Surfactant therapy using a bronchofiberscope in respiratory distress syndrome.

BACKGROUND: Avoiding endotracheal intubation and using nasal continuous positive airway pressure as the initial treatment is recommended in infants with respiratory distress syndrome (RDS), and modes of lesser invasive surfactant administration have recently been reported. We report a pilot study assessing the feasibility of surfactant therapy using a bronchofiberscope (STUB) in RDS. METHODS: Surfactant was administered to 31 preterm infants (gestational age range of 28 weeks 0 days to 36 weeks 6 days) diagnosed with RDS, through the working channel of the bronchofiberscope or endotracheal tubes. Patient characteristics, outcomes, adverse events, and comorbidities were assessed in the two groups. RESULTS: Twelve infants received STUB. Two of the 12 infants (17%) needed subsequent intubation and additional surfactant administration. Nineteen infants received surfactant through endotracheal tubes. Four of the 19 infants (21%) required additional surfactants. There was no significant difference in the number of infants that needed additional surfactant (p = 1.00). Gestational age, birthweight, length of hospitalization, adverse events, such as desaturations and bradycardias, and comorbidities were similar between the two groups. Days of invasive ventilation were significantly shorter in the STUB group (p = 0.0002). CONCLUSION: STUB was feasible in this small cohort and reduced the need for intubation to 17%, leading to fewer days of invasive ventilation, without increasing comorbidities and adverse events. To the best of our knowledge, this is the first study to administer surfactants using bronchofiberscopes.

Germline-Activating RRAS2 Mutations Cause Noonan Syndrome.

Noonan syndrome (NS) is characterized by distinctive craniofacial appearance, short stature, and congenital heart disease. Approximately 80% of individuals with NS harbor mutations in genes whose products are involved in the RAS/mitogen-activating protein kinase (MAPK) pathway. However, the underlying genetic causes in nearly 20% of individuals with NS phenotype remain unexplained. Here, we report four de novo RRAS2 variants in three individuals with NS. RRAS2 is a member of the RAS subfamily and is ubiquitously expressed. Three variants, c.70_78dup (p.Gly24_Gly26dup), c.216A>T (p.Gln72His), and c.215A>T (p.Gln72Leu), have been found in cancers; our functional analyses showed that these three changes induced elevated association of RAF1 and that they activated ERK1/2 and ELK1. Notably, prominent activation of ERK1/2 and ELK1 by p.Gln72Leu associates with the severe phenotype of the individual harboring this change. To examine variant pathogenicity in vivo, we generated zebrafish models. Larvae overexpressing c.70_78dup (p.Gly24_Gly26dup) or c.216A>T (p.Gln72His) variants, but not wild-type RRAS2 RNAs, showed craniofacial defects and macrocephaly. The same dose injection of mRNA encoding c.215A>T (p.Gln72Leu) caused severe developmental impairments and low dose overexpression of this variant induced craniofacial defects. In contrast, the RRAS2 c.224T>G (p.Phe75Cys) change, located on the same allele with p.Gln72His in an individual with NS, resulted in no aberrant in vitro or in vivo phenotypes by itself. Together, our findings suggest that activating RRAS2 mutations can cause NS and expand the involvement of RRAS2 proto-oncogene to rare germline disorders.

Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm.

BACKGROUND: A definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that warrant genetic testing. Electrical activity of the diaphragm (Edi) reflects neural respiratory drive from respiratory center to diaphragm. We evaluated the function of the respiratory center in CCHS by Edi monitoring. METHODS: Monitoring of Edi was performed in six CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously. RESULTS: The Edi peak during wakefulness was 14.0 (10.3-21.0) µV and the Edi peak during sleep was 6.7 (3.8-8.0) µV. The Edi peak during sleep was significantly lower than the Edi peak during wakefulness, and patients were in a state of hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in the Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06µV/mmHg. Maximum EtCO2 or TcPco2 was 51 mmHg, and the average SpO2 was 91.5% during monitoring. CONCLUSIONS: We confirmed that Edi monitoring could evaluate the function of the respiratory center and reproduce the hypoventilation of CCHS. The present study suggested that Edi monitoring is a useful examination in deciding whether to perform genetic testing or not and it may lead to an early diagnosis of CCHS.

Anti-human neutrophil antigen-1a, -1b, and -2 antibodies in neonates and children with immune neutropenias analyzed by extracted granulocyte antigen immunofluorescence assay.

BACKGROUND: Anti-human neutrophil antigen (HNA) antibodies have been implicated in the development of neonatal alloimmune neutropenia (NAN) and autoimmune neutropenia (AIN). There are many conventional assay methods that detect anti-HNA antibodies. However, a method to measure multiple samples and detect several anti-HNA antibodies simultaneously is needed. STUDY DESIGN AND METHODS: We developed a new method, the extracted granulocyte antigen immunofluorescence assay (EGIFA), to analyze anti-HNA-1a, -1b, and -2 antibodies in sera. The results obtained by EGIFA were evaluated in comparison with those from several standard assay methods. Anti-HNA antibodies in serum samples from nine familial cases with suspected NAN (n = 19) and children with suspected AIN (n = 88) were also measured by EGIFA. RESULTS: The evaluation of nine serum samples with anti-HNA antibodies suggested that EGIFA demonstrated equivalent specificity and superior sensitivity to monoclonal antibody-specific immobilization of granulocyte antigens and had comparable sensitivity to the granulocyte indirect immunofluorescence test. EGIFA successfully detected anti-HNA-1a or -1b antibodies in seven of nine familial cases with suspected NAN. EGIFA detected anti-HNA antibodies in 40.9% of children with suspected AIN. Among them, isolated anti-HNA-1a or -1b antibody was detected in 4.5 or 12.5% of children, respectively, and anti-HNA-2 antibody was identified in 3.4% of children. The 30.8% (16 of 52) of children negative for anti-HNA antibody by EGIFA were positive for anti-HLA antibody. CONCLUSION: EGIFA facilitated the measurement of anti-HNA-1a, -1b, and/or -2 antibodies in sera. The prompt measurement of anti-HNA antibodies will improve the diagnosis and clinical management of patients with suspected NAN or AIN.

Recombinant human soluble thrombomodulin and danaparoid combination anticoagulant therapy for disseminated intravascular coagulation in a child with streptococcal toxic shock syndrome: A case report.

Disseminated intravascular coagulation (DIC) is a common and morbid complication of streptococcal toxic shock syndrome (STSS). Because DIC with STSS progresses rapidly, prompt and proper care is critical. The present report describes the case of a 10-year-old boy who survived STSS with DIC without sequelae after treatment with combination anticoagulant therapy of recombinant human soluble thrombomodulin (rhTM) and danaparoid. RhTM and antithrombin-III were administered on day 1. RhTM administration was continued. Despite this, on day 2, his general condition remained poor, his fever persisted and his DIC score increased from an initial 5 points upon admission to 9 points. Therefore, danaparoid was additionally administered from day 2 onwards. The patient recovered without serious complications. Combination anticoagulant therapy of rhTM and danaparoid for DIC in a child with STSS was effective and safe. Therefore, this combination therapy could be used as an option for managing high-risk, rapidly progressing disease states, which predispose to morbid sequelae and death, such as DIC with STSS. RhTM and danaparoid therapy may reduce the risk of serious complications, such as organ failure, and improve the prognosis not only in STSS but also in other conditions with infection and DIC concurrence, such as sepsis.

Lateral buttock congenital dermal sinus tract.

A 6-month-old female presented with purulent discharge from a dimple in the right lateral buttock. A subcutaneous abscess was palpated on the right paravertebral region at the L5-S1 level. She had low-grade fever with laboratory findings of leukocytosis and elevation of C-reactive protein levels. Klebsiella and Enterococcus species were cultured from the pus. Computed tomography (CT) clearly showed a tract traversing the subcutaneous tissue and connecting to the abscess. Magnetic resonance (MR) imaging showed no abnormality in the spinal canal. The diagnosis was infected congenital dermal sinus (CDS) in the right buttock. After normalization of body temperature and laboratory findings in response to antibiotic treatment, the dermal sinus tract was surgically removed. Intraoperative findings showed that the tract gradually tapered and ended at the subcutaneous abscess space over the lumbosacral fascia. Histological examination confirmed the lesion was dermal sinus. Although laterally placed CDS in the buttocks is extremely rare with only 5 previous cases reported, lateral CDS should be included in the differential diagnosis of a dimple in the buttocks. CT as well as MR imaging should be performed to evaluate suspected lateral CDS.

Significance of immature platelet fraction and CD41-positive cells at birth in early onset neonatal thrombocytopenia.

Early thrombocytopenia is a common hematological abnormality in sick neonates. Here, we examined the relationship between early thrombocytopenia in neonates and parameters associated with thrombopoiesis to identify predictive factors at birth. Two hundred and forty-four neonates admitted to the neonatal intensive care unit were divided into thrombocytopenic (n = 55, 23%) and non-thrombocytopenic (n = 189, 77%) groups based on platelet counts, which were monitored within 72 h of birth. Immature platelet fraction (IPF) and platelet count at birth were determined simultaneously soon after phlebotomy with an automated hematology analyzer. Megakaryocytes and their precursors positive for CD41 in peripheral blood were examined at birth by flow cytometry. The thrombocytopenic group showed significantly higher IPF percentage and lower percentage of CD41+ mononuclear cells (MNCs) than did the non-thrombocytopenic group (P < 0.01). Moreover, the percentage of CD41+ MNCs significantly differentiated neonates with platelet counts >150 x 10(3)/microL at birth and nadir platelet count <150 x 10(3)/microL over the clinical course from neonates without thrombocytopenia. These observations suggest that the percentage of CD41+ MNCs at birth and IPF percentage are useful predictors of early thrombocytopenia in the majority of sick neonates.

Significance of the detection of antineutrophil antibodies in children with chronic neutropenia.

We evaluated the clinical characteristics of 41 children with chronic neutropenia based on the quantitative analysis of antineutrophil antibodies in serum by flow cytometry. According to the strength of antineutrophil antibodies, the patients were divided into 3 groups: 12 patients presented negative antibodies, 13 patients showed weak positive antibodies, and 16 patients showed strong positive antibodies. No significant differences were seen in age of diagnosis, severity of neutropenia, and infectious complications associated with neutropenia among the 3 groups. The spontaneous resolution of neutropenia was observed in all patients with negative antibodies and in 22 of 29 patients with positive antibodies. The age of the recovery of neutropenia and the duration until spontaneous resolution of neutropenia were significantly dependent on the antibody strength at the time of diagnosis. These results demonstrate that the quantification of antineutrophil antibodies at the time of diagnosis may be useful in considering the clinical course of chronic neutropenia in childhood.

Efficacy of prophylactic use of trimethoprim-sulfamethoxazole in autoimmune neutropenia in infancy.

PURPOSE: Most children with autoimmune neutropenia (AIN) have a benign clinical course because of the spontaneous resolution of neutropenia. The authors observed the clinical course of AIN in infancy accompanied by the prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX) during neutropenia. PATIENTS AND METHODS: Eight infants with AIN were followed by serial tests for antineutrophil antibodies and management of infectious complications. RESULTS: The spontaneous disappearance of antineutrophil antibodies that preceded the normalization of the neutrophil count was found in all patients. Until the resolution of neutropenia, TMP-SMX was administered in five patients, resulting in a reduction in the incidence of infection with no adverse effects. CONCLUSIONS: These observations demonstrate the possibility of the safety and usefulness of TMP-SMX treatment in patients with AIN.

A case of post-transplant hyperparathyroidism treated with ethanol injection.

A 15-year-old boy with chronic renal failure secondary to Alport's syndrome underwent living-related renal transplantation from his 48-year-old father. His primary immunosuppressive regimen was composed of tacrolimus, mizolibine, and methylprednisolone. The postoperative course was satisfactory with one episode of mild acute rejection, treated successfully with methylprednisolone pulse therapy. Two months later, hypercalcemia (11.8-13.2 mg/dl) and hypophosphatemia (2.5-3.0 mg/dl) were noted without any bone symptoms. The serum intact-parathyroid hormone (PTH) and serum alkaline phosphatase levels were 240 pg/ml and 2483 IU/l, respectively. Ultrasound studies revealed enlargement of the two parathyroid glands. Under the diagnosis of tertiary hyperparathyroidism, he underwent percutaneous ethanol injection (PEIT) into the left parathyroid gland. Although levels of serum calcium and phosphorus returned to normal ranges and the intact PTH level decreased to 95 pg/ml with the three injections, another injection was needed to normalize recurrent hypercalcemia 2 months later. The patient experienced only transient mild dysphonia and local pain after PEIT. Although PEIT is believed less effective than parathyroidectomy, it has some advantages such as applicability to high-risk patients, repeatability of treatment, low incidence and severity of side effects.