Mitochondrial DNA variants as genetic risk factors for Parkinson disease.

BACKGROUND AND PURPOSE: Investigation of the relationship between mitochondrial DNA (mtDNA) variants and Parkinson disease (PD) remains an issue awaiting more supportive evidence. Moreover, an affirming cellular model study is also lacking. METHODS: The index mtDNA variants and their defining mitochondrial haplogroup were determined in 725 PD patients and 744 non-PD controls. Full-length mtDNA sequences were also conducted in 110 cases harboring various haplogroups. Cybrid cellular models, composed by fusion of mitochondria-depleted rho-zero cells and donor mitochondria, were used for a rotenone-induced PD simulation study. RESULTS: Multivariate logistic regression analysis revealed that subjects harboring the mitochondrial haplogroup B5 have resistance against PD (odds ratio 0.50, 95% confidence interval 0.32-0.78; P = 0.002). Furthermore, a composite mtDNA variant group consisting of A10398G and G8584A at the coding region was found to have resistance against PD (odds ratio 0.50, 95% confidence interval 0.33-0.78; P = 0.001). In cellular studies, B4 and B5 cybrids were selected according to their higher resistance to rotenone, in comparison with cybrids harboring other haplogroups. The B5 cybrid, containing G8584A/A10398G variants, showed more resistance to rotenone than the B4 cybrid not harboring these variants. This is supported by findings of low reactive oxygen species generation and a low apoptosis rate in the B5 cybrid, whereas a higher expression of autophagy was observed in the B4 cybrid particularly under medium dosage and longer treatment time with rotenone. CONCLUSIONS: Our studies, offering positive results from clinical investigations and cybrid experiments, provide data supporting the role of variant mtDNA in the risk of PD.

Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension.

Glucocorticoids are administered to premature infants to accelerate pulmonary maturation. In experimental model, prenatal dexamethasone (DEX) results in reduced nephron number and adulthood hypertension. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), can cause oxidative stress and is involved in the development of hypertension. L-citrulline can be converted to l-arginine (the substrate for NOS) in the body. Thus we intended to determine if maternal L-citrulline therapy can prevent prenatal DEX-induced programmed hypertension by restoration ADMA/nitric oxide (NO) balance, alterations of renin-angiotensin system (RAS) and sodium transporters, and epigenetic regulation by histone deacetylases (HDACs). Male offspring were assigned to four groups: control, pregnancy rats received intraperitoneal DEX (0.2 mg/kg body weight) daily on gestational days 15 and 16 (DEX), pregnancy rats received 0.25% L-citrulline in drinking water during the entire pregnancy and lactation period (CIT), and DEX + CIT. We found DEX group developed hypertension at 16 weeks of age, which was prevented by maternal L-citrulline therapy. Prenatal DEX exposure increased plasma ADMA concentrations and reduced renal NO production. However, L-citrulline reduced plasma ADMA level and increased renal level of NO in DEX + CIT group. Next, prenatal DEX-induced programmed hypertension is related to increased mRNA expression of angiotensin and angiotensin II type 1 receptor, and class I HDACs in the kidney. Prenatal DEX exposure increased renal protein abundance of Na(+)/Cl(-) cotransporter (NCC), which was prevented by L-citrulline therapy. The beneficial effects of L-citrulline therapy include restoration of ADMA/NO balance and alteration of NCC, to prevent the prenatal DEX-induced programmed hypertension.

Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells.

BACKGROUND: A T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 16189 can generate a variable length polycytosine tract (poly-C). This tract variance has been associated with disease. A suggested pathogenesis is that it interferes with the replication process of mtDNA, which in turn decreases the mtDNA copy number and generates disease. METHODS: In this study, 837 healthy adults' blood samples were collected and determined for their mtDNA D-loop sequence. The mtDNA copy number in the leucocytes and serum levels of oxidative thiobarbituric acid reactive substance (TBARS) and antioxidative thiols were measured. All subjects were then categorised into three groups: wild type or variant mtDNA with presence of an interrupted/uninterrupted poly-C at 16180-16195 segment. RESULTS: A step-wise multiple linear regression analysis identified factors affecting expression of mtDNA copy number including TBARS, thiols, age, body mass index and the mtDNA poly-C variant. Subjects harbouring a variant uninterrupted poly-C showed lowest mean (SD) mtDNA copy number (330 (178)), whereas an increased copy number was noted in subjects harbouring variant, interrupted poly-C (420 (273)) in comparison with wild type (358 (215)). The difference between the three groups and between the uninterrupted poly-C and the composite data from the interrupted poly-C and wild type remained consistent after adjustment for TBARS, thiols, age and body mass index (p=0.001 and p=0.011, respectively). A trend for decreased mtDNA copy number in association with increased number of continuous cytosine within the 16180-16195 segment was noted (p(trend)<0.006). CONCLUSIONS: Our results substantiate a previous suggestion that the mtDNA 16189 variant can cause alteration of mtDNA copy number in human blood cells.

Liver transplantation for biliary atresia in Taiwan: a national study.

A national database for orthotopic liver transplantation (OLT) among biliary atresia (BA) cases in Taiwan has not been reported. Using the National Health Insurance (NHI) database to investigate the prognostic features of patients with BA receiving OLT, we studied the prognosis of this procedure for BA. The NHI in Taiwan covers most of the population (>99%). From 1996-2004, 106 BA patients underwent transplantation. A linear time trend analysis was performed to estimate the annual slope for BA patients to receive OLT. The rate of increase per year of 2.6 cases was significant (R(2) = .649; P = .029). The 5-year overall survival after OLT was 97.1% +/- 1.6%, which was not different between those who had or had not previously undergone portoenterostomy (94.9% vs 97.8%; P = .160). It was not different among patients undergoing transplantation during the various seasons (P = .505). Our data confirmed the effectiveness of OLT for the treatment of BA in children with or without KP in Taiwan.

Cross-tolerance of recipient-derived transforming growth factor-beta dendritic cells.

Administration of donor-derived immature dendritic cells (DC) treated with transforming growth factor-beta (TGF-beta) to prevent allograft rejection is not applicable for clinical use. We therefore attempted to explore the use of recipient-derived DC pulsed with donor antigens via the indirect pathway (cross-priming). DC were propagated from C3H (H2(k)) bone marrow (BM) using granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). TGF-beta (0.2 ng/mL) was added at the initiation of culture. The resultant TGF-beta DC were pulsed with B10 (H2(b)) splenocyte lysate. Expression of major histocompatibility complex (MHC) class I and II was not affected, while CD40, CD80, and CD86 costimulatory molecules on DC were significantly inhibited by treatment with TGF-beta. C3H DC pulsed with B10 antigens stimulated a proliferative response in C3H T cells which was inhibited when DC were treated with TGF-beta, and the cytotoxic T-lymphocyte (CTL) activity was also inhibited. This observation correlated with reduced interferon-gamma (IFN-gamma) and increased IL-10 production. A single injection of TGF-beta DC prolonged allograft survival (median survival time [MST] 18 days vs 10 days in no-DC treatment control; P < .05). These data indicated that an approach utilizing recipient DC as a "vaccine" strategy is possible.

Application of recipient-derived dendritic cells to induce donor-specific T-cell hyporesponsiveness.

Administration of donor-derived immature dendritic cells (DC) treated with NF-kappaB oligodeoxyribonucleotides (ODN) prevents allograft rejection. We attempted to explore the use of recipient-derived DC pulsed with donor antigens, in which the donor antigens were presented to host T cells via an indirect pathway (cross-priming). Expression of CD40, CD80, and CD86 on DC was significantly inhibited by treatment with NF-kappaB ODN, whereas MHC class I and II were minimally affected. Normal C3H DC pulsed with B10 antigens stimulated proliferative responses and donor-specific CTL activity in C3H T cells, both of which were, however, markedly inhibited when DC were treated with NF-kappaB ODN. This manipulation was associated with reduced IFN-gamma and increased IL-10 production in the supernate, suggesting a Th2 bias. More frequent apoptotic T cells were observed in cultures with NF-kappaB ODN DC. In contrast to administration of normal DC pulsed with donor antigens that accelerated rejection of B10 cardiac allografts (median survival time [MST] 7 days versus 10 days in no-DC treatment control, P < .05), a single injection of 2 x 10(6) NF-kappaB ODN DC significantly prolonged allograft survival (MST 50 days, P < .05 compared with no-DC treatment control). The anti-donor CTL activity in infiltrating T cells isolated from cardiac grafts in recipients that received NF-kappaB ODN DC was significantly suppressed. These data indicate that vaccination with immature DC, propagated from recipient BM is an attractive approach to induce T-cell hyporesponsiveness.

Infradiaphragmatic pulmonary sequestration combined with cystic adenomatoid malformation: unusual postnatal computed tomographic features.

We present a surgically proven case of infradiaphragmatic pulmonary sequestration combined with cystic adenomatoid malformation. Prenatal magnetic resonance imaging revealed a well-defined hyperintense mass with a hypointense septum in the left infradiaphragmatic region. Postdelivery computed tomography (CT) and 3-month follow-up CT showed replacement of intralesional cystic areas by solid content. Such unusual postnatal CT changes, to our knowledge, have not been previously documented.

Different management options for anaphylactoid purpura with intussusception: a case report.

Intussusception is the most common surgical indication of anaphylactoid purpura. About 50% of cases are of the ileo-ileal type. Surgical intervention, rather than radiologic reduction, is preferable for older children suffering from anaphylactoid purpura with intussusception, where a lead point lesion is often found. The authors report a case of anaphylactoid purpura with intussusception with spontaneous reduction, and postulate that subsequent to relieving bowel-wall edema using antihistamine and steroid therapy, the ileo-ileal intussusception may spontaneously reduce.

False aneurysm and mediastinal hematoma: complications of simultaneous transcatheter therapy for coarctation of the aorta and patent ductus arteriosus in an infant.

We report an infant with intractable congestive heart failure caused by coarctation of the aorta, patent ductus arteriosus, atrial septal defect, and multiple muscular ventricular septal defects. He had received balloon angioplasty for dilating the aortic coarctation and a Gianturco coil for closing the ductus at a single therapeutic catheterization session at 4 months old. After balloon angioplasty, his heart failure had dramatically resolved. A false aneurysm and mediastinal hematoma were noted on the following day. The hematoma revealed total resolution 10 weeks later. He was asymptomatic throughout 12 months of follow-up.

Pulmonary valvular stenosis complicated by cerebrovascular accident and congestive heart failure in a young child.

Pulmonary valvular stenosis (PS) with intact ventricular septum is a common congenital heart disease. In general, mild PS has a benign clinical course. However, in severe PS and some cases of moderate stenosis, increasing severity of the lesion may occur. The manifestations of either cerebrovascular accident (CVA) or congestive heart failure (CHF) are rarely reported in pediatric patients with PS. In this report, we describe a girl with severe PS complicated by seizures and sudden onset of hemiparesis at 13 months of age who developed CHF when 16 months old. CHF was cured after successful balloon valvuloplasty. She remained well without residual hemiparesis or recurrent seizures during the 1-year follow-up. Early balloon valvuloplasty should be emphasized in patients with severe PS, even if there are no significant clinical symptoms. With prompt balloon valvuloplasty, these complications can be effectively prevented.

Successful liver transplantation in a child with biliary atresia and hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is characterized by hypoxemia in patients with severe chronic liver disease and pulmonary vasodilatation in the absence of primary cardiac or pulmonary disease. Severe hypoxemia resulting from HPS is generally considered a contraindication to liver transplantation. We describe the case of a 6-year-old girl with biliary atresia complicated with HPS who was successfully treated with liver transplantation. Cyanosis and dyspnea had initially developed at the age of 5 years. Arterial blood gas showed a PaO2 of 46.6 mm Hg on room air. The diagnosis of HPS was confirmed by contrast echocardiography, lung perfusion scan with 99mTc macroaggregate albumin, and pulmonary angiography. The lung scan revealed an intrapulmonary shunt of 24%. She underwent living donor liver transplantation and received a left lateral segment graft from her mother. One year after successful liver transplantation, she had normal arterial oxygen saturation and a normal lung scan without intrapulmonary shunting. This case demonstrates that HPS associated with end-stage liver disease is potentially curable by liver transplantation.

Pancreatitis with gallbladder ascariasis in a child: case report.

A 10-year-old girl was admitted for abdominal pain for 1 week. Morning vomiting with 5 Ascaris and diarrhea with Ascaris were found. Radiograph of the abdomen disclosed no significant abnormality. Abdominal sonogram revealed a normal biliary tree; but mildly enlarged pancreatic thickness, and thickened gallbladder wall. Within the thickened gallbladder wall a linear echogenic structure with worm-like movement suspected of being Ascaris was found. We report this case because pediatric pancreatitis and a gallbladder wall thickened with worm-movement have rarely been reported. Urgent treatment and surgery are required for the very ill child with a tensely distended abdomen or signs of peritoneal irritation. Early diagnosis is very important to prevent further complications. We emphasize the role of sonography in the diagnosis of this case and the prevention of progressive deterioration.

Sonographic features of small-bowel intussusception in pediatric patients.

OBJECTIVE: Small-bowel intussusception (SBI) for pediatric patients is unusual and difficult to diagnose preoperatively. This study sought to determine the sonographic findings of pediatric SBI. METHODS: The sonographic features and surgical findings of 13 pediatric patients (7 boys, 6 girls; age range 4 months-15 years; average age 4 years and 2 months) with SBI encountered in the authors' hospital over a 12-year period were retrospectively reviewed. RESULTS: Most of the patients presented with nonspecific symptoms, including vomiting, abdominal pain, and/or irritable crying. Sonographic screening in the emergency department revealed a doughnut or crescent-in-doughnut sign, or a multiple-concentric-rings sign for 11 of the 13 patients, and the lesions appeared short. Eight lesions were found in the paraumbilical or left abdominal regions. Sonographic measurement of the size of the lesions from these 11 patients ranged from 2 cm to 3.7 cm (average 2.77 cm). Subsequent barium enemas were performed for these 11 patients, none of which revealed colon lesions. Surgery revealed ileoileal intussusceptions for eight cases, jejunoileal for three, and jejunojejunal for the remaining two. Bowel ischemia or necrosis and pathologic lead points were demonstrated for seven and six patients, respectively, although none were recognized preoperatively. CONCLUSIONS: Small-bowel intussusception is often over-looked due to nonspecific clinical presentations. Sonographic demonstration of a 2-3-cm sized, short, doughnut-like lesion, especially in the left abdomen or paraumbilical regions, should lead to strong suspicion of SBI.

Endoscopic variceal ligation for intractable esophageal variceal bleeding in children with idiopathic extrahepatic portal vein occlusion: report of three cases.

Extrahepatic portal vein occlusion (EPVO) is an important cause of extrahepatic portal hypertension and variceal hemorrhage in children. We report 3 children with a diagnosis of EPVO and intractable esophageal variceal bleeding who underwent scheduled endoscopic variceal ligation (EVL) and prophylactic propranolol therapy for eradication of esophageal varices. Complete variceal obliteration was achieved in all 3 children following 3-4 treatment sessions. There were no significant complications or gastrointestinal hemorrhage during a follow-up period of 9 to 31 months after variceal eradication. In conclusion, EVL and long-term propranolol prophylaxis is safe and effective in eradicating bleeding esophageal varices in children with EPVO.

Unruptured aneurysm of sinus of Valsalva with right ventricular outflow tract obstruction.

Aneurysm of the sinus of Valsalva (ASV) is a rare anomaly. It may be congenital or acquired basis. In pediatric patients, most are congenital in origin. It is frequently associated with other congenital disease, most frequently ventricular septal defect (VSD). Pathologically, this is due to the total absence of normal elastic fibers. Patients with ASV are generally asymptomatic unless aneurysm rupture occurs. Unruptured ASV with right ventricular outflow tract (RVOT) obstruction is very rare. Herein we describe an unusual ASV with RVOT obstruction associated with VSD in a 14-year-old boy. He had experienced heart failure and exertional dyspnea for 2 months. The diagnosis was made by echocardiography, angiography and surgery. After surgical repair of the VSD and resection of the ASV, dyspnea and heart failure were relieved. The patient remained well during the 3 years of follow-up.

Hepatic focal nodular hyperplasia in children: report of three cases.

Hepatic focal nodular hyperplasia is very rare in children. We present 3 cases aged from 8 to 17 years. All of them are girls, none of whom used oral contraceptives. Case 1 was a hepatitis B carrier and was incidentally found to have focal nodular hyperplasia (FNH). The other 2 cases presented with abdominal pain. Abdominal computed tomography revealed a solitary liver tumor in cases 2 and 3, but no abnormalities in case 1. A 7-cm tumor was located in the left lobe of the liver with compression of the stomach in the 2nd case. Abdominal magnetic resonance imaging (MRI) showed a mass with isointense density to liver parenchyma on T1WI and hyperdensity on T2WI in the 1st and the 3rd cases. The inferior vena cava was compressed and displaced anteriorly in the 1st case. Because of differences in the clinical presentation and imaging studies, the 1st and 2nd cases received resection while the 3rd case was treated conservatively. Pathologic findings confirmed the diagnosis of focal nodular hyperplasia in all 3 cases. We emphasize the importance of an MRI scan in the diagnosis of hepatic focal nodular hyperplasia, and different clinical manifestations and imaging studies may lead to different management.

Bezoars in children: report of four cases.

We reviewed the histories of four children (2 boys and 2 girls, aged 6 mo to 10 yr) with surgically proven bezoars, treated from 1991 to 1998. Two had gastric bezoars and two had intestinal bezoars. All four patients presented with gastrointestinal symptoms and none had undergone previous surgery. Three had a history of abnormal ingestion, including one who ate a pickled fruit from the Boraginaceae (locally known as Po-pu-tsu) plant for 1 year. Plain radiographs revealed intestinal obstruction in all four patients. Abdominal sonography disclosed a hyperechoic band-like lesion and acoustic shadow in both cases of gastric bezoar, and these bezoars were subsequently confirmed by gastric endoscopy. Lower gastrointestinal studies showed obstruction considered most likely to be due to bezoar in one case, while computed tomography (CT) revealed a characteristic small bowel mottled gas pattern in another. Surgical treatment relieved obstruction in all four patients. Bezoar should be suspected in patients with intestinal obstruction who have a history of ingestion of unusual substances. The findings of this report suggest that sonography and endoscopy are useful in the diagnosis of gastric bezoar, while CT is useful in the detection of intestinal bezoar.

Infantile hypertrophic pyloric stenosis in a 5-month-old baby: case report.

Hypertrophic pyloric stenosis is commonly seen in infants 2 to 4 weeks old. We report a case of pyloric stenosis diagnosed in a boy 5 months and 11 days old suffering from the sudden onset of vomiting. Gastric volvulus was initially diagnosed at another hospital. Abdominal ultrasonography at first using an Acuson 5-MHz transducer revealed a negative diagnosis. However, a tubular pyloric mass measuring 5.5 mm in thickness, 15 mm in the transverse diameter, and 2.0 cm in length was detected by a 7-MHz transducer immediately after the infant vomited. On physical examination, no abdominal mass was palpable. This suggested that this might have been a case of hypertrophic pyloric stenosis which was missed until the infant was older than 5 months. We believe this is the oldest reported case of infantile hypertrophic pyloric stenosis in Taiwan.

Toxic megacolon in Salmonella colitis: report of two cases.

Toxic megacolon is a complication that usually presents in inflammatory bowel disease such as ulcerative colitis or Crohn's disease. It also occurs in typhoid fever, acute bacillary dysentery, amebic colitis, ischemic colitis, pseudomembranous colitis and severe salmonellosis. This report describes the occurrence of toxic megacolon in two young children with Salmonella colitis manifesting as abdominal distension, diarrhea and fever. The clinical course of these two cases suggests that toxic megacolon is a severe complication of salmonellosis in children, irrespective of the use of antibiotics. In the light of its paucity in children and severity, accurate diagnosis and appropriate intensive medical-surgical management is essential.

The significance of functioning gallbladder visualization on hepatobiliary scintigraphy in infants with persistent jaundice.

UNLABELLED: The purpose of this study was to determine whether gallbladder visualization can help exclude biliary atresia in hepatobiliary scintigraphic studies of infants with persistent jaundice. METHODS: One hundred fifty-two infants with persistent jaundice (49 patients with a final diagnosis of biliary atresia and 103 with biliary patency) were studied using both hepatobiliary scintigraphy and abdominal sonography. Food was withheld for 4 h before the examination, and the infants were fed nothing but glucose until 6 h after the initial injection of (99m)Tc-disofenin or until the gallbladder was seen. If the gallbladder was seen, the infants were fed milk, and imaging was continued to observe gallbladder contractility. RESULTS: In none of the 49 patients with biliary atresia could the gallbladder be seen with hepatobiliary scintigraphy, but abdominal sonography revealed 9 normal-sized gallbladders. Of the 103 patients with biliary patency, hepatobiliary scintigraphy detected the gallbladder more frequently (74%, 76/103) than did abdominal sonography (63%, 65/103). All visualized gallbladders contracted after the infants were fed milk. If we include visualization of both the gallbladder and bowel radioactivity as criteria, the specificity of biliary atresia on hepatobiliary scintigraphy increases to 86% (89/103). CONCLUSION: Gallbladders were usually visible on hepatobiliary scintigraphy of fasting patients with biliary patency. A functioning gallbladder, with or without visualization of bowel radioactivity, indicated biliary patency.