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Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function, and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs), and Plexin D1 located at cell–cell junctions mediates many of these events. However, available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial-specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology, and disease. Synopsis: Fluid shear stress from blood flow induces vascular endothelium remodeling by triggering signaling events through the PECAM-1/VE-cadherin/VEGF receptor/Plexin D1 complex at cell-cell junctions. This study shows that the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) activates Gαi2 and Gαq/11 to induce shear stress-dependent activation of this pathway. Shear stress-induced activation of Gαi2 and Gαq/11 is required for endothelial cell alignment and activation of junctional signaling events. Lphn2 is the upstream GPCR that co-localizes and interacts with PECAM-1 to activate its signaling. Deletion of Lphn2 from zebrafish and mice blocks multiple flow-dependent developmental and adult vascular remodeling processes. Shear stress-induced activation of Gαi2 and Gαq/11 by the adhesion receptor latrophilin-2 is required for PECAM-1 signaling and vascular remodeling in zebrafish and mice. [ABSTRACT FROM AUTHOR]

Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs, underdeveloped lungs, and thoracic hypoplasia. Neonates with TD develop severe respiratory problems due to thoracic hypoplasia and require respiratory management for survival. Despite the resolution of respiratory problems, long‐term survival cases are rare. Previous studies have reported that surgical procedures in patients with TD are limited to those necessary for survival, including tracheostomy, laminectomy, and ventricular shunt. A 1‐year‐old boy with TD was treated with laparoscopic herniorrhaphy. To the best of our knowledge, this is the first report of TD treated with laparoscopic procedure. [ABSTRACT FROM AUTHOR]

Background: Hernioplasty is one of the most commonly performed surgeries. However, the optimal procedure for young adults has not been defined yet. Our study compared the outcomes of laparoscopic percutaneous extraperitoneal closure (LPEC) in young adults with outcomes in children. Material and Methods: We retrospectively reviewed patients aged 0–30 years who underwent LPEC. Data regarding age, sex, hernia type, surgical time, pre‐intraoperative laterality, contralateral patent processus vaginalis (CPPV), and complications were analyzed. Results: LPEC was performed on 2642 patients in our hospital. Of these, 51 patients were young adults (aged 15–30 years). Asymptomatic CPPV in unilateral patients was frequent in the <15‐year age group (50.2%) compared to the 15–30‐year age group (15.9%). The median surgical time was shorter in the <15‐year age group (19 min, interquartile range [IQR]: 24–33) compared to that of the 15–30‐year age group (33 min, IQR: 23.3–40.8). Conclusions: This is the first report on the outcomes in young adult patients who underwent LPEC. The median surgical time was longer in the 15–30‐year age group than in the <15‐year age group. The median follow‐up was 4.7 years with no intra‐postoperative complications, such as postoperative bleeding, infection, persistent pain, and recurrence. LPEC is an effective, cosmetic, and safe surgical treatment in young adults and children. [ABSTRACT FROM AUTHOR]

Bochdalek hernia (BH) is characterized by a defect of the posterolateral diaphragm and intrathoracic herniation of abdominal organs. The laparoscopic or thoracoscopic approach has recently become the surgical standard. However, studies on combined approaches are limited. An 8‐year‐old boy diagnosed with left BH was treated using a combined laparoscopic and thoracoscopic approach. On laparoscopy, BH with hernia sac was identified. Spleen, pancreas tail, kidney, and transverse colon had herniated into the left thoracic cavity. After the adhesion between transverse colon and hernia sac was dissected, all abdominal organs were restored to the abdominal cavity. On thoracoscopy, an 8 × 8 cm hernia orifice defect was identified and closed by suture. The postoperative course was uneventful, with no recurrence. A combined laparoscopic and thoracoscopic approach is safe and effective with a good field of view for left BH with hernia sac in children. To the best of our knowledge, this is the first case with left BH reporting the use of both approaches in a child without conversion. [ABSTRACT FROM AUTHOR]

Background: Incisional hernia (IH) is a major complication of abdominal surgery. Although previous studies reported that the incidence of IH after abdominal surgery in adults was 5-50% and that various independent risk factors were involved, IH in children is still not well known. The objective of our study was to investigate the incidence and risk factors for IH in children.Methods: We retrospectively reviewed all children who underwent abdominal surgery at the Jikei University Hospitals (Jikei University Hospital, Kashiwa Hospital, Katsushika Medical Center and Daisan Hospital) between January 2001 and December 2016. Abdominal surgery in children was defined as open laparotomy and laparoscopic abdominal surgery in patients ≤ 15 years old. Conventional open repair for inguinal hernias, umbilical hernia repair, congenital abdominal defect repair and orchiopexy were excluded.Results: Overall, 2049 children were performed abdominal surgery. Among them, 14 children (10 males and 4 females) developed IH, and the incidence of IH was 0.68% (14/2049). There is no significant difference between laparotomy and laparoscopic surgery. The statistically significant variables and identified risk factors were operation in neonates, laparoscopic fundoplication and open supraumbilical pyloromyotomy. In all patients who had IH repair, there was no recurrence during the follow-up period 50.4 months (range 1 months-10 years) except two recurrence cases.Conclusion: The incidence of IH in children is significantly lower than that in adults, and the above three risk factors were revealed. Before abdominal surgery, we recommend that pediatric surgeons should mention the risk of developing IH when the patient has the above risk factors. [ABSTRACT FROM AUTHOR]

Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor with low-grade malignancy in children. A complete surgical resection can achieve a favorable prognosis. Although several reports have indicated that enucleation is considered a safe and effective treatment, the most significant complication is injury to the main pancreatic duct. The usefulness and safety of tumor enucleation after preoperative placement of an endoscopic nasopancreatic drainage stent (NPDS) has recently been reported. We present the case of SPT in a 10-year-old girl. To avoid and detect injury to the main pancreatic duct during operation, an NPDS was endoscopically placed before laparotomy. The patient underwent a complete enucleation of the tumor with the guidance of an NPDS. Our case is the first report of a successful enucleation of an SPT with a preoperative placement of an NPDS. This procedure may lead to safe enucleation of a pancreatic tumor with low malignancy, such as SPT, in children. [ABSTRACT FROM AUTHOR]

To cope with life-threatening high osmolarity, yeast activates the high-osmolarity glycerol (HOG) signaling pathway, whose core element is the Hog1 MAP kinase cascade. Activated Hog1 regulates the cell cycle, protein translation, and gene expression. Upstream of the HOG pathway are functionally redundant SLN1 and SHO1 signaling branches. However, neither the osmosensor nor the signal generator of the SHO1 branch has been clearly defined. Here, we show that the mucin-like transmembrane proteins Hkr1 and Msb2 are the potential osmosensors for the SHO1 branch. Hyperactive forms of Hkr1 and Msb2 can activate the HOG pathway only in the presence of Sho1, whereas a hyperactive Sho1 mutant activates the HOG pathway in the absence of both Hkr1 and Msb2, indicating that Hkr1 and Msb2 are the most upstream elements known so far in the SHO1 branch. Hkr1 and Msb2 individually form a complex with Sho1, and, upon high external osmolarity stress, appear to induce Sho1 to generate an intracellular signal. Furthermore, Msb2, but not Hkr1, can also generate an intracellular signal in a Sho1-independent manner. [ABSTRACT FROM AUTHOR]

The yeast high osmolarity glycerol (HOG) signaling pathway can be activated by either of the two upstream pathways, termed the SHO1 and SLN1 branches. When stimulated by high osmolarity, the SHO1 branch activates an MAP kinase module composed of the Ste11 MAPKKK, the Pbs2 MAPKK, and the Hog1 MAPK. To investigate how osmostress activates this MAPK module, we isolated both gain-of-function and loss-of-function alleles in four key genes involved in the SHO1 branch, namely SHO1, CDC42, STE50, and STE11. These mutants were characterized using an HOG-dependent reporter gene, 8xCRE-lacZ. We found that Cdc42, in addition to binding and activating the PAK-like kinases Ste20 and Cla4, binds to the Ste11–Ste50 complex to bring activated Ste20/Cla4 to their substrate Ste11. Activated Ste11 and its HOG pathway-specific substrate, Pbs2, are brought together by Sho1; the Ste11–Ste50 complex binds to the cytoplasmic domain of Sho1, to which Pbs2 also binds. Thus, Cdc42, Ste50, and Sho1 act as adaptor proteins that control the flow of the osmostress signal from Ste20/Cla4 to Ste11, then to Pbs2. [ABSTRACT FROM AUTHOR]