Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterized by external ear anomalies with sensorineural hearing loss, limb anomalies, renal and anorectal malformations. TBS is caused by mutations in SALL1, a gene mapped to chromosome 16q12.1. We report three generations of a family with SALL1 c.1326delC (p.Ser442fs) mutation, showing increased clinical severity over generations. The members of the first generation demonstrated polydactyly and deafness. In the second generation, the mother and uncle of the proband additionally had renal and/or anal anomalies. The proband in the third generation showed the most severe symptoms including congenital heart disease. Increase in clinical severity in successive generations in TBS cannot be explained genetically. There is wide clinical variation in TBS; however, most affected parents are usually mildly affected and may have similarly or more severely affected children. Social and/or physical bias at reproduction may contribute to an apparent increase in clinical severity over generations in TBS.
The arachidonic acid (AA) cascade plays a significant role in platelet aggregation. AA released from membrane phospholipids is metabolized by cyclooxygenase (COX) pathway to thromboxane A 2 (TXA 2) or by 12S-lipoxygenase (ALOX12) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE). In contrast to a well-known role of the COX pathway in platelet aggregation, the role of ALOX12 is not well understood. Platelets of ALOX12-deficient mice exhibit increased sensitivity for ADP-induced aggregation. However, recent evidence strongly suggests a significant role of ALOX12 in platelet aggregation and calcium signaling. 12-HPETE potentiates thrombin-and thromboxane-induced platelet aggregation, and calcium signaling. Inhibition experiments of ALOX12 demonstrated decreased platelet aggregation and calcium signaling in stimulated platelets. We studied a family with a dominantly inherited bleeding diathesis using next-generation sequencing analysis. Platelet aggregation studies revealed that the proband's platelets had defective aggregation responses to ADP, TXA 2 mimetic U46619, collagen, and AA, normal affinity of TXA 2 receptor for U46619, and normal induction of GTPase activity upon stimulation with U46619. However, the production of inositol 1,4,5-triphosphate (IP 3) was only increased up to 30% of the control upon U46619 stimulation, suggesting a defect in phospholipase C-β2 (PLCB2) activation downstream from TXA 2 receptors. Affected family members had no mutation of PLCB2, but had a heterozygous c.1946A > G (p.Tyr649Cys) mutation of ALOX12. ALOX12 activity in platelets from the affected members was decreased to 25-35% of the control. Our data strongly suggested that a heterozygous c.1946A > G ALOX12 mutation was a disease-causing mutation; however, further experiments are required to confirm the pathogenesis of ALOX12 mutation in platelet aggregation.
A 45-year-old male suffered from persistent swelling and redness, with pain in his left lower leg and ankle. Pathological findings isolated from the ankle joint by arthroscopic synovectomy showed mild synovitis. Initially, this case was diagnosed as chronic mild arthritis and later treated as phlegmon because of the persistent redness and swelling inflammatory findings in his left lower leg. A systemic survey was performed. Based on the findings-such as chronic ankle arthritis with ipsilateral plantar pustulosis, chronic recurrent multifocal osteomyelitis in left distal tibia with magnetic resonance imaging (MRI), calcaneal osteitis with computed tomography, and pathological findings that neither malignant tumor nor infection was detected-this case reached the definitive diagnosis of SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome. The hot spots detected in the bilateral sternoclavicular and costosternal joints with bone scintigraphy and their arthritic change detected by computed tomography also supported the diagnosis of SAPHO syndrome. This case was refractory to nonsteroidal antiinflammatory drugs (NSAIDS); therefore, the TNF inhibitor certolizumab pegol was tried. This agent rapidly improved not only the chief complaints but also the objective symptoms and laboratory findings at most six weeks after its administration.
<b><i>Introduction:</i></b> Because excessive physical stress is harmful, reducing pain and discomfort in premature neonates during mechanical ventilation is a major challenge for physicians. There are no consensus and systematic review on the use of fentanyl, the most commonly used pain reliever in preterm neonates during mechanical ventilation. We aim to compare the benefits and harms of fentanyl versus placebo or no drug for preterm neonates receiving mechanical ventilation. <b><i>Methods:</i></b> A systematic review of randomized controlled trials (RCTs) was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Scientific databases such as MEDLINE, Embase, CENTRAL, and CINAHL were searched. All preterm infants on mechanical ventilation and enrolled in an RCT of fentanyl versus control were included. <b><i>Results:</i></b> Of 256 reports initially retrieved, 4 reports met the eligibility criteria. Fentanyl was not associated with mortality risk compared to the control (risk ratio: 0.72, 95% confidence intervals [CIs]: 0.36–1.44). No increase in ventilation duration (mean difference [MD]: 0.04, 95% CIs: −0.63–0.71) and no effect on hospital stay length (MD: 4.00, 95% CIs: −7.12–15.12) were found. Fentanyl intervention does not affect any other morbidities, including bronchopulmonary dysplasia, periventricular leukomalacia, patent ductus arteriosus, intraventricular hemorrhage (IVH), severe IVH, sepsis, and necrotizing enterocolitis. <b><i>Conclusion:</i></b> The present systematic review and meta-analysis failed to demonstrate the benefit of administering fentanyl to preterm infants on mechanical ventilation in mortality and morbidities. Follow-up studies are required to investigate the long-term neurodevelopment of the children.
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