RNA-seq analysis were conducted on peripheral blood mononuclear cells from five different groups: naïve subjects vaccinated with AZD1222 (AZ) or Ad5-nCoV (Cso), individuals previously infected and later vaccinated (hybrid) with AZD1222 (AZ-hb) or Ad5-nCoV (Cso-hb), and those who were infected and had recovered from COVID-19 (Inf). The results showed that AZ induced more robust neutralizing antibody responses than Cso. The single-cell RNA data revealed a high frequency of memory B cells in the Cso and Cso-hb. In contrast, AZ and AZ-hb groups exhibited the highest proportion of activated naïve B cells expressing CXCR4. Transcriptomic analysis of CD4+ and CD8+ T cells demonstrated a heterogeneous response following vaccination, hybrid immunity, or natural infection. However, a single dose of Ad5-nCoV was sufficient to strongly activate CD4+ T cells (naïve and memory) expressing ANX1 and FOS, similar to the hybrid response observed with AZ. An interesting finding was the robust activation of a subset of CD8+ T cells expressing GZMB, GZMH, and IFNG genes in the Cso-hb group. Our findings suggest that both vaccines effectively stimulated the cellular immune response; however, the Ad5-nCoV induced a more robust CD8+ T-cell response in previously infected individuals.

Single-cell transcriptomic analysis of B cells reveals new insights into atypical memory B cells in COVID-19.

Here, we performed single-cell RNA sequencing of S1 and receptor binding domain protein-specific B cells from convalescent COVID-19 patients with different clinical manifestations. This study aimed to evaluate the role and developmental pathway of atypical memory B cells (MBCs) in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The results revealed a proinflammatory signature across B cell subsets associated with disease severity, as evidenced by the upregulation of genes such as GADD45B, MAP3K8, and NFKBIA in critical and severe individuals. Furthermore, the analysis of atypical MBCs suggested a developmental pathway similar to that of conventional MBCs through germinal centers, as indicated by the expression of several genes involved in germinal center processes, including CXCR4, CXCR5, BCL2, and MYC. Additionally, the upregulation of genes characteristic of the immune response in COVID-19, such as ZFP36 and DUSP1, suggested that the differentiation and activation of atypical MBCs may be influenced by exposure to SARS-CoV-2 and that these genes may contribute to the immune response for COVID-19 recovery. Our study contributes to a better understanding of atypical MBCs in COVID-19 and the role of other B cell subsets across different clinical manifestations.

Evaluation of interleukin-1 and interleukin-6 receptor antagonists in a murine model of acute lung injury.

The acute exudative phase of acute respiratory distress syndrome (ARDS), a severe form of respiratory failure, is characterized by alveolar damage, pulmonary oedema, and an exacerbated inflammatory response. There is no effective treatment for this condition, but based on the major contribution of inflammation, anti-inflammatory strategies have been evaluated in animal models and clinical trials, with conflicting results. In COVID-19 ARDS patients, interleukin (IL)-1 and IL-6 receptor antagonists (IL-1Ra and IL-6Ra, kineret and tocilizumab, respectively) have shown some efficacy. Moreover, we have previously developed novel peptides modulating IL-1R and IL-6R activity (rytvela and HSJ633, respectively) while preserving immune vigilance and cytoprotective pathways. We aimed to assess the efficacy of these novel IL-1Ra and IL-6Ra, compared to commercially available drugs (kineret, tocilizumab) during the exudative phase (day 7) of bleomycin-induced acute lung injury (ALI) in mice. Our results first showed that none of the IL-1Ra and IL-6Ra compounds attenuated bleomycin-induced weight loss and venous P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ increase. Histological analyses and lung water content measurements also showed that these drugs did not improve lung injury scores or pulmonary oedema, after the bleomycin challenge. Finally, IL-1Ra and IL-6Ra failed to alleviate the inflammatory status of the mice, as indicated by cytokine levels and alveolar neutrophil infiltration. Altogether, these results indicate a lack of beneficial effects of IL-1R and IL-6R antagonists on key parameters of ALI in the bleomycin mouse model.

Impact of ENaC downregulation in transgenic mice on the outcomes of acute lung injury induced by bleomycin.

NEW FINDINGS: What is the central question of this study? How does the downregulation of ENaC, the major driving force for alveolar fluid clearance, impact acute lung injury outcomes induced by bleomycin, featuring alveolar damage, as observed during ARDS exudative phase? What is the main finding and its importance? ENaC downregulation in αENaC(-/-)Tg+ mice did not elicit a substantial worsening impact on the main bleomycin outcomes. In ARDS patients, both ENaC alteration and alveolar damage are observed. Thus, novel therapeutic avenues, favouring alveolar integrity restauration, in addition to lung oedema resolution capacity, mainly driven by ENaC, would be essential. ABSTRACT: The exudative phase of acute respiratory distress syndrome (ARDS) is characterized by extended alveolar damage, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Na+ reabsorption through ENaC channels is a major driving force for alveolar fluid clearance (AFC) in physiological and pathological conditions. It has previously been shown that partial αENaC impairment in transgenic (αENaC(-/-)Tg+) mice results in reduced AFC in basal conditions and increased wet/dry ratio after thiourea-induced lung oedema, a model in which the integrity of the alveolar epithelium is preserved. The goal of this study was to further investigate the impact of αENaC downregulation in αENaC(-/-)Tg+ mice using an experimental model of acute lung injury induced by bleomycin. A non-significant trend in enhanced weight loss and mortality rates was observed after the bleomycin challenge in αENaC(-/-)Tg+ compared to wild-type (WT) mice. Bronchoalveolar lavage analyses revealed increased TNFα levels and protein concentrations, as indexes of lung inflammation and alveolar damage, in αENaC(-/-)Tg+ mice, compared to WT, at day 3 post-bleomycin, although a statistical difference was no longer measured at day 7. Differential immune cell counts were similar in WT and αENaC(-/-)Tg+ mice challenged with bleomycin. Moreover, lung weight measurements indicated similar oedema levels in WT mice and in transgenic mice with impaired ENaC channels. Altogether, our data indicated that change in ENaC expression does not elicit a significant impact on lung oedema level/resolution in the bleomycin model, featuring alveolar damage.

CRIB scores as a tool for assessing risk for the development of pulmonary hypertension in extremely preterm infants with bronchopulmonary dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) increases the risk for developing pulmonary hypertension (PH). However, the risk factors associated with BPD-associated PH remain unclear. Our primary aim was to determine perinatal risk factors associated with the development of PH in infants with BPD. STUDY DESIGN: We retrospectively reviewed medical records of 303 infants born at ≤ 28 weeks' gestation. Infants were categorized as having no, mild, moderate, or severe BPD. PH was diagnosed by echocardiogram. Data were analyzed using Fisher exact test, two-sample t-test, and multivariable logistic regression. RESULTS: The incidence of PH in our cohort was 12%. Infants with PH had lower birth weights and gestational ages (p < 0.001). After controlling for confounding variables, severe BPD (p < 0.001), and higher Clinical Risk Index for Babies (CRIB) scores (p = 0.04) were associated with the development of PH. CONCLUSION: Severe BPD increases the risk for developing PH. Higher CRIB scores correlate with PH development in infants with BPD. We speculate that CRIB scores may allow for early categorization of preterm infants with a higher likelihood of developing PH.

Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.

BACKGROUND & AIMS: Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. METHODS: We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. RESULTS: We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls. CONCLUSIONS: Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA.

Function of KvLQT1 potassium channels in a mouse model of bleomycin-induced acute lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by an exacerbated inflammatory response, severe damage to the alveolar-capillary barrier and a secondary infiltration of protein-rich fluid into the airspaces, ultimately leading to respiratory failure. Resolution of ARDS depends on the ability of the alveolar epithelium to reabsorb lung fluid through active transepithelial ion transport, to control the inflammatory response, and to restore a cohesive and functional epithelium through effective repair processes. Interestingly, several lines of evidence have demonstrated the important role of potassium (K+) channels in the regulation of epithelial repair processes. Furthermore, these channels have previously been shown to be involved in sodium/fluid absorption across alveolar epithelial cells, and we have recently demonstrated the contribution of KvLQT1 channels to the resolution of thiourea-induced pulmonary edema in vivo. The aim of our study was to investigate the role of the KCNQ1 pore-forming subunit of KvLQT1 channels in the outcome of ARDS parameters in a model of acute lung injury (ALI). We used a molecular approach with KvLQT1-KO mice challenged with bleomycin, a well-established ALI model that mimics the key features of the exudative phase of ARDS on day 7. Our data showed that KvLQT1 deletion exacerbated the negative outcome of bleomycin on lung function (resistance, elastance and compliance). An alteration in the profile of infiltrating immune cells was also observed in KvLQT1-KO mice while histological analysis showed less interstitial and/or alveolar inflammatory response induced by bleomycin in KvLQT1-KO mice. Finally, a reduced repair rate of KvLQT1-KO alveolar cells after injury was observed. This work highlights the complex contribution of KvLQT1 in the development and resolution of ARDS parameters in a model of ALI.

SNAPPE-II and MDAS scores as predictors for surgical intervention in very low birth weight neonates with necrotizing enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal emergency in preterm and term neonates, with the majority of cases affecting neonates classified as very low birth weight (VLBW, bw <1500 g). Scores for neonatal acute physiology-perinatal extension-II (SNAPPE-II) and metabolic derangement acuity score (MDAS) have been developed and utilized to assess neonatal morbidity and mortality including the subset of VLBW neonates. Serial SNAPPE-II and MDAS scores have been reported in neonates with necrotizing enterocolitis to assist in surgical management, yielding mixed results. OBJECTIVE: To determine the relationship between clinical and/or laboratory deterioration using SNAPPE-II and MDAS scores measured at the time of NEC diagnosis and surgical management of NEC. METHODS: We retrospectively evaluated preterm neonates ≥23 weeks gestational age who developed pneumatosis intestinalis on radiographic imaging coupled with clinical signs of NEC. SNAPPE-II and MDAS scores were calculated within twelve hours of birth and within twelve hours of initial finding of pneumatosis intestinalis. Baseline characteristics and clinical variables between those who did and did not require surgical intervention were compared. Logistic regression and receiver - operator characteristics (ROC) curve analyses were also performed, and areas under the curve (AUC) computed, to assess the performance of SNAPPE-II and MDAS scoring systems to differentiate neonates with NEC in the two groups. RESULTS: Sixty-four neonates were evaluated in our study of which 20 required surgical management of NEC. While the baseline SNAPPE-II and MDAS scores did not differ between the surgical management and medical management only groups, when rescored within 12 h of NEC diagnosis, the surgical management group had significantly higher SNAPPE -II (38 (18.5-69) vs. 19 (10-34.5), p = .04) and MDAS (2.5 (1-3) vs. 1 (0-2), p = .0004) scores. The AUCs for MDAS 0.77 (95% CI 0.65-0.89 and 0.71 (95% CI 0.57-0.85) for SNAPPE-II, indicating an acceptable level of diagnostic ability of both scoring systems to differentiate between those who did and did not need surgical management. CONCLUSION: SNAPPE II and MDAS scores performed within 12 h of NEC diagnosis may be useful in predicting which preterm VLBW neonates will require surgical intervention.

The Implementation of Renal Denervation in the Management of Resistant Hypertension Despite Use of Multitherapy Antihypertensives at Maximally Tolerated Doses: A Contemporary Literature Review.

Refractory hypertension is highly prevalent among the hypertensive population, and current clinical management has failed to provide optimal control for these individuals. This subtype of arterial hypertension is defined as a persistently elevated systolic blood pressure reading of 140 mmHg, or higher, despite multiple antihypertensive use at maximally tolerated dosing. These patients have an elevated risk of cardiovascular and renal complications, urging for the need of more effective therapeutic management. Renal sympathetic efferent nerves have been noted to play an important role in volume and blood pressure homeostasis. Before the implementation of oral antihypertensives, the use of surgical lumbar sympathectomy for the reduction of persistent hypertension was considered a life-saving approach. However, individuals were left with debilitating side effects, such as postural hypotension, syncope, and impotence. A new and minimally invasive technique has been proposed, where the kidneys undergo selective denervation in hopes of providing decreased cardiovascular morbidity and mortality for patients with resistant hypertension. Some studies demonstrated promising outcomes with a reduction in blood pressure, a decrease in medication reliance, and a potential long-lasting effect of the procedure with an overall improvement in cardiovascular health. Unfortunately, most of the available data was obtained from observational, uncontrolled studies with short-term follow-up, small sample sizes, and high variability in blood pressure measurement. Therefore, further evidence is needed to determine whether renal denervation provides long-term benefits for blood pressure control and improves outcomes for mortality and cardiovascular events in this patient population.

Beyond Syncopal Episodes: A Complicated Hyperkalemic Emergency Manifesting As Complete Heart Block and Seizure Versus Convulsive Syncope Cascade.

We present a case involving an 87-year-old woman who had a hyperkalemic emergency. This condition was further complicated by complete heart block (CHB) and seizure-like activity. This case emphasizes the challenge of differentiating between seizures and convulsive syncope. Achieving an accurate diagnosis is essential for determining the appropriate medical treatment. This case report highlights the various symptoms and complications associated with hyperkalemia, emphasizing the importance of conducting a thorough examination to explore other potential causes. Additionally, it emphasizes the usefulness of the head-upright tilt test (HUTT) as a method to differentiate convulsive syncope from seizures, particularly in cases involving vagal stimulation.

19n01, a broadly neutralizing antibody against omicron BA.1, BA.2, BA.4/5, and other SARS-CoV-2 variants of concern.

This study reports the isolation and characterization of a human monoclonal antibody (mAb) called 19n01. This mAb was isolated by using single-cell RNAseq of B cells from donors infected with the ancestral strain. This mAb possesses a potent and broad capacity to bind and neutralize all previously circulating variants of concern (VOCs), including Omicron sublineages BA.1, BA.2, and BA.4/5. The pseudovirus neutralization assay revealed robust neutralization capacity against the G614 strain, BA.1, BA.2, and BA.4/5, with inhibitory concentration (IC50) values ranging from 0.0035 to 0.0164 µg/mL. The microneutralization assay using the G614 strain and VOCs demonstrated IC50 values of 0.013-0.267 µg/mL. Biophysical and structural analysis showed that 19n01 cross-competes with ACE2 binding to the receptor-binding domain (RBD) and the kinetic parameters confirmed the high affinity against the Omicron sublineages (KD of 61 and 30 nM for BA.2 and BA.4/5, respectively). These results suggest that the 19n01 is a remarkably potent and broadly reactive mAb.

Impact of KvLQT1 potassium channel modulation on alveolar fluid homeostasis in an animal model of thiourea-induced lung edema.

Alveolar ion and fluid absorption is essential for lung homeostasis in healthy conditions as well as for the resorption of lung edema, a key feature of acute respiratory distress syndrome. Liquid absorption is driven by active transepithelial sodium transport, through apical ENaC Na+ channels and basolateral Na+/K+-ATPase. Our previous work unveiled that KvLQT1 K+ channels also participate in the control of Na+/liquid absorption in alveolar epithelial cells. Our aim was to further investigate the function of KvLQT1 channels and their interplay with other channels/transporters involved in ion/liquid transport in vivo using adult wild-type (WT) and KvLQT1 knock-out (KO) mice under physiological conditions and after thiourea-induced lung edema. A slight but significant increase in water lung content (WLC) was observed in naïve KvLQT1-KO mice, relative to WT littermates, whereas lung function was generally preserved and histological structure unaltered. Following thiourea-induced lung edema, KvLQT1-KO did not worsen WLC or lung function. Similarly, lung edema was not aggravated by the administration of a KvLQT1 inhibitor (chromanol). However, KvLQT1 activation (R-L3) significantly reduced WLC in thiourea-challenged WT mice. The benefits of R-L3 were prevented in KO or chromanol-treated WT mice. Furthermore, R-L3 treatment had no effect on thiourea-induced endothelial barrier alteration but restored or enhanced the levels of epithelial alveolar AQP5, Na+/K+-ATPase, and ENaC expressions. Altogether, the results indicate the benefits of KvLQT1 activation in the resolution of lung edema, probably through the observed up-regulation of epithelial alveolar channels/transporters involved in ion/water transport.

Optic neuromyelitis after vaccination against SARS-CoV-2.

Neuromyelitis optica is an autoimmune demyelinating astrocytopathy of the central nervous system that primarily affects the optic nerve and spinal cord. It is considered a multifactorial disease associated with antibodies against aquaporin 4, with complement cascade activation and lymphocytic infiltration leading to axonal loss and causing significant morbidity and disability. In addition, cases of inflammatory diseases of the central nervous system have been described after vaccination against SARS-CoV-2, mainly acute disseminated encephalomyelitis. Also, a few cases of neuromyelitis optica spectrum disorder, mostly aquaporin 4+, have been reported. We describe a patient who developed symptoms suggestive of acute disseminated encephalomyelitis the next day after vaccination against SARS-CoV-2. Three months later, a longitudinally extensive transverse myelitis compatible with aquaporin 4+ neuromyelitis optica was successfully treated with an interleukin 6 inhibitor. There is no proven association and research is needed to establish whether optic neuromyelitis is related to vaccination; this is a single case report from which no conclusion can be drawn.

Unusual complication of Herpes simplex encephalitis: complete Klüver-Bucy syndrome.

Klüver-Bucy syndrome is a rare neurobehavioral disorder caused by a bilateral temporal lobe lesion affecting the hippocampus and amygdala; clinically characterised by hyperorality, hypermetamorphosis, placidity, altered sexual behaviour, eating, disorders and visual impairment, agnosia and amnesia. However, the complete syndrome is rarely seen, and diagnosis does not require all the symptoms to be manifested simultaneously.We describe a patient who developed a complete Klüver-Bucy syndrome secondary to bilateral temporal involvement due to herpetic encephalitis.

Antigen Targeting of Porcine Skin DEC205+ Dendritic Cells.

Dendritic cell (DC) targeting by DEC205+ cells effectively promotes the internalization of antigens that may trigger a specific immune response. In this study, we evaluated the ability of a recombinant antibody, anti-DEC205 (rAb ZH9F7), to trigger cellular endocytosis in subpopulations of DCs and targeted cells after intradermal injection and subsequent migration toward lymph nodes. Furthermore, the cellular immune response was evaluated in pigs after intradermal application of the antigenized rAb ZH9F7 combined with porcine circovirus type 2 cap antigen (rAb ZH9F7-Cap). We demonstrated that rAb ZH9F7 recognized conventional type 1 and 2 DCs from the blood and skin and monocytes. It promoted receptor-mediated endocytosis and migration of cDCs and moDCs toward regional lymph nodes. Intradermal application of rAb ZH9F7-Cap induced a higher frequency of IFN-γ-secreting CD4+CD8+ T lymphocytes and antibodies against Cap protein than that in the control group. In conclusion, the rAb ZH9F7-Cap system promoted the target of skin cDC1 and cDC2, provoking migration to the regional lymph nodes and inducing a Th1 response, as evidenced by the proliferation of double-positive CD4+CD8+ T cells, which correlates with an enhanced ability to target the cDC1 subset both in vitro and in vivo.

Analysis of IgG, IgA and IgM antibodies against SARS-CoV-2 spike protein S1 in convalescent and vaccinated patients with the Pfizer-BioNTech and CanSinoBio vaccines.

The SARS-CoV-2 virus was detected for the first time in December 2019 in Wuhan, China. Currently, this virus has spread around the world, and new variants have emerged. This new pandemic virus provoked the rapid development of diagnostic tools, therapies and vaccines to control this new disease called COVID-19. Antibody detection by ELISA has been broadly used to recognize the number of persons infected with this virus or to evaluate the response of vaccinated individuals. As the pandemic spread, new questions arose, such as the prevalence of antibodies after natural infection and the response induced by the different vaccines. In Mexico, as in other countries, mRNA and viral-vectored vaccines have been widely used among the population. In this work, we developed an indirect ELISA test to evaluate S1 antibodies in convalescent and vaccinated individuals. By using this test, we showed that IgG antibodies against the S1 protein of SARS-CoV-2 were detected up to 42 weeks after the onset of the symptoms, in contrast to IgA and IgM, which decreased 14 weeks after the onset of symptoms. The evaluation of the antibody response in individuals vaccinated with Pfizer-BioNTech and CanSinoBio vaccines showed no differences 2 weeks after vaccination. However, after completing the two doses of Pfizer-BioNTech and the one dose of CanSinoBio, a significantly higher response of IgG antibodies was observed in persons vaccinated with Pfizer-BioNTech than in those vaccinated with CanSinoBio. In conclusion, these results confirm that after natural infection with SARS-CoV-2, it is possible to detect antibodies for up to 10 months. Additionally, our results showed that one dose of the CanSinoBio vaccine induces a lower response of IgG antibodies than that induced by the complete scheme of the Pfizer-BioNTech vaccine.

Changing pace: Using implementation intentions to enhance social distancing behavior during the COVID-19 pandemic.

Since the first case of COVID-19 in the U.S. on January 20, 2020, the disease caused by the new strain of coronavirus has spread exponentially across the country. While the spread of this disease can be significantly slowed if people practice "social distancing," it is difficult to break old habits and acquire new behaviors at the needed speed. The purpose of this study is to challenge how health risk messages are currently communicated (specifically by considering how the Center of Disease Control (CDC) communicates its recommendations for social distancing) and suggest an alternative way. We tested and applied the use of a robust behavioral intervention known as "if-then" plans (plans that spell out in advance how one wants to achieve a goal they have previously set) to encourage the acquisition of a new behavior (e.g., social distancing) during this time of crisis. Using a longitudinal mixed design (within-/between-subjects study) daily diary study, we hypothesized and observed (via multilevel modeling) that those randomized into the experimental group (those who created and practiced if-then plans) demonstrated increased social distancing over time, whereas engagement in social distancing did not change in the control condition (those who observed the CDC guidelines). These results were sustained in a 3-week follow-up examination for those who were strongly committed to the goal to social distance. Such evidence suggests that risk communication messaging that includes if-then plans is an effective way of acquiring new behaviors. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3.

Biliary atresia (BA) is a progressive, idiopathic obliteration of the extrahepatic biliary system occurring exclusively in the neonatal period. It is the most common disease leading to liver transplantation in children. The etiology of BA is unknown, although infectious, immune and genetic causes have been suggested. Although the recurrence of BA in families is not common, there are more than 30 multiplex families reported and an underlying genetic susceptibility has been hypothesized. We screened a cohort of 35 BA patients for genomic alterations that might confer susceptibility to BA. DNA was genotyped on the Illumina Human Hap 550 Beadchip platform, which analyzes over 550,000 single nucleotide polymorphisms (SNPs) for genomic deletions and duplications. Areas of increased and decreased copy number were compared to those found in control populations. To identify regions that could serve as susceptibility factors for BA, we searched for regions that were found in BA patients, but not in controls. We identified two unrelated BA patients with overlapping heterozygous deletions of 2q37.3. Patient 1 had a 1.76 Mb (280 SNP), heterozygous deletion containing 30 genes. Patient 2 had a 5.87 Mb (1,346 SNP) heterozygous deletion containing 55 genes. The overlapping 1.76 Mb deletion on chromosome 2q37.3 from 240,936,900 to 242,692,820 constitutes the critical region and the genes within this region could be candidates for susceptibility to BA.

The effect of hemodynamically significant patent ductus arteriosus on acute kidney injury and systemic hypertension in extremely low gestational age newborns.

Background: Acute kidney injury (AKI) in preterm neonates is becoming an increasingly recognized morbidity in the neonatal intensive care unit neonatal intensive care unit (NICU), yet its epidemiology, delineation and relation to numerous toxic exposures and common morbidities such as systemic hypertension is just evolving. With a frequency of the patent ductus arteriosus (PDA) as high as 70% in preterm infants born before 28-week gestation, the role of the hemodynamically significant PDA (hs-PDA) remains unclear. Objective: To determine if AKI and systemic hypertension is more common in extremely low gestational age newborns (ELGAN) with hs PDA compared to ELGAN with no or non-hs PDA using modified AKIN and Neonatal Risk, Injury, Failure, Loss of Kidney Function, and End-stage (N-RIFLE) scoring systems. Methods: This was a retrospective cohort study of infants ≤28 weeks gestational age born between 2010 and 2016 who had echocardiographic PDA evaluation completed for hemodynamical significance as well as serial serum creatinine and urine output measurement documented, needed for the two AKI scoring systems: modified AKIN (based on serial serum creatinine) and N-RIFLE (using urine output data). Blood pressure measurements and therapy were evaluated during the hospitalization and on the day of NICU discharge. Baseline characteristics and outcome variables were compared between the hs-PDA and no or non-hs PDA using unpaired t-tests for continuous variables and chi square tests for categorical data. Results: One hundred fifty-one infants were eligible of which 110 had hs-PDA. Infants with hs-PDA were smaller (777 versus 867 g, p = .026), less mature (25.8 versus 26.4 weeks, p = .023) and had greater exposure to nephrotoxic drugs (14 versus 9.4 days, p = .001). Other clinical and demographic variables were similar between the two groups. The overall incidence of AKI was not different between the hs-PDA and no PDA or non-hs PDA groups when evaluated by the acute kidney injury network (AKIN) or N-RIFLE staging; however, preterm newborns with hs-PDA demonstrated a trend towards increased risk of AKI injury (12.7 versus 0.02%, p = .06). The N-RIFLE and AKIN scoring systems demonstrated very poor degree of agreement (kappa = 0.00853) in our study. There was no difference in the rates of hypertension during the hospitalization as well as on the day of NICU discharge. Conclusion: Preterm neonates with hs-PDA had similar rates of AKI and hypertension as neonates with no or non-hs PDA.

Dexamethasone fails to improve bleomycin-induced acute lung injury in mice.

Acute respiratory distress syndrome (ARDS) features an exudative phase characterized by alveolar damage, lung edema and exacerbated inflammatory response. Given their anti-inflammatory properties, the potential therapeutic effect of corticosteroids has been evaluated in ARDS clinical trials and experimental models of ALI. These studies produced contradictory results. Therefore, our aim was to investigate the effects of dexamethasone in an animal model of bleomycin-induced acute lung injury and then to determine if the lack of response could be related to an impairment in repair ability of alveolar epithelial cells after injury. NMRI mice were challenged with bleomycin and then treated daily with dexamethasone or saline. Bronchoalveolar lavages (BAL) and lungs were collected for assessment of the inflammatory response and wet/dry ratio (lung edema) and for histological analyses. The effect of bleomycin and dexamethasone on wound repair was also evaluated in vitro on primary alveolar epithelial cell (ATII) cultures. Our data first showed that dexamethasone treatment did not reduce the weight loss or mortality rates induced by bleomycin. Although the TNF-α level in BAL of bleomycin-treated mice was reduced by dexamethasone, the neutrophil infiltration remained unchanged. Dexamethasone also failed to reduce lung edema and damage scores. Finally, bleomycin elicited a time- and dose-dependent reduction in repair rates of ATII cell cultures. This inhibitory effect was further enhanced by dexamethasone, which also affected the expression of ß3- and ß6-integrins, key proteins of alveolar repair. Altogether, our data indicate that the inability of dexamethasone to improve the resolution of ALI might be due to his deleterious effect on the alveolar epithelium repair.