Controlling the arterial supply into the pancreatic head region as a whole peripancreatic arterial arcade via a mesenteric approach during isolated pancreatoduodenectomy.

PURPOSE: The peripancreatic arterial system forms various arterial arcades and collateral branches; therefore, it stands to reason that the arterial supply into the pancreatic head region should be controlled as a whole peripancreatic arterial arcade rather than as the three major supplying arteries during isolated pancreatoduodenectomy (PD). We investigated the clinical importance of early control of the whole peripancreatic arterial arcade during PD. METHODS: The subjects of this retrospective study were 63 consecutive patients who underwent PD via a mesenteric approach at our hospital between October, 2014 and February, 2017. The patients were divided into an early control group (n = 27) and a late control group (n = 36) for comparative analysis. RESULTS: The peripancreatic arterial arcades and collateral branches were seen on preoperative multidetector row computed tomography (CT) images and during PD in all 63 patients. The early control group had significantly less intraoperative blood loss than the late control group. Early control of the whole peripancreatic arterial arcade was an independent factor associated with lower intraoperative blood loss in the multivariable analysis (P = 0.012). CONCLUSION: The arterial supply into the pancreatic head region should be controlled as a whole peripancreatic arterial arcade rather than as the three major supplying arteries during isolated PD.

Differences in Clinical Findings Based on the Duration of Symptoms and Age of Children With Ileocolic Intussusception: A Single-Institution Survey in Rural Japan.

OBJECTIVES: The objective of this study was to determine whether the rates of abdominal pain or irritability, vomiting, and hematochezia differ depending on the duration of symptoms and age of the children with ileocolic intussusception. METHODS: We retrospectively investigated the charts of ileocolic intussusception children between January 2008 and December 2017 at a rural general hospital in Japan. Children were separated into 2 groups: the early visiting group, including children examined within 6 hours after onset, and the late visiting group, including children examined more than 6 hours after onset. We further separated them into 2 groups based on age: the infant group (age, <18 months) and the child group (age, ≥18 months). We compared clinical features, such as abdominal pain or irritability, vomiting, and hematochezia, between each group. RESULTS: Among 105 children with ileocolic intussusception, 51 were in the early visiting group and 49 were in the infant group. Hematochezia less frequently occurred in the early visiting group than in the late visiting group (29% vs 50%, P = 0.046). Furthermore, abdominal pain or irritability occurred less frequently in the infant group than in the child group (79.6% vs 98.2%, P = 0.003). Conversely, vomiting and hematochezia were more frequent in the infant group than in the child group (83.7% vs 51.8%, P < 0.001; 55.1% vs 26.8%, P = 0.005). CONCLUSIONS: Clinical features of pediatric ileocolic intussusception may depend on symptom duration and age.

Fulminant myocarditis following recurrent generalized erythrokeratoderma in a child with a heterozygous GJA1 variant.

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.

Sivelestat sodium hydrate treatment for refractory Kawasaki disease.

BACKGROUND: There is still no definite treatment for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional i.v. immunoglobulin (IVIG) for KD resistant to initial IVIG therapy. METHODS: This study is a prospective non-randomized, open-label and single-arm study undertaken in a population of refractory KD patients at Chiba University Hospital from December 2006 to March 2016. The subjects had KD resistant to initial IVIG (2 g/kg) and received SSH (0.2 mg/kg/h for 5 days) combined with additional IVIG (2 g/kg) as a second-line therapy. We evaluated the safety and efficacy of the treatment during the study period. RESULTS: Forty-six KD patients were enrolled in this study and no serious adverse event was noted. Of these, 45 patients were evaluated for the incidence of coronary artery lesions, which occurred in one patient (2.2%; 95% CI: 0.5-15.2). Twenty-eight (62.2%) responded promptly and were afebrile after the therapy. The median total duration of fever was 8 days (range, 6-28 days). CONCLUSIONS: Additional IVIG combined with SSH as a second-line therapy for KD refractory to initial IVIG therapy was safe and well tolerated and could be a promising option for severe KD. Further investigations are expected to clarify the safety and timing of SSH treatment for KD.

Splenic vein reconstruction is unnecessary in pancreatoduodenectomy combined with resection of the superior mesenteric vein-portal vein confluence according to short-term outcomes.

BACKGROUND: Superior mesenteric vein-portal vein confluence resection combined with pancreatoduodenectomy (SMPVrPD) is occasionally required for resection of pancreatic head tumors. It remains unclear whether such situations require splenic vein (SV) reconstruction for decompression of left-sided portal hypertension (LSPH). METHODS: The data from 93 of 104 patients who underwent pancreatoduodenectomy (PD) for pancreatic head malignancies were reviewed. Surgical outcomes in three groups-standard PD (control group), PD combined with vascular resection and SV preservation (SVp group), and SMPVrPD with SV resection (SVr group)-were compared. The influence of division and preservation of the two natural confluences (left gastric vein-portal vein and/or inferior mesenteric vein-SV confluences) on portal hemodynamics were evaluated using three-dimensional computed tomographic portography. RESULTS: No mortality occurred. The morbidity rates were not significantly different among the three groups (18/43, 8/21, and 7/29, respectively; p = 0.306). In the SVr group, three patients had gastric remnant venous congestion, and three had esophageal varices without hemorrhagic potential. No patients had splenomegaly, or severe or prolonged thrombocytopenia. These LSPH-associated findings were less frequently observed when the two confluences were preserved. CONCLUSIONS: SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH.

A case report of a child with pulmonary hypertension associated with SARS-CoV-2 infection.

We encountered a pediatric case of pulmonary hypertension triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 14-year-old girl was brought to the emergency department of our hospital with fever, respiratory distress, and impaired consciousness. She tested positive for SARS-CoV-2 upon a polymerase chain reaction examination and had prolonged hypoxemia without pneumonia. An echocardiography revealed elevated right ventricular pressure. She was diagnosed with pilocytic astrocytoma at the age of 10 years and underwent a resection of a pituitary tumor. Hormone replacement therapy was administered postoperatively, but her growth hormones were not activated because of concerns about tumor recurrence. Echocardiography at the age of 13 years showed normal right ventricular pressure. On admission, she had an abnormal liver function, elevated liver fibrosis markers, a decreased platelet count, and hepatosplenomegaly, suggesting pulmonary and portal hypertension. The diagnosis was pulmonary hypertension associated with SARS-CoV-2 infection. The mechanism of the pulmonary hypertension was thought to be portal hypertension owing to growth hormone deficiency and SARS-CoV-2 infection. The patient's symptoms improved with oxygenation and bed rest without additional targeted pulmonary hypertension therapy, and her right ventricular pressure decreased. This case demonstrates that a pediatric patient with subclinical pulmonary hypertension may develop pulmonary hypertension triggered by SARS-CoV-2 infection.

Case report: Progressive pulmonary artery hypertension in a case of megalencephaly-capillary malformation syndrome.

Megalencephaly-capillary malformation syndrome (MCAP, OMIM # 602501) is caused by hyperactivity of the thephosphoinositide-3-kinase (PI3K)-Vakt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which results in megalencephaly, capillary malformations, asymmetrical overgrowth, and connective tissue dysplasia. Herein, we report the case of a 7-month-old girl with MCAP due to a PIK3CA somatic mosaic variant who presented with atrial tachycardia, finally diagnosed as pulmonary arterial hypertension (PAH). Oxygen therapy and sildenafil decreased pulmonary blood pressure and improved atrial tachycardia. Previous studies reported an association between the PI3K/AKT/mTOR pathway and abnormal pulmonary arterial smooth muscle cell proliferation, which may be associated with PAH. PAH should be considered a potentially lethal complication in MCAP patients, even when no structural cardiac abnormalities are identified in the neonatal period.

Long-term management of recurrent papillary thyroid carcinoma treated with lenvatinib for over 5 years: a case report.

BACKGROUND: Few reports exist of the long-term management of recurrent and progressive papillary thyroid carcinoma (PTC) with a tyrosine kinase inhibitor for over 5 years. CASE PRESENTATION: A 57-year-old woman was referred to a psychiatric hospital for the treatment of schizophrenia. The patient had been diagnosed with a PTC at the age of 40 and subsequently underwent a left thyroid lobectomy. At 47, completion total thyroidectomy and lymph node dissection were performed and the patient assessed as radioactive iodine refractory postoperatively. External radiation therapy was performed for Rouviere lymph nodes. At 57, neck and mediastinal lymph nodes, and lung metastases had progressed, and the trachea became narrowed by para-tracheal lymph node compression. After 2 weeks of sorafenib therapy on an outpatient basis, the patient was discovered unconsciousness at home and transferred to hospital by ambulance; sorafenib therapy was stopped. The patient was diagnosed with reversible posterior leukoencephalopathy syndrome by brain magnetic resonance imaging. External radiation therapy to the site of the tracheal stenosis in the neck and mediastinum was performed. The patient's mental symptoms worsened, and she was referred to a psychiatric hospital, Kachi Memorial Hospital, in July 2015. In September, the patient's mental state stabilized and in November, after computed tomography revealed rapid disease progression, lenvatinib was commenced at a daily dose of 24 mg. Measurable solid recurrence sites were neck lymph nodes in the pre-laryngeal subcutaneous space, right lobe of the lung, and left adrenal. After 3 months, the tumors shrank in a partial response (PR). Because of several adverse events, occasional dose reductions or discontinuations of lenvatinib were sometimes necessary. Since re-starting lenvatinib, treatment with this for 51 consecutive months was achieved while maintaining a PR. Although a new bone metastasis was noted after 57 months of lenvatinib, treatment was continued for another 9 months. The patient subsequently passed away in June 2021. CONCLUSIONS: The long-term treatment of recurrent PTC with lenvatinib was feasible, with manageable adverse events, for more than 5 years.

Increased Myosin light chain 9 expression during Kawasaki disease vasculitis.

Introduction: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly afflicts children. KD development is known to be associated with an aberrant immune response and abnormal platelet activation, however its etiology is still largely unknown. Myosin light chain 9 (Myl9) is known to regulate cellular contractility of both non-muscle and smooth muscle cells, and can be released from platelets, whereas any relations of Myl9 expression to KD vasculitis have not been examined. Methods: Plasma Myl9 concentrations in KD patients and children with febrile illness were measured and associated with KD clinical course and prognosis. Myl9 release from platelets in KD patients was also evaluated in vitro. Myl9 expression was determined in coronary arteries from Lactobacillus casei cell wall extract (LCWE)-injected mice that develop experimental KD vasculitis, as well as in cardiac tissues obtained at autopsy from KD patients. Results and discussion: Plasma Myl9 levels were significantly higher in KD patients during the acute phase compared with healthy controls or patients with other febrile illnesses, declined following IVIG therapy in IVIG-responders but not in non-responders. In vitro, platelets from KD patients released Myl9 independently of thrombin stimulation. In the LCWE-injected mice, Myl9 was detected in cardiac tissue at an early stage before inflammatory cell infiltration was observed. In tissues obtained at autopsy from KD patients, the highest Myl9 expression was observed in thrombi during the acute phase and in the intima and adventitia of coronary arteries during the chronic phase. Thus, our studies show that Myl9 expression is significantly increased during KD vasculitis and that Myl9 levels may be a useful biomarker to estimate inflammation and IVIG responsiveness to KD.

Propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis mimicking Kawasaki disease.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rare in children and is characterised as necrotising vasculitis predominantly affecting small and medium-sized vessels. Propylthiouracil (PTU), an antithyroid drug, has been implicated in drug-induced AAV. In contrast, Kawasaki disease (KD) is a common systemic vasculitis, typically observed in children, which affects the medium-sized vessels, including the coronary arteries. An 11-year-old girl who developed AAV while receiving PTU therapy for Graves' disease is described. She was admitted to hospital following a 2-day history of fever, cervical adenopathy, cheilitis and papular rash, 3 weeks after an increase in the PTU dose. Despite discontinuation of PTU and the administration of intravenous antibiotic therapy, her clinical condition deteriorated and over the next 2 days she developed severe diarrhoea, conjunctival injection and swelling and redness of the right index finger. Additional findings included liver dysfunction, hydrops of the gallbladder, coagulopathy and urine abnormalities, suggesting glomerulonephritis. She met the diagnostic criteria for KD and received intravenous immunoglobulin (IVIG) combined with prednisolone, with rapid resolution of clinical and laboratory parameters. Peeling of the right index fingertip became evident on Day 12 of admission. Serial ultrasound cardiography demonstrated no evidence of cardiac involvement. A high titre of myeloperoxidase ANCA was detected in the patient's serum on admission, and the titre decreased during the convalescent stage. This case demonstrates that children with PTU-associated AAV may present with clinical features mimicking KD, and that IVIG along with corticosteroid therapy may be effective in treating patients with drug-induced severe systemic AAV.

Anterior cingulate cortex involvement in non-paraneoplastic limbic encephalitis.

BACKGROUND: Non-paraneoplastic limbic encephalitis is characterized by attention deficit, loss of emotion control, and impaired memory. Viral infection can cause acute encephalitis in children, occasionally exhibiting clinical features of limbic dysfunction. However, how viral infection affects the limbic system remains to be elucidated. CASE DESCRIPTION: A 5-year-old Japanese boy was admitted to our hospital because of high fever and status epilepticus. After seizures were controlled by diazepam, he exhibited attention deficit, loss of emotion control, and impaired memory, suggesting acute limbic encephalitis. Since titers of antibodies against Coxsackie virus A10 were significantly elevated in the serum, we diagnosed him with non-paraneoplastic limbic encephalitis associated with the viral infection. Brain magnetic resonance imaging demonstrated involvement of anterior cingulate cortex as well as white matter of the frontal lobe in the acute period. After steroid pulse therapy, these brain lesions subsequently disappeared in a time-dependent manner, beginning with the frontal lobe white matter and extending to the anterior cingulate cortex, and his psychological symptoms also disappeared. CONCLUSION: To the best of our knowledge, this is the first report to show the involvement of the region from the anterior cingulate cortex to the frontal lobe white matter. Clinical features such as seizures, attention deficit, loss of emotion control, and impaired memory suggest that this viral limbic encephalitis possibly extended from the frontal white matter to the anterior cingulate cortex via inter-neuronal connections in a time-dependent manner.

Facial nerve palsy associated with atomoxetine-induced hypertension.

BACKGROUND: Peripheral facial nerve palsy is characterized by unilateral facial paresis due to ipsilateral facial nerve dysfunction. Most cases are idiopathic; however, some have specific etiologies, such as herpesvirus infection, immunological disorders, and hypertension. Atomoxetine is a norepinephrine reuptake inhibitor that is used in the treatment of attention deficit hyperactivity disorder (ADHD). This drug is known to cause adverse effects, such as nausea, appetite loss, headache, insomnia, and hypertension. CASE DESCRIPTION: We herein describe a case of sudden-onset right peripheral facial palsy in a 9-year-old Japanese boy. The patient's systolic blood pressure was as high as 200 mmHg, and he was therefore admitted to our hospital for investigation. Extensive surveillance including blood examination; endocrinological testing; imaging studies such as computed tomography, magnetic resonance imaging, and renography; and renal biopsy did not reveal any abnormalities. The patient had ADHD and was under treatment with atomoxetine. We discontinued treatment with atomoxetine; the patient showed gradual improvement. His hypertension and facial palsy resolved. We therefore diagnosed the patient with peripheral facial palsy associated with atomoxetine-induced hypertension. CONCLUSION: Although peripheral facial nerve palsy is usually benign and self-limiting, blood pressure should be monitored in children under treatment with atomoxetine and the possibility of drug-induced hypertension should be considered in order to prevent palsy associated with hypertension.

Early ligation of the dorsal pancreatic artery with a mesenteric approach reduces intraoperative blood loss during pancreatoduodenectomy.

BACKGROUND: Early ligation of the inferior pancreatoduodenal artery has been advocated to reduce blood loss during pancreatoduodenectomy. However, the impact of early ligation of the dorsal pancreatic artery (DPA) remains unclear. This study was performed to investigate the clinical implications of early ligation of the DPA. METHODS: From October 2014 to April 2017, 34 consecutive patients underwent pancreatoduodenectomy using a mesenteric approach. The patients were divided into the early DPA ligation group (n = 15) and late DPA ligation group (n = 19). The clinical features were retrospectively compared between the two groups (H29-044). RESULTS: Preoperative multidetector row computed tomography and intraoperative findings revealed that the right branch of the DPA supplied the pancreatic head region in all cases. Intraoperative blood loss was significantly lower in the early than late ligation group (median 609 ml [range 94-1,013 ml] vs. 764 ml [range 367-1,828 ml], respectively; P = 0.008). Multivariable analysis revealed that early DPA ligation was independently associated with blood loss (P = 0.023). The DPAs arising from the superior mesenteric artery underwent early ligation at a significantly higher rate. CONCLUSIONS: Early ligation of the DPA during pancreaticoduodenectomy with a mesenteric approach could reduce intraoperative blood loss.

Gastric venous congestion and bleeding in association with total pancreatectomy.

BACKGROUND: Gastric venous congestion and bleeding in association with total pancreatectomy (TP) were evaluated. METHODS: Thirty-eight patients of TP were retrospectively analyzed. TP was classified as TP with distal gastrectomy (TPDG), pylorus-preserving TP (PPTP), subtotal stomach-preserving TP (SSPTP), and TP with segmental duodenectomy (TPSD). RESULTS: Portal vein or superior mesenteric vein resection and reconstruction was performed in 24 patients (62.2%). Gastric bleeding occurred immediately after tumor resection in one of eight patients who underwent SSPTP, and urgent anastomosis between the right gastroepiploic and left ovarian vein stopped the bleeding. Another case of gastric bleeding was observed a few hours after TP in one of nine patients who underwent PPTP, and hemostasis was achieved after conservative therapy. Gastric bleeding was not observed in 16 patients who underwent TPDG and five who underwent TPSD. Some patients underwent preservation of gastric drainage veins (left gastric vein, right gastric vein, or right gastroepiploic vein). Neither patient with bleeding underwent preservation of a gastric drainage vein. CONCLUSIONS: To preserve the subtotal or whole stomach when performing TP, one of the gastric drainage veins should undergo preservation or reconstruction, and anastomosis between the right gastroepiploic vein and left ovarian vein may be beneficial.

Nodular fasciitis of the breast.

We report a case of nodular fasciitis of the breast, which is a rare histological type of breast tumor. A 41-year-old woman had noticed a mass in her right breast. The mass was elastic-hard, 15 mm x 15 mm in size, and located mainly in the upper outer quadrant of the right breast. Mammography demonstrated an oval dense mass with spiculation. Ultrasonography revealed a hypoechoic lesion, 8 mm x 10 mm in size. Fine needle aspiration cytology and core needle biopsy showed no evidence of malignancy. Excisional biopsy was performed. The tumor was characterized by a proliferation of fibroblastic cells. Histologically, the excised tumor was consistent with nodular fasciitis of the breast. Nodular fasciitis should be considered in the differential diagnosis of a mass suspicious for breast cancer.

Clinical features of children with nontyphoidal Salmonella bacteremia: A single institution survey in rural Japan.

Nontyphoidal Salmonella (NTS) can cause bacterial enterocolitis. Although some children with NTS infection develop bacteremia, its clinical manifestations have not been discussed adequately. Therefore, we examined children with NTS bacteremia. We retrospectively examined the medical records of 15 patients aged less than 15 years. Salmonella spp. were detected in the blood cultures of these patients between 1991 and 2014. We divided an additional sample group of 34 patients diagnosed with an NTS infection between 2005 and 2014, into 2 groups. Group bacteremia (B) included patients in whose blood cultures Salmonella spp. were detected, and group non-bacteremia (NB) included patients in whom Salmonella infection was not detected. We compared each group using Wilcoxon test and Fisher's exact test. The number of patients with fever, diarrhea, or abdominal pain was 15 (100%), 13 (87%), and 9 (60%), respectively, in the first sample of patients. However, vomiting and bloody stool were observed in only 5 patients (33%). More than 70% of patients exhibited a reduced white blood cell count, while C-reactive protein levels were variable in the patients. Salmonella spp. were detected via stool culture in 10 patients (67%). Diarrhea persisted for more than 4 days more frequently in group B than group NB (p = 0.004). The number of patients whose fever persisted for more than 4 days was significantly higher in group B than group NB (p = 0.030). Therefore, if NTS bacteremia is suspected, blood cultures should be collected and antibiotics should be initiated in cases with diarrhea or fever for more than 4 days. Furthermore, a negative stool culture result does not preclude the possibility of NTS bacteremia.

Up-regulation of the gene encoding protein kinase A type I alpha regulatory subunit in nodular hyperplasia of parathyroid glands in patients with chronic renal failure.

CONTEXT: Hyperplasia of parathyroid glands in patients with chronic renal failure is classified into diffuse (DH) and nodular (NH) types, and NH is often refractory to routine medical therapy. OBJECTIVE: Although it is considered that the parenchymal cells initially proliferate diffusely and then some of them are transformed to form nodules consisting of monoclonal cells, the underlying molecular mechanism for such a transformation is not fully understood. In this study we tried to identify the genes that are up-regulated in NH. DESIGN AND SETTING: The cDNA population prepared from DH was subtracted from that prepared from NH by a PCR-based cDNA subtraction method. The resultant cDNAs were cloned and sequenced. To confirm the up-regulation of the identified genes, a total of 35 parathyroid glands (18 DH, 16 NH, and one mixed) obtained from 21 patients were analyzed. RESULTS: One of the nuclear genes identified was the PRKAR1A gene, which encodes type Ialpha regulatory subunit (RIalpha) of cAMP-dependent protein kinase (PKA). Immunohistochemical analysis demonstrated that RIalpha was abundantly expressed in the nodular region, whereas the adjacent diffuse region displayed relatively low expression. Northern and Western blot analyses demonstrated up-regulation of RIalpha expression in most NH tested. Determination of PKA activities revealed that free PKA activities measured in the absence of cAMP in the assay were inversely correlated with RIalpha expression, indicating the functional significance of RIalpha up-regulation. CONCLUSIONS: These results suggest that the aberrant expression of RIalpha is involved in the diffuse to nodular transformation of hyperplasia of parathyroid glands by impairing cAMP/PKA signal transduction.

Differential expression of cyclin-dependent kinase inhibitors, p27Kip1 and p57Kip2, by corticotropin in rat adrenal cortex.

An important role for the cyclin-dependent kinase inhibitors (CDKIs), p27Kip1 and p57Kip2, in the proliferation and differentiation of adrenal cells has been suggested by their knockout mice, which display adrenal hyperplasia. Adrenal development and function are primarily regulated by ACTH. In the present study, we investigated the effects of ACTH on the expression of p27Kip1, p57Kip2 and proliferating cell nuclear antigen (PCNA) in rat adrenals. Male Wistar rats were treated with dexamethasone (Dex) to inhibit endogenous ACTH secretion. ACTH was then administered to the rats, and the adrenals were examined by Western blot and immunohistochemical analyses. Dex treatment induced shrinkage of adrenals where no PCNA-expressing cells were detected, but most of the cells expressed p27Kip1. Subsequent ACTH treatment resulted in the marked suppression of p27Kip1 expression, specifically in adrenocortical cells at 12 h after the stimulus. At 48 h, the p27Kip1 suppression still continued in the cortex, while the PCNA-expressing cells appeared mainly around the zona glomerulosa and increased at 72 h. At this time, the p27Kip1-expressing cells also appeared in the same zone. In contrast to p27Kip1, the expression of p57Kip2 was not detected in the Dex-treated adrenal. However, its expression was markedly induced by ACTH in the zona glomerulosa at 48 and 72 h. The results demonstrate that the primary site for mitogenic action of ACTH in rat adrenocortex is the zona glomerulosa, and that ACTH modulates proliferation of adrenocortical cells by regulating p27Kip1 and p57Kip2 expression in a time- and site-specific manner.

Variations in ORAI1 Gene Associated with Kawasaki Disease.

Kawasaki disease (KD; MIM#61175) is a systemic vasculitis syndrome with unknown etiology which predominantly affects infants and children. Recent findings of susceptibility genes for KD suggest possible involvement of the Ca(2+)/NFAT pathway in the pathogenesis of KD. ORAI1 is a Ca(2+) release activated Ca(2+) (CRAC) channel mediating store-operated Ca(2+) entry (SOCE) on the plasma membrane. The gene for ORAI1 is located in chromosome 12q24 where a positive linkage signal was observed in our previous affected sib-pair study of KD. A common non-synonymous single nucleotide polymorphism located within exon 2 of ORAI1 (rs3741596) was significantly associated with KD (P = 0.028 in the discovery sample set (729 KD cases and 1,315 controls), P = 0.0056 in the replication sample set (1,813 KD cases vs. 1,097 controls) and P = 0.00041 in a meta-analysis by the Mantel-Haenszel method). Interestingly, frequency of the risk allele of rs3741596 is more than 20 times higher in Japanese compared to Europeans. We also found a rare 6 base-pair in-frame insertion variant associated with KD (rs141919534; 2,544 KD cases vs. 2,414 controls, P = 0.012). These data indicate that ORAI1 gene variations are associated with KD and may suggest the potential importance of the Ca(2+)/NFAT pathway in the pathogenesis of this disorder.