Landscape genetics and population structure in Valley Oak (Quercus lobata Née).

PREMISE OF THE STUDY: Although long-distance pollen movement is common in wind-pollinated trees, barriers to gene flow may occur in species that have discontinuous ranges or are confined to certain habitat types. We investigated the genetic structure of Quercus lobata Née populations throughout much of their range in California. We assessed the connectivity of populations and determined if barriers to gene flow occurred, and if so, if they corresponded to landscape features. METHODS: We collected leaf samples from 270 trees from 12 stands of Quercus lobata and genotyped these trees using eight polymorphic microsatellite loci. Genetic structure and clustering was evaluated using genetic distance methods, Bayesian clustering approaches, and network analysis of spatial genetic structure. KEY RESULTS: The southernmost population of Quercus lobata sampled from the Santa Monica area comprised a separate genetic cluster from the rest of the species, suggesting that Transverse Ranges such as the San Gabriel Mountains limit gene flow. Population differentiation among the other sites was small but significant. Network analysis reflected higher connectivity among populations along the Central Coast range, with few connections spanning the dry, low Central Valley. CONCLUSIONS: While long distance pollen movement has been shown to be common in oaks, on larger spatial scales, topographic features such as mountain ranges and the large, flat Central Valley of California limit gene flow. Such landscape features explain gene flow patterns much better than geographic distance alone.

A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown that approximately 70% of familial PAH and also 11-40% of idiopathic PAH (IPAH) cases have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene. In addition, mutations in the activin receptor-like kinase 1 (ALK1) gene have been reported in PAH patients. Since both the BMPR2 and ALK1 belonging to the transforming growth factor (TGF)-beta superfamily are known to predispose to PAH, mutations in other genes of the TGF-beta/BMP signalling pathways may also predispose to PAH. METHODS: We screened for mutations in ENDOGLIN(ENG), SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD8 genes, which are involved in the TGF-beta/BMP signallings, in 23 patients with IPAH who had no mutations in BMPR2 or ALK1. RESULTS: A nonsense mutation in SMAD8 designated c.606 C>A, p.C202X was identified in one patient. The father of this patient was also identified as having the same mutation. Functional analysis showed the truncated form of the SMAD8 C202X protein was not phosphorylated by constitutively active ALK3 and ALK1. The SMAD8 mutant was also unable to interact with SMAD4. The response to BMP was analysed using promoter-reporter activities with SMAD4 and/or ca-ALK3. The transcriptional activation of the SMAD8 mutant was inefficient compared with the SMAD8 wild type. CONCLUSION: We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest the involvement of SMAD8 in the pathogenesis of PAH.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Conservation of BMP signaling in zebrafish mesoderm patterning.

To investigate the conservation of mechanisms for mesodermal patterning between zebrafish and Xenopus, we isolated two cDNA clones encoding bone morphogenetic protein (BMP)-related proteins from a zebrafish cDNA library. Based on their predicted amino acid sequences, these two clones were designated as zbmp-2 and zbmp-4. Whole-mount in situ hybridization analysis revealed that in gastrula embryo, both genes were localized in the ventral part of the embryo, consistent with the proposed function of Xenopus BMP-4 in ventral mesoderm specification. zbmp-4 expression, however, was also seen in the embryonic shield, the most dorsal mesodermal structure. To examine the ability of zbmp-2 to ventralize mesoderm, we injected synthetic mRNA into zebrafish embryos and found that overexpression of this gene eliminated dorsal structures including notochord at both morphological and molecular level. In contrast, expression of ventral marker gene eve1 was expanded to the dorsal side. These effects are analogous to the ventralization of embryos caused by ectopic xBMP-4 expression. Taken together, one may conclude that the developmental mechanisms for mesodermal patterning regulated by BMPs are evolutionarily conserved between amphibians and teleosts.

Short-term hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension.

In 4 patients with primary pulmonary hypertension, there was a -24% +/- 20% decrease in pulmonary vascular resistance, a significant increase of cardiac index by +27 +/- 14% in all 4 patients; a -15 +/- 12% decrease in pulmonary artery pressure in 3 patients; and in 3 patients with 12% secondary pulmonary hypertension, there was a -24 +/- 14% decrease in pulmonary vascular resistance. Beraprost appears to be effective as a new pulmonary vasodilative agent.

Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait.

The epidemiology of Hodgkin's lymphoma (HL) shows wide geographic variation in histological subtypes and in its association with the Epstein-Barr virus (EBV). The proportion of EBV positive HL is low in industrialized countries, high in non-industrialized countries and intermediate in early-industrialized countries. Reports from the Persian Gulf and Middle East are very limited. The aim of this study was to determine the epidemiology of HL in Kuwait, an early-industrialized country in the Persian Gulf, and to delineate the extent of its association with EBV. We reviewed 134 cases of HL for histological classification and demographic data. 107 cases were examined for the presence of EBV using immunohistochemistry (IHC) for the latent membrane protein I (LMPI) and in-situ hybridization (ISH) for EBVencoded RNA (EBER). 70.4% of the patients were males and 29.6% were females. The male: female ratio was 2.4:1. The mean age was 30.6 years (range, 4-71 years). Mixed cellularity HL (MCHL) was the most common subtype (45.5%), followed by nodular sclerosis (37.3%), nodular lymphocyte predominant (6.7%), lymphocyte rich (3%) and lymphocyte depletion (3%). 4.5% of cases were unclassifiable. EBV expression was seen in 56%, was significantly higher in MCHL, in children, and in males. Our findings suggest that the frequency of EBV expression in HL in Kuwait is similar to other early-industrialized countries. Further research from other countries in the Persian Gulf and the Middle East should shed more light on the epidemiology of HL and its relation to EBV in this region.

Evaluation of viral myocarditis in children by radionuclide method.

Evaluation of viral myocarditis is essential for the clinician to assess the prognosis. In this study, Tl-201 myocardial scintigraphy and Tc-99m gated cardiac blood pool scan were performed in 16 patients with myocarditis diagnosed by clinical symptoms and laboratory findings and these nuclear medicine techniques were followed up for 5 years. Exercise Tl-201 scintigraphy using a bicycle ergometer was performed in 8 patients by SPECT imaging. There were mild to severe persistent defects found in all cases (100%), but pressure rate products showed normal response. The Tl-201 defect ratio improved gradually, but did not change significantly. In the resting Tl-201 image one of 16 patients showed severe multifocal defects. LVEF increased significantly from 1 year to 5 years after onset, while RVEF measured by gated blood pool scans showed slight increases 3 years to 5 years after diagnosis. It was concluded that myocardial perfusion improved only incompletely. Cardiac function (LVEF and RVEF) improved gradually, and pressure rate products were normal. Myocarditis should therefore be followed up in order to assess the prognosis; moreover, the relationship of myocarditis to dilated cardiomyopathy needs to be further studied.

[Surgical treatment of total anomalous pulmonary venous connection--clinical aspects of pulmonary venous obstruction].

During November 1986 and May 1997, 19 patients with total anomalous pulmonary venous connection (TAPVC) underwent repair surgery. 20 operations including two reoperations were performed. 8 of 19 patients were classified as Darling type Ia, 5 as type IIa, 4 as type III and 2 patients were type IV. Two patients were operated under emergency circumstances within 24 hours after admission, 7 patients were after a short term stabilization of 4.4 days, and the other 11 patients received surgical treatment after a mean of 8.8 days as scheduled cases. For the anostomosis, the common pulmonary venous chamber or the vertical vein was connected with the left atrium in type Ia and III cases; in type IIa and IV cases the cut-back method was performed. Persistent pulmonary hypertension and post-operative pulmonary venous obstruction (PVO) affected the post-operative clinical course. Persistent pulmonary hypertension caused the death of one patient with type IIa and III each, just after operation. One type IV patient died 50 days after operation. The autopsy revealed post-operative obstructions of the remote parts of the pulmonary veins on the anostomosis site. Two patients (type IIa, III) successfully underwent reoperation due to PVO. Post-operative cardiac catheterization was performed after 12 month in 12 cases. Persistent pulmonary hypertension was found in 4 patients, and a type III patient was reoperated because of stenosis of the anostomosis site. The other three patients had persistent pulmonary hypertension without any demonstrable PVO. Persistent pulmonary hypertension and PVO are combined as TAPVC complex. The difficulty to reoperated patients with persistent pulmonary hypertension caused by PVO is one major problem. So preoperative prevention of PVO by normalization the morphologic changes of the pulmonary veins by using drugs could be a different view point in TAPVC therapy after the initial operation.

[Meningoencephalitis in Kawasaki disease].

Kawasaki disease (KD) is a syndrome characterized by various degrees of vasculitis in small-and medium-sized arteries. We discussed the characteristic manifestations and prognosis of 5 KD patients (male 3, female 2) with meningoencephalitis in the acute stage. The incidence was 3.7% (5 of 138 patients) in our institute. The age of onset was between 3 months and 15 months. The clinical manifestations included disturbance of consciousness and seizures; disturbance of consciousness developed in all patients in the early acute stage. The duration was between 2 and 11 days; seizures developed as status convulsions in two. Electroencephalograms (EEG) demonstrated certain abnormalities in 2 of 4 patients studied. Computed-tomographic scanning (CT scan) revealed fluid collection in the frontal extracerebral space, and monocyte-predominant pleocytosis was observed in the cerebrospinal fluid (CSF) in all 5 patients studied. The age of onset in the 5 KD patients was significantly earlier than that in non-complicated cases (n = 138, P less than 0.01). Blood hemoglobin (P less than 0.05) and hematocrit (P less than 0.05), serum total protein (P less than 0.01), and serum albumin levels (P less than 0.01) were also significantly lower. Moreover the period until CRP values turned negative was significantly longer (P less than 0.05) and erythrocyte sedimentation rate was significantly lower (P less than 0.01) in these 5 patients. It was considered that meningoencephalitis in KD may develop in cases having more severe and prolonged inflammatory changes; the clinical findings revealed a serious form of KD. We suggest that this might because by vasculitis of small arteries, arterioles, capillaries, and venules, which consists of infiltration of lymphocytes and large mononuclear cells, and edema. There was no neurological sequela in 4 of the 5 patients. However, one patient was found to have hearing difficulty 3 years after the onset. Therefore, the prognosis of meningoencephalitis in KD was considered to be generally favorable.

[Neurological involvements with transient gait disturbance in subacute phase of Kawasaki disease; a case report].

A 1-year-and-9-months old boy with gait disturbance during the 3rd week of Kawasaki disease (KD) was described. He had been previously healthy, and developed high fever and rash. The diagnosis of KD was based on 5 of 6 major criteria on the 3rd clinical day. He was initially treated with intravenous gamma-globulin 400 mg/kg/day for five days. On the 17th clinical day, the patient developed gait disturbance after most clinical signs disappeared. His gait was wide- based and unstable. Generalized hypotonia with poor traction response was also seen. Pyramidal tract signs including exaggerated patellar and Achilles tendon reflexes and positive bilateral Mendel-Bechterew reflex were presented. Cerebrospinal fluid was normal. Brain CT, MRI, and 123I-IMP SPECT images were normal without broad hemorrhage or infarction of the cerebral parenchyma. Gait disturbance recovered spontaneously within one month without any sequelae.

[Noonan syndrome associated with atrial septal defect, pulmonary stenosis, and completely unroofed coronary sinus without LSVC: a case report].

An eight-year-old boy, Noonan syndrome associated with ASD and PS, was referred to our department for surgical repair. During operation, the coronary sinus ostium was not found. Farther more exploration revealed completely unroofed coronary sinus without LSVC. The large ASD (confluent with coronary sinus ASD) was closed with a ePTFE patch. The pulmonary valve was thickened moderately and each commissure was adhesive, but not dysplastic. PS was released with commissurotomy and subpulmonary muscle resection. The postoperative course was uneventful and the patient discharged at 14 postoperative day. At present, he has been followed at outpatient without PS and any sign and symptom of myocardial hypertrophy.

[Nitric oxide and endothelins in pulmonary hypertension].

For recent decades, the medical treatment of primary pulmonary hypertension(PH) have shown an improved outcome as a bridge to lung transplantation. Both nitric oxide (NO) and endothelin(ET) have reported as a major vasoactive mediators in initiating PH. NO is a potent vasodilator released from endothelial cells to adjacent smooth muscle cells in vascular wall. Inhalation of NO has exerted dramatic effects with minimum complication for PH patients. ET-1, after binding to ETA receptor, promotes a strong vasoconstriction, cell growth and platelet aggregation. ETB receptor promotes the clearance of circulating ET-1 in the lung, and stimulates the release of NO and PGI2. Therapeutic trials of ETA receptor antagonist and NO donors for PH may be promising because of their direct action against vasoconstriction.

[Current status and future prospect of prostacyclin therapy for pulmonary hypertension--intravenous, subcutaneous, inhaled and oral PGI2 derivatives].

Prostacyclin (PGI2) is a potent and a promising vasodilative agent in the treatment of pulmonary hypertension (PH). Epoprostenol (Flolan), an intravenous PGI2, has been used for PPH, and exerts dramatic effects such as reducing pulmonary vascular resistance and increasing cardiac output leading to an improvement of exercise tolerance. However, continuous i.v. infusion accompanies infection, thrombosis, occlusion, battery problems and variable side effects of PGI2 itself. Uniprost, administered subcutaneously, has a rather long half-life. It also needs an ambulatory infusion pump system. Beraprost, an oral PGI2 analogue, is also effective in mild PH patients. It can be absorbed easily and administered tid, or qid fashion. Inhaled iloprost may be an alternative option, but both iloprost and beraprost require frequent administrations because of their short half-life.

[Serum/tissue interleukin-6 concentrations and constitutional abnormalities in 4 patients with cardiac myxoma].

Immunological features and the production of interleukin-6 (IL-6) in 4 patients with cardiac myxoma were studied. The patients' age ranged from 11 years old to 57 years old; all 4 patients were female. Case 1, an 11-year-old female patient with myxoma located in the right ventricle, was considered to be a familial case. Her mother had myxomas in the right and left atrium, and had undergone removal of both tumors 3 years before. Peripheral blood examination revealed various inflammatory parameters in all of these patients. White blood cell (WBC) count was over 8,000/cmm in 3 of the 4 patients, positive CRP was found in 2 patients, IgG was higher than 1,500 mg/dl in 3 patients, positive anti-nuclear antibody was seen in 1 patient, and positive rheumatoid factor was identified in 1 patient. The OKT 4/8 ratio of lymphocyte subpopulation was 4.65 in one patient. The lymphocyte mitogenic response to PHA was increased in 2 patients. Serum IL-6 increased in 3 of 4 patients, and returned to normal within 3 to 4 weeks after operation. The IL-6 concentration in the homogenized sample remarkably increased in all 4 patients. Tumors larger than 4 cm contained higher tissue IL-6 concentrations than those smaller than 2 cm. The cultured myxoma cells produced abundant IL-6 in the culture medium supernatant. We conclude that inflammatory signs and immunological abnormalities are common in patients with large cardiac myxoma, and, in addition, serum IL-6 levels may increase in such patients.(ABSTRACT TRUNCATED AT 250 WORDS)