A novel Src kinase inhibitor, M475271, inhibits VEGF-induced human umbilical vein endothelial cell proliferation and migration

Vascular endothelial growth factor (VEGF) was reported to be a potent proangiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that showed selective inhibition of Src kinase activity and tumor growth in vivo. Here, we examined the effect of M475271 on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration and their intracellular mechanisms. Our findings showed that M475271 pretreatment resulted in a significant inhibition of VEGF-induced HUVEC proliferation, [(3)H]thymidine incorporation, and migration. M475271 inhibited VEGF-induced Flk-1 and Src phosphorylation and their association. Confocal laser microscopic examination confirmed the inhibitory effect of M475271 on VEGF-induced Flk-1/Src association. M475271 inhibited VEGF-induced extracellular signal-regulated kinase1/2 (ERK1/2) and p38 but not Akt activation in a concentration-dependent manner. M475271, PI3-K inhibitor, and p38 inhibitor inhibited VEGF-induced HUVEC proliferation and migration. However, a MEK1/2 inhibitor inhibited VEGF-induced proliferation but not migration. These findings suggest that M475271 attenuates VEGF-induced HUVEC proliferation and migration through the inhibition of signaling pathways involving Src, ERK1/2, and/or p38. Taken together, these data indicate that M475271 may be a useful candidate for inhibition of endothelial cell proliferation and migration relevant to angiogenesis.     

Perforation of the colon in neonates

Purpose

Gastrointestinal perforation is a catastrophic condition in neonates, especially in premature neonates. Although perforation is commonly observed in the small intestine during the neonatal period, perforation of the colon is a rare condition. This study analyzed the clinical findings and results of perforation of the colon in neonates.

Methods

Between 1989 and 2004, 8 neonates were treated for spontaneous perforation of the colon at our institute. These patients were retrospectively reviewed.

Results

Gestational ages ranged from 36 to 41 weeks. Seven patients weighed above 2500 g, whereas one patient weighed 1800 g at birth. Perforations developed within 7 days after birth in 6 patients and before birth in two. Associated bowel diseases included rectosigmoid type of Hirschsprung's disease in two patients, immature ganglia in one, imperforate anus in one, colonic atresia in one, and necrotizing enterocolitis in one. An obvious cause was not identified in the remaining two. Six patients without definite anatomic obstructions, such as imperforate anus or colonic atresia, required evaluations for suspected Hirschsprung's disease. All 8 patients underwent colostomy and recovered from peritonitis. Seven survived, but one died of sudden infant death syndrome.

Conclusions

In this study, perforation of the colon during the neonatal period mostly occurred in term or near-term neonates and carried a good prognosis. During management, it was important to identify Hirschsprung's and its allied disorders as a cause of perforation.     

Signal intensity changes on MRI during the healing process of spinal Langerhans cell granulomatosis: report of two cases

Two patients with spinal Langerhans cell granulomatosis were followed by magnetic resonance imaging, and the observed signal changes were detailed. Both patients had no neurologic abnormalities but back pain. They were treated by immobilization with a brace and bed rest. Their back pain disappeared after about a month. At the first visit, the tumorous lesions involving vertebrae showed mainly low signal intensity on T1-weighted imaging (T1WI) and high intensity on T2-weighted imaging (T2WI). They were clearly enhanced by gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). Their original intensities changed to iso-intensities on both T1WI and T2WI without enhancement by Gd-DTPA after a year. These signal changes might indicate the healing stage of the involved vertebrae and recommend the removal of the spinal brace.     

Atlantoaxial transarticular screw fixation and posterior fusion using ultra-high-molecular-weight polyethylene cable

This article attempts to evaluate the effectiveness of the ultra-high-molecular-weight polyethylene (UHMW-PE) cable system in atlantoaxial transarticular screw fixation and posterior fusion through the clinical results of 10 postoperative patients with atlantoaxial subluxation secondary to rheumatoid arthritis. Among them, one patient with only one screw placed owing to an anomalous vertebral artery had the correction loss of the 3-mm atlas-dens interval after surgery. Another patient had a second operation to remove the screw and cable after 2 years 11 months because a unilateral transarticular screw had come to protrude through the lateral mass of the atlas ventrally. All patients had achieved C1-C2 osseous fusion without any complications associated with this cable system. The UHMW-PE cable is a very useful material as sublaminar wiring in atlantoaxial transarticular screw fixation and posterior fusion.     

Spontaneous pulmonary torsion secondary to pseudo-Meigs' syndrome

We present a case of pulmonary lobar torsion secondary to pseudo-Meigs syndrome. A 45-year-old woman with colonic cancer and metastatic ovarian cancer was suffering from dyspnea. CT scan showed massive pleural effusion, air trapping and twisted bronchus of the middle lobe. At thoracotomy, the middle lobe was torqued at 180 degrees around its bronchovascular pedicle in a counterclockwise direction. The infarcted middle lobe was resected. The pleural effusion had never recurred after resection of the metastatic ovary. This is the first report of spontaneous pulmonary torsion caused by massive pleural effusion secondary to pseudo-Meigs syndrome.     

Histopathological diagnosis and prognostic factors in adrenocortical carcinoma

A great majority of adrenocortical tumors are benign, and many adrenocortical carcinomas (ACC) are obviously malignant at presentation. The histopathological diagnosis of ACC is occasionally difficult, particularly with stage I and stage II disease. The prognosis of ACC is generally poor. Surgery is the major treatment, with chemotherapy and radio-therapy being applicable to only restricted patients. The Weiss criteria are useful in diagnosing the common adult type of ACC. Histopathological prognostic factors of ACC have not been fully established because of the rarity of the disease. In this article, we first describe the current histopathological diagnostic and prognostic factors of ACC, highlighting the special types of ACC to which Weiss’s criteria are not fully applicable. These special type tumors include pediatric adrenocortical tumors, oncocytomas, and aldosterone-producing tumors of pure zona glomerulosa type. Then we present three cases with unusual small adrenocortical tumors. One patient had an unequivocal ACC showing metastatic disease. One had a histologically defined ACC with no metastasis or macroscopic invasion. The third was a pediatric patient with a tumor showing a nodule-in-nodule pattern with insulin-like growth factor II expression.     

Neurodevelopmental outcome in children with posthemorrhagic hydrocephalus

To determine the factors affecting the neurodevelopmental outcome in children with posthemorrhagic hydrocephalus, 78 children with intraventricular hemorrhage grade 3 or 4 were analyzed concerning the outcome in relation to the grade of intraventricular hemorrhage and intervention (surgical, medical, or no intervention) by means of a follow-up study. The mean age of the subjects at the last follow-up was 9.8 years. In children with intraventricular hemorrhage grade 4 with parenchymal hemorrhage, the outcomes in the group not requiring intervention were better than those in the groups requiring intervention, whereas in children with intraventricular hemorrhage grade 3 without parenchymal hemorrhage, there were no differences in the outcomes among the three groups with and without intervention. For the subjects who had undergone the same intervention, the outcomes in children with intraventricular hemorrhage grade 4 were worse than those in children with intraventricular hemorrhage grade 3. The outcomes in the children with surgical intervention only correlated with the grade of intraventricular hemorrhage. From these findings, we concluded that the outcomes in children with posthemorrhagic hydrocephalus were far more affected by the existence or extent of parenchymal hemorrhage than by the hydrocephalic process, which was suggested to be effectively controlled by the intervention.     

Epilepsy in Wolf-Hirschhorn syndrome (4p-)

PURPOSE: We investigated the evolution of epilepsy, seizure types, and effective drugs in Wolf-Hirschhorn syndrome, which is a malformation syndrome often with refractory seizures and status epilepticus. METHODS: We reviewed 11 cases of Wolf-Hirschhorn syndrome (age range, 2-25 years; SD, 7.2 years) and who were treated in Osaka University or Osaka Medical Center of Research Institute for Maternal and Child Health. RESULTS: In all patients, febrile or afebrile convulsions had developed. Epileptic seizures included alternative hemiconvulsions, generalized tonic-clonic seizures, focal clonic seizures, tonic seizures, and epileptic spasms. Seizures were often induced by a high fever or a hot bath. Status epilepticus occurred in all patients, including one patient who died at the first status epilepticus. In some cases, intratracheal intubation was needed because of respiratory insufficiency. The effective antiepileptic drugs for long-term use were sodium bromide (four of four), followed by clorazepate (CLP; one of two), and nitrazepam (NZP; two of four). Sodium bromide was particularly effective for preventing status epilepticus. The mean age of last status epilepticus in patients receiving sodium bromide (1 year 8 months) was significantly younger than that in those not treated with sodium bromide (3 year 4 months). CONCLUSIONS: We identified that, in most patients of Wolf-Hirschhorn syndrome, the frequency of both seizures and status epilepticus decreased gradually after age 5 years. However, during infancy, status epilepticus sometimes resulted in permanent disability or even death. We propose that sodium bromide should be used as the initial treatment for the prevention of the development of status epilepticus associated with Wolf-Hirschhorn syndrome.