Increasing methylation of the CDKN2A gene is associated with the progression of adult T-cell leukemia

In this study, we examined the methylation status of the CDKN2A gene in patients with different forms of adult T-cell leukemia (ATL) using Southern blot analysis, methylation-specific PCR (MSPCR), and nucleotide sequencing. We found that the CDKN2A gene was more frequently methylated in fresh tumor cells isolated from patients with acute ATL (47%) or lymphoma-type ATL (73%) than in those with less malignant chronic (17%) and smoldering (17%) ATL. In addition, deletions of the CDKN2A gene were found in 24% of acute ATL patients; thus, abnormalities of the CDKN2A gene totaled 71% in acute ATL patients. In contrast, no CDKN2A gene methylation was found in asymptomatic carriers or uninfected individuals. Methylation of the p15 gene was not found in any samples from 36 ATL patients. Direct sequencing of the CDKN2A gene after sodium bisulfite treatment of genomic DNA revealed that the methylation of CpG sites had occurred in 24 of 32 ATL cases (75%) including chronic and smoldering ATL, even when MSPCR and the Southern blot had failed to detect CDKN2A gene methylation. Among fresh ATL samples with methylation, methylation was detected in the promoter region and exon in 17 of 24 cases, and methylation in the exon without promoter region was detected in 7 of 24 cases. In one case, the pattern of methylation proved to be different between peripheral blood cells and lymph node cells, suggesting the presence of multiple subclones with regard to methylation patterns, despite the same HTLV-I integration site. Quantitative PCR showed a marked decrease in CDKN2A mRNA expression in the cells with a methylated CDKN2A gene, especially if the promoter region was methylated. These findings suggest that CpG methylation decreases CDKN2A expression and represents a critical factor in the disease progression of ATL.     

In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus

We evaluated the therapeutic efficacy and neurotoxicity of adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1-weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.     

Gastroesophageal reflux disease in children with asthma: treatment implications

An association between asthma and gastroesophageal reflux disease (GERD) has long been recognized both mechanistically and epidemiologically. The clinical relevance of this interplay continues to be explored, with special interest given to the role of GERD in the worsening of asthma. The effect of GERD is most frequently contemplated in patients with asthma that is difficult to control. Medical and surgical anti-reflux trials attempting to alter asthma symptoms have reported mixed but generally underwhelming results, although asthma symptom scores are generally improved following effective treatment of GERD. Many of the pharmaceutical studies can be criticised for having too short a duration or for likely incomplete acid suppression. Few trials have specifically studied pediatric populations. Because GERD is a common condition, particularly in young children, the role reflux plays in the worsening of asthma symptoms and the potential benefit on asthma of anti-reflux therapy warrants further exploration. Whether or not treating symptomatic GERD reduces the symptoms and severity of asthma in children, GERD coexisting with asthma should be aggressively treated. GERD symptoms in most patients with or without asthma can be controlled medically with continuous use of proton pump inhibitors such as omeprazole and lansoprazole and to a lesser extent by histamine H(2) receptor antagonists such as famotidine and cimetidine.     

Disappearance of hemifacial spasm after ventriculoperitoneal shunting in a patient with achondroplasia--case report

A 15-year-old boy with achondroplasia developed right hemifacial spasm associated with headache, vomiting, and hearing disturbance. Computed tomography showed hydrocephalus. A ventriculoperitoneal shunt was placed. His hydrocephalus subsequently resolved, the hemifacial spasm and headache disappeared, and his hearing disturbance improved. The episodes of hemifacial spasm were probably related to a small posterior cranial fossa volume, the so-called crowding of the posterior fossa. Increased intracranial pressure due to hydrocephalus apparently contributed to further reduction in the posterior cranial fossa volume and led to the hemifacial spasms. In addition, his hearing disturbance may have been the result of dysfunction of the cochlear nerve due to the increase in intracranial pressure caused by hydrocephalus.     

A new bubble oxygenator (OCVC oxygenator): Development and clinical application

A new bubble oxygenator, designed for simple operation and clinical efficacy in intracardiac surgery, has been developed and clinically evaluated. This device is characterized by an oxygenating chamber with controllable blood-volume, integral heat exchanger and two-stage microfilter of gravity drainage system, an apparatus for creating and uniformly distributing oxygen bubbles, and construction materials of the device known to be minimally traumatic to the blood. Clinical experience in 132 infantile and pediatric open heart procedures has demonstrated its effectiveness as measured by embolic complications and simplicity in maintaining physiologic blood gas levels.     

Comparison of the "toxic" and antigenic regions in toxin alpha isolated from Naja nigricollis venom

The present paper describes the “toxic” site and one topologically distinct antigenic determinant of N. nigricollis toxin α.     

A Child Case of Acute Right Coronary Obstruction Due to Catheter-Induced Coronary Dissection:

We report on a 10-year-old child who suffered from acute right coronary obstruction due to catheter-induced coronary dissection. Immediate placement of a perfusion catheter into the obstructed right coronary artery and subsequent overnight reperfusion allowed successful recovery of the right coronary artery lumen without implantation of a stent. Follow-up angiography demonstrated spontaneous regression of the dissected coronary artery and normal right and left ventricular wall motion. The indication of stent implantation should be carefully determined in a child case of iatrogenic coronary dissection because stenting may induce coronary stenosis during growth.     

Emergent endovascular treatment of ruptured vertebral artery dissecting aneurysms

The goal of this study was to evaluate the results of endovascular and surgical treatments for ruptured vertebral artery dissecting aneurysms (VADAs) to determine which treatment is preferable. We evaluated the cases of 25 consecutive patients with ruptured VADAs treated in our institution. From 1992 to 1997, five patients were treated surgically. Since 1998, 20 patients with VADAs have been treated with endovascular therapy. The goal of the treatment was to exclude the aneurysm from the circulation. Among the five patients undergoing surgery, three aneurysms were treated with proximal clipping, one with trapping, and one with dome clipping. None of the patients were treated during the acute stage of rupture. Transient complications occurred in two patients. Of the 20 patients treated through the endovascular approach, 15 were treated within 24 h of rupture, but 12 had rebleeding before treatment. Eighteen aneurysms were occluded, along with the affected vertebral artery (VA), by using detachable coils (internal trapping), and one was occluded with the VA preserved. A stent-assisted occlusion of one aneurysm was done in a patient who had a contralateral hypoplastic VA. In both groups, the outcome of each patient depended greatly on the patients condition before treatment and whether there was rebleeding. No posttreatment bleeding occurred. All procedures were effective, but endovascular treatment was less invasive and easier to use during the acute stage of subarachnoid hemorrhage. Although this report does not describe a controlled study, we found that endovascular treatment is preferable for treating ruptured VADAs in the acute stage.     

Evaluation of tumor FDG transport and metabolism in primary central nervous system lymphoma using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) kinetic analysis

OBJECTIVE: Although 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used as a promising tool to diagnose primary central nervous system lymphoma (PCNSL) because the tumor shows very high FDG accumulation, no data exist evaluating the extent of tumor FDG transport and metabolism. The aim of this study was to evaluate the feasibility of FDG-PET kinetic analysis in measurement of uptake parameters of FDG in the lymphoma tissues and in the assessment of treatment effects in patients with PCNSL. METHODS: Dynamic FDG-PET examination was performed in 7 histologically proven PCNSL patients before and after methotrexate-based chemotherapy. RESULTS: Before the chemotherapy, the highest CMRglc in the tumor for all 7 patients was 79.4 +/- 27.2 micromol/100 g/min. This value was significantly higher than that observed in the normal cortex in 14 control patients (44.3 +/- 6.0 micromol/100 g/min, p < 0.001). The phosphorylation (k3) activity was also significantly higher in the tumor (0.093 +/- 0.026 min(-1)) compared with the normal cortex (0.064 +/- 0.014 min(-1), p < 0.05). On the other hand, the transporter (K1) activity in the tumor (0.079 +/- 0.016 ml/min) was similar to that observed in the normal cortex (0.082 +/- 0.012 ml/min). The chemotherapy significantly reduced the volume of the tumor in 6 of 7 patients and the highest CMRglc in the tumor examined 18.0 +/- 5.5 days after the chemotherapy (34.0 +/- 21.8 micromol/100 g/min) was significantly lower than that observed before the chemotherapy (p < 0.01). This reduction in FDG uptake was concomitant with a significant reduction in both the K1 and k3 values (p < 0.05). The reduction in the k3 value after the chemotherapy was marked in 6 of 7 patients in whom the tumor responded to the first chemotherapy. CONCLUSIONS: Dynamic image acquisition can separate regional FDG uptake into FDG transport and phosphorylation activity in the lymphoma tissues. Tumor FDG uptake was significantly higher with accelerated phosphorylation activity compared with that observed in the normal cortex.