Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors

Activating mutations of KIT and platelet-derived growth factor receptor alpha (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.     

Elastin content of the renal pelvis and ureter determines post-pyeloplasty recovery

PURPOSE: We evaluated the collagen-to-smooth muscle tissue matrix ratio and percentage of elastin in the renal pelvis, ureteropelvic junction (UPJ) and ureter, and compared these findings with the degree of obstruction, patient age and post-pyeloplasty renal recovery. MATERIALS AND METHODS: We analyzed histological sections from 75 patients with UPJ obstruction. Nine patients were excluded owing to bilateral UPJ obstruction and an improper specimen. We divided the specimen obtained from pyeloplasty into 3 parts, namely the renal pelvis above the obstruction, the obstructed UPJ portion and the ureter below the obstruction. To examine the collagen and smooth muscle, sections were stained using Masson's trichrome, and elastic van Giesson stain was used for elastin, smooth muscle and collagen. Collagen, smooth muscle and elastin populations were identified, and the tissue matrix ratio and percentage of elastin were calculated by color image analysis. RESULTS: In patients with lower ratios of collagen-to-smooth muscle in the UPJ proper hydronephrosis was more improved postoperatively (p = 0.049). In patients with a lower percentage of elastin in the renal pelvis, UPJ and ureter hydronephrosis was more improved postoperatively (p <0.0001). CONCLUSIONS: Because the UPJ portion was resected during pyeloplasty, the renal pelvis and the ureter remaining after pyeloplasty are likely to be related to improved hydronephrosis. A higher percentage of elastin in the renal pelvis and ureter contributes to inelasticity and low compliance, and results in a slower recovery from hydronephrosis after pyeloplasty.     

Robust ascertainment-adjusted parameter estimation

Nonrandom ascertainment is commonly used in genetic studies of rare diseases, since this design is often more convenient than the random-sampling design. When there is an underlying latent heterogeneity, Epstein et al. ([2002] Am. J. Hum. Genet. 70:886-895) showed that it is possible to get unbiased or consistent estimation of population parameters under ascertainment adjustment, but Glidden and Liang ([2002] Genet. Epidemiol. 23:201-208) showed in a simulation study that the resulting estimates are highly sensitive to misspecification of the latent components. To overcome this difficulty, we consider a heavy-tailed model for latent variables that allows a robust estimation of the parameters. We describe a hierarchical-likelihood approach that avoids the integration used in the standard marginal likelihood approach. We revisit and extend the previous simulation, and show that the resulting estimator is efficient and robust against misspecification of the distribution of latent variables.     

Synthetic colloids attenuate leukocyte-endothelial interactions by inhibition of integrin function

BACKGROUND: It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions. METHODS: Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils. RESULTS: Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins. CONCLUSIONS: This study shows that synthetic colloids inhibit neutrophil adhesion by a neutrophil-dependent mechanism rather than interfering with endothelial cell activation. This suggests that inhibition of leukocyte sequestration by volume support is a common and transient phenomenon depending on the colloid concentration in plasma.     

Urinary ascites without hydronephrosis in a neonate with urethral atresia

Urethral atresia is a rare and usually fatal cause of prenatal bladder outlet obstruction. We present a case of urethral atresia with urinary ascites to highlight the difficulties in making the diagnosis in the absence of hydronephrosis. We also discuss possible reasons why this patient maintained normal renal and pulmonary function.     

Spontaneous Achilles tendon rupture in a patient with systemic lupus erythematosus due to ischemic necrosis after methyl prednisolone pulse therapy

Spontaneous tendon rupture in a patient with systemic lupus erythematosus (SLE) is a rare but potentially disabling complication. Minor trauma, local inflammation and long term corticosteroid therapy are regarded as possible causes. However, ischemic necrosis of the tendon resulting from hypercoagulability and methyl prednisolone (MTP) pulse therapy has not been reported. We present a 20-year old female, newly diagnosed with lupus, who has high titer antiphospholipid antibodies, hyperhomocysteinemia and protein S deficiency. Her severe clinical symptoms of lupus were improved after MTP pulse therapy. Several days later, cold sensation over the right lower leg developed. On day 15 after pulse therapy, acute onset of right heel pain occurred when she was ascending stairs. Rupture of the right Achilles tendon was demonstrated by sonography and MRI. A Doppler sonography revealed narrowing and abrupt cessation of blood flow in the right popliteal artery. Heparin treatment was started. The angiography performed two days after heparinization revealed narrow caliber and decreased flow of the right tibial artery below the right ankle. Surgical repair of the tendon was successful and the pathology of the resected tendon revealed focal necrosis, degeneration and capillary proliferation. MTP pulse therapy in a lupus patient with hypercoaguable state with hyperhomocysteinemia, protein S deficiency and high titer antiphospholipid antibodies may cause spontaneous tendon rupture.     

A case of congenital junctional ectopic tachycardia: diagnosis and successful radiofrequency catheter ablation in infancy

It is difficult to make a definitive diagnosis of congenital junctional ectopic tachycardia (JET) in utero. We report a case in which congenial JET was suspected by fetal M-mode echocardiography. Fetal M-mode tracing of the atria and ventricle clearly showed a gradual acceleration of ventricular activity at the beginning of tachycardia, the warming-up sign of ectopic tachycardia, which was followed by simultaneous contractions of atrium and ventricle. This report also describes successful emergent radiofrequency catheter ablation of congenital JET in infancy with preservation of normal AV nodal conduction for this patient.     

Twin AV node and induced supraventricular tachycardia in Fontan palliation patients

INTRODUCTION: The coexistence of two distinct atrioventricular (AV) nodes has been described in congenital heart disease requiring Fontan type palliation. The purpose of this study was to evaluate the occurrence of twin AV node according to anatomical subgroups, and to determine its relation to tachycardia. METHODS: From 2001 to 2003, we performed an electrophysiologic (EP) study upon 52 consecutive patients who had undergone cardiac catheterization after Fontan completion. Atrial pacing was performed at three or more different atrial sites. RESULTS: In 10/52 patients, two different QRS complexes were recorded at different pacing sites, suggesting twin AV node (9/20 in right isomerism, 1/8 discordance AV connections, 0/24 other complex anomalies). AV reciprocating tachycardia (AVRT), presumably involving two AV nodes and a connecting sling, was induced in 6 of 10 patients who had twin AV node (4/6 used posterior AV node as an antegrade limb, 2/6 used an anterior AV node as an antegrade limb). Heterotaxy syndrome (P < 0.001) and complete AV septal defect (P = 0.002) were found to be risk factors for twin AV node. Junctional tachycardia (JT; HR > 150/min) with either VA dissociation (7/9) or second degree VA block (2/9) were induced by pacing or isoproterenol infusion in 9/52 patients. CONCLUSION: JT induction was associated with a twin AV node (P = 0.04), or a history of early postoperative junctional ectopic tachycardia (P = 0.02). A complicated AV node conduction system such as twin AV node was frequent in heterotaxy syndrome. Both AVRT and JT with VA block may be important causes of tachyarrhythmia in this patient group.