Relationship between placental autophagy and inflammasome activities with morbidity of extremely preterm infants.

BACKGROUND: The placenta is the major regulatory element of the in-utero environment, and alterations in placental cellular functions in infection, inflammation, and hypoxemia lead to adverse preterm birth outcomes. The importance of regulation of autophagy and inflammasome activities has been shown in the pathogenesis of morbidities in immature animal models. This study aimed to determine the relationship between placental autophagy and inflammasome activities with morbidity in extremely preterm infants. METHODS: Premature infants born between 24th to 29th gestational weeks were evaluated prospectively. Placental LC3B and NLRP3 immunostainings were performed to assess autophagy and inflammasome activities. Preterm morbidities including respiratory distress syndrome (RDS), patent ductus ateriosus: (PDA), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), periventricular leukomalacia (PVL), sepsis, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and mortality were evaluated. RESULTS: Fifty-nine infants with a mean gestational age of 26.9 ± 1.5 weeks were included. Anti-LC3B staining scores were moderate or intense positive in 75% of the placentas. Anti-LC3B activity was not associated with the existance of evaluated neonatal morbidities or mortality. Autophagy and inflammasome coexistence were demonstrated in 35 placentas (59.3%). Anti-NLRP3 staining score was moderate or intensely positive in 75% of the placentas. Infants with BPD had a lower rate of positive anti -NLRP3 staining than infants without BPD (42.9 vs 57.1%, p=0.048). Infants who had hemodynamic significant patent ductus arteriosus (hsPDA) and surgical- NEC showed significantly intense anti-NLRP3 staining compared to infants who did not (18.8% vs 0%, p= 0.027 and 33% vs 7.5%, p=0.048 respectively). CONCLUSIONS: The results showed that autophagy and inflammatory activities were present in varying amounts in the placenta of preterm infants. Association of decreased or increased rates of inflammasome activities with certain diseases such as BPD, hsPDA and surgical-NEC indicates the role of the intrauterin inflammatory process and the importance of critical balance in inflammation. Because of the complex pathophysiology of preterm morbidities, placental autophagy and inflammasome activities seem worthy of further investigation.

A novel Mecom gene mutation associated with amegakaryocytic thrombocytopenia in a premature infant.

BACKGROUND: Hereditary bone marrow failure syndromes are a category of biologically different syndromes that can cause cytopenia in at least one hematopoietic cell lineage. CASE: We present a 29-week-old male infant who had a low Apgar Score, advanced delivery room resuscitation, widespread petechial rash, and ecchymoses at birth, without any dysmorphic features. Initial laboratory tests revealed bicytopenia (platelet count 7x10 3 /uL, hemoglobin of 3.9 g/dL, neutrophil 2.0x103 /uL) with findings of disseminated intravasculer coagulation (DIC). Imaging studies demonstrated accompanying left-sided congenital pulmonary airway malformation. On the second postnatal week pancytopenia occurred and the bone marrow findings were consistent with congenital amegakaryocytic thrombocytopenia. Further evaluations for differential diagnosis of pancitopenia were performed and the results of congenital viral infections, metabolic and immunologic tests were negative. While supportive treatments were in progress, haploidentical bone marrow transplantation (BMT) was performed from the father at 84th day due to unavailability of HLA-matched relative or nonrelative donor. Whole exome sequencing revealed a novel heterozygous frameshift variation (c.1242dupT [p. Thr538fs]) in exon 8 of the MECOM gene and validated by Sanger sequencing. No variation was detected in the parents genetic analysis. CONCLUSIONS: In this report, we present a patient with congenital bone marrow failure successfully treated with haploidentic BMT and describe a novel, de novo pathogenic variant in MECOM gene.

The role of MRI-based texture analysis to predict the severity of brain injury in neonates with perinatal asphyxia.

OBJECTIVE: To evaluate the efficacy of the MRI-based texture analysis (TA) of the basal ganglia and thalami to distinguish moderate-to-severe hypoxic-ischemic encephalopathy (HIE) from mild HIE in neonates. METHODS: This study included 68 neonates (15 with mild, 20 with moderate-to-severe HIE, and 33 control) were born at 37 gestational weeks or later and underwent MRI in first 10 days after birth. The basal ganglia and thalami were delineated for TA on the apparent diffusion coefficient (ADC) maps, T1-, and T2 weighted images. The basal ganglia, thalami, and the posterior limb of the internal capsule (PLIC) were also evaluated visually on diffusion-weighted imaging and T1 weighted sequence. Receiver operating characteristic curve and logistic regression analyses were used. RESULTS: Totally, 56 texture features for the basal ganglia and 46 features for the thalami were significantly different between the HIE groups on the ADC maps, T2-, and T2 weighted sequences. Using a Histogram_entropy log-10 value as >1.8 from the basal ganglia on the ADC maps (p < 0.001; OR, 266) and the absence of hyperintensity of the PLIC on T1 weighted images (p = 0.012; OR, 17.11) were found as independent predictors for moderate-to-severe HIE. Using only a Histogram_entropy log-10 value had an equal diagnostic yield when compared to its combination with other texture features and imaging findings. CONCLUSION: The Histogram_entropy log-10 value can be used as an indicator to differentiate from moderate-to-severe to mild HIE. ADVANCES IN KNOWLEDGE: MRI-based TA may provide quantitative findings to indicate different stages in neonates with perinatal asphyxia.

Endotracheal Surfactant Combined With Budesonide for Neonatal ARDS.

Acute respiratory distress syndrome (ARDS) is a clinical condition characterized by acute diffuse inflammatory lung injury and severe hypoxemia. In 2017, the Montreux Consensus defined diagnostic criteria for ARDS in the neonatal period. The management of ARDS includes strict adherence to lung-protective ventilation strategies and therapeutic agents to improve gas exchange. We report two similar cases of premature infants with gestational ages of 23 and 24 weeks diagnosed with neonatal ARDS according to the Montreux definition. These patients developed acute worsening of oxygenation on the 30th and 28th day of life, respectively, while they were ventilated on volume-guarantee assist/control mode. Chest X-rays revealed bilateral diffuse opacity, there were no cardiogenic origins for pulmonary edema, and their oxygenation indexes were >8. Both cases fulfilled the neonatal ARDS criteria and the patients' clinical conditions were associated with late onset neonatal sepsis. After lung recruitment maneuver, the infants began HFO volume-guarantee ventilation and received surfactant treatment. Since they showed a poor short-term response, intratracheal surfactant of 100 mg/kg plus budesonide of 0.25 mg/kg were administered and their oxygenation indexes were reduced stepwise. Both patients survived and were discharged home with spontaneous breathing of room air. Neonatal ARDS is generally an underdiagnosed condition associated with sepsis, pneumonia, and meconium aspiration. Impaired surfactant activity and reduced lung compliance play important roles in its pathophysiology. To our knowledge, this is the first case report indicating the possible therapeutic role of budesonide plus surfactant in ARDS treatment. Since ARDS is an entity not recognized in newborns, we want to emphasize neonatal ARDS diagnosis and underline that the combination of budesonide and surfactant may be a novel therapeutic option in the treatment of ARDS.

Volume Guarantee High-Frequency Oscillatory Ventilation in Preterm Infants With RDS: Tidal Volume and DCO2 Levels for Optimal Ventilation Using Open-Lung Strategies.

High frequency oscillatory ventilation with volume-guarantee (HFOV-VG) is a promising lung protective ventilator mode for the treatment of respiratory failure in newborns. However, indicators of optimal ventilation during HFOV-VG mode are not identified yet. In this study, we aimed to evaluate optimal high-frequency tidal volume (VThf) and the dissociation coefficient of CO2 (DCO2) levels to achieve normocapnia during HFOV-VG after lung recruitment in very low birthweight infants with respiratory distress syndrome (RDS). Preterm babies under the 32nd postmenstrual week with severe RDS that received HFOV-VG using open-lung strategy between January 2014 and January 2019 were retrospectively evaluated. All included patients were treated with the Dräger Babylog VN500 ventilator in the HFOV-VG mode. In total, 53 infants with a mean gestational age of 26.8 ± 2.3 weeks were evaluated. HFOV mean optimal airway pressure (MAPhf) level after lung recruitment was found to be 10.2 ± 1.7 mbar. Overall, the mean applied VThf per kg was 1.64 ± 0.25 mL/kg in the study sample. To provide normocapnia, the mean VThf was 1.61 ± 0.25 mL/kg and the mean DCO2corr was 29.84 ± 7.88 [mL/kg]2/s. No significant correlation was found between pCO2 levels with VThf (per kg) or DCO2corr levels. VThf levels to maintain normocarbia were significantly lower with 12 Hz frequency compared to 10 Hz frequency (1.50 ± 0.24 vs. 1.65 ± 0.25 mL/ kg, p < 0.001, respectively). A weak but significant positive correlation was found between mean airway pressure (MAPhf) and VThf levels. To our knowledge, this is the largest study to evaluate the optimal HFOV-VG settings in premature infants with RDS, using the open-lung strategy. According to the results, a specific set of numbers could not be recommended to achieve normocarbia. Following the trend of each patient and small adjustments according to the closely monitored pCO2 levels seems logical.

[A Case of Congenital Syphilis and Prozone Phenomenon]. / Konjenital Sifilis Olgusu ve Prozon Fenomeni.

The screening for syphilis during pregnancy is important to prevent intrauterine transmission and complications. Prozone phenomenon may cause a false negative result in non-treponemal syphilis tests, which complicates an accurate diagnosis. In this case report a newborn syphilis case was presented to emphasize the importance of reverse algorithm in diagnosis and the prozone phenomenon which can cause problems in rapid plasma reagin (RPR) test. The 2920 g infant patient was born from a 24-year-old mother with no known diseases, at the 35th week of gestation by cesarean section due to premature rupture of membranes. The initial physical examination of the newborn revealed erythema and exfoliation of the bilateral hands and feet. Laboratory results revealed CRP: 90 mg/L, WBC: 19.2 x 103/µl, hemoglobin: 9.5 g/dl, platelet count: 214 x 103/µl, HIV-Ag/Ab: non-reactive, anti-Toxoplasma gondii IgM and IgG: negative, anti-cytomegalovirus IgM: negative, anti-cytomegalovirus IgG: positive (128.7 AU/ml), anti-Rubella IgM: negative, anti-Rubella IgG: positive (26 IU/ml), anti-Treponema pallidum (anti-T.pallidum) antibody [IgM and IgG by the chemiluminescence microparticle enzyme immunoassay (Architect Syphilis TP; Abbott Japan Co, Japan)]: positive (Signal Cut Off value (S/CO): 28.35), and RPR (Omega Diagnostics, UK): negative. All of the above ELISA tests were performed by using Architect (Abbott Diagnostics, Wiesbaden, Germany) kits. When the RPR test was repeated with serial dilutions of the serum in order to detect prozone phenomenon, positive reaction was detected starting from 1:2 and ending at 1:64 dilution. It was determined that the mother was not tested for syphilis during her pregnancy. When both the mother and the father were tested for syphilis, the mother's anti-T.pallidum total antibody test result was reactive (S/CO: 30.52) and the RPR was positive at 1:32 dilution, while the father's anti-T.pallidum total antibody test result was reactive (S/CO: 16.05) and the RPR was negative. A four-fold difference between the maternal and infant RPR dilutions is required by the guidelines for a laboratory diagnosis of congenital syphilis. Although this criterion was not met in the newborn, the case was accepted as congenital syphilis due to clinical findings. Congenital syphilis must be considered in the differential diagnosis in the presence of skin manifestations at the birth and early neonatal period. Accurate and early diagnosis of the disease is important to start appropriate treatment and prevent complications. As described in the presented case, the use of reverse syphilis test algorithm will enable to reach the correct diagnosis of the infection. If the result of the treponemal test is positive and the RPR test is negative, prozone phenomenon should be considered and the RPR test should be repeated with serial serum dilutions.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening idiosyncratic drug reaction. It presents with extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis) and internal organ involvement. It has been described in association with more than 50 drugs. To the best of our knowledge neither cefotaxime nor clindamycin has been previously reported to induce DRESS syndrome in children. Clindamycin was reported only in adults as a cause of DRESS syndrome in the literature. In this report, we aimed to present a child with DRESS syndrome that developed after cefotaxime and clindamycin treatment. A 6-year-old boy was diagnosed with the left lower lobe pneumonia and pleural effusion. Parenteral cefotaxime and clindamycin were then started, after which the patient improved clinically and was discharged 7 days later with oral amoxicillin clavulanate treatment. After four days he was readmitted to the hospital with fever and cough. Chest X-ray revealed left lower lobe pneumonia and pleural effusion. We considered that the pneumonia was unresponsive to oral antibiotic treatment, and therefore parenteral cefotaxime and clindamycin were re-administered. As a result, his clinical and radiological findings were improved within 10 days. On the 12th of day of hospitalization, the body temperature has risen to 39°C, which we considered to be caused by antibiotics and stopped antibiotic treatment. At the same day he developed generalized maculopapular erythematous rash, which was considered an allergic reaction secondary to antibiotics. Despite the antihistaminic drug administration, the clinical status quickly deteriorated with generalized edema, lymphadenopathies and hepatosplenomegaly. Laboratory tests revealed a white blood cell count of 4300/µl, a lymphocyte count of 1300/µl, a hemoglobin level of 11.2 gr/dl, a platelet count of 120.000/µl, an eosinophilia ratio of 10% on peripheral blood smear, a C-reactive protein level of 20 mg/dl, a procalcitonin level of 23.94 ng/ml and an erythrocyte sedimentation rate of 48 mm/h. Anti nuclear antibody, anti-double stranded DNA, the serologic tests for Epstein Bar virus, herpes simplex virus, parvovirus, mycoplasma, toxoplasmosis, rubella, cytomegalovirus were all found negative. Bone marrow aspiration was consistent with an autoimmune reaction. An echocardiographic examination was normal. Thoracic tomography revealed multiple enlarged axillary, supraclavicular and anterior mediastinal lymph nodes. As the patient met 8 out of 9 RegiSCAR criteria for the diagnosis of DRESS, we started pulse methyl prednisolone (30 mg/kg/day) for three days followed by 2 mg/kg/day. On the 2nd day fever resolved and cutaneous rash and edema improved. Ten days after developing eruptions the patient was discharged. To our knowledge, we report the first pediatric case of DRESS syndrome following treatment with cefotaxime and clindamycin. Pediatricians should be aware of this potential complication associated with these commonly prescribed antibiotics.