Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism.

To elucidate the molecular basis for endocrine tumorigenesis, p53 mutations in human endocrine tumors were analyzed by using polymerase chain reaction-single strand conformation polymorphism. Exons 5 through 10 of the p53 gene were studied in genomic DNAs from 134 primary endocrine tumors and 6 human endocrine cancer-derived cell lines. Mutations were detected and identified in 4 endocrine tumors, including one parathyroid adenoma and three thyroid carcinoma cell lines. The sites of these mutations were in exons 5 (codon 151 and 152) and 7 (codon 248 and 255). In all of three tumor cell lines, but not in a parathyroid adenoma, the normal allele encoding the p53 gene was lost. However, p53 mutations were not found in any other endocrine tumors or cell lines. Based upon these results, we concluded that the p53 gene may play a role in the tumorigenesis of a limited number of parathyroid adenoma and thyroid cancers, and that the p53 mutation with an allelic loss of the p53 gene is an important factor in malignant tumorigenesis of the thyroid gland.     

Experimental study of vagotomy for prevention of stress ulcer after hepatectomy of cirrhotic livers. Its influence on hepatic regeneration

We experimentally studied the influence of vagotomy on hepatic regeneration in rats after hepatectomy of cirrhotic livers. In animals that underwent hepatectomy plus vagotomy the reduction in gastric pH was suppressed, but gastric mucosal blood flow was less than that in control animals that received hepatectomy alone. The suppression of 3H-thymidine uptake percentage and thymidine kinase activity after hepatectomy was more marked in animals treated with hepatectomy plus vagotomy than in controls treated with hepatectomy alone. Hepatic DNA level tended to be lower in animals treated with hepatectomy plus vagotomy than in controls. In animals treated with hepatectomy plus vagotomy, the peak level of the mitotic index was lower and the hepatic regeneration rate was evidently suppressed. These results suggest that it is not appropriate to apply vagotomy, during hepatectomy of cirrhotic livers, for the prevention of postoperative stress ulcer because it causes a marked reduction in gastric mucosal blood flow and suppresses hepatic regeneration.     

Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor).

CTGF/CCN2, a hypertrophic chondrocyte-specific gene product, possessed the ability to repair damaged articular cartilage in two animal models, which were experimental osteoarthritis and full-thickness defects of articular cartilage. These findings suggest that CTGF/CCN2 may be useful in regeneration of articular cartilage. INTRODUCTION: Connective tissue growth factor (CTGF)/CCN2 is a unique growth factor that stimulates the proliferation and differentiation, but not hypertrophy, of articular chondrocytes in vitro. The objective of this study was to investigate the therapeutic use of CTGF/CCN2. MATERIALS AND METHODS: The effects of recombinant CTGF/CCN2 (rCTGF/CCN2) on repair of damaged cartilage were evaluated by using both the monoiodoacetic acid (MIA)-induced experimental rat osteoarthritis (OA) model and full-thickness defects of rat articular cartilage in vivo. RESULTS: In the MIA-induced OA model, quantitative real-time RT-PCR assays showed a significant increase in the level of CTGF/CCN2 mRNA, and immunohistochemical analysis and in situ hybridization revealed that the clustered chondrocytes, in which clustering indicates an attempt to repair the damaged cartilage, produced CTGF/CCN2. Therefore, CTGF/CCN2 was suspected to play critical roles in cartilage repair. In fact, a single injection of rCTGF/CCN2 incorporated in gelatin hydrogel (rCTGF/CCN2-hydrogel) into the joint cavity of MIA-induced OA model rats repaired their articular cartilage to the extent that it became histologically similar to normal articular cartilage. Next, to examine the effect of rCTGF/CCN2 on the repair of articular cartilage, we created defects (2 mm in diameter) on the surface of articular cartilage in situ and implanted rCTGF/CCN2-hydrogel or PBS-hydrogel therein with collagen sponge. In the group implanted with rCTGF/CCN2-hydrogel collagen, new cartilage filled the defect 4 weeks postoperatively. In contrast, only soft tissue repair occurred when the PBS-hydrogel collagen was implanted. Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro. CONCLUSION: These findings suggest the utility of CTGF/CCN2 in the regeneration of articular cartilage.     

The relationship of serotonin to depression in Parkinson's disease

We have previously reported a correlation between depression in patients with idiopathic Parkinson's disease and decreased concentrations of the cerebrospinal fluid content of the serotonin metabolite, 5-HIAA. To further examine this relationship, we repeated the study in a new cohort of patients while they remained on dopaminergic medications, conducted follow-up interviews and examinations in our original cohort, and conducted an open trial of the serotonin precursor, 5-hydroxytryptophan in a group of new patients with depression. We were again able to demonstrate a significant reduction in cerebrospinal 5-HIAA in depressed patients in comparison to controls and patients without depression. Demented patients with Parkinson's disease, particularly those with concurrent depression, had the lowest values of 5-HIAA. No new cases of depression occurred in our original cohort after 2 1/2 years of follow-up, and depression remitted following conventional or experimental treatment in four patients. Depression improved in six of the seven new patients following oral 5-hydroxytryptophan. Three of these patients allowed a repeat lumbar puncture, and the concentration of 5-HIAA increased following 5-hydroxytryptophan. These three studies support our hypothesis that depression in idiopathic Parkinson's disease is associated with a reduction in brain serotonin. However, it also suggests that other factors, biological or environmental, may be causal factors.     

Surgical Treatment of Intractable Seizures Due to Hypothalamic Hamartoma

Summary: A 6.5-year-old boy developed seizures at age 2.8 years consisting of episodes of unconsciousness and laughing attacks. By age 6 years, multiple seizure types, including generalized tonic-clonic (GTC), complex partial (CPS) and akinetic seizures, and drop attacks were occurring several times daily. EEG showed multifocal epileptic discharges. Antiepileptic drugs (AEDs) did not control the seizures. With progression of the epilepsy, cognitive deterioration developed. There were no manifestations of precocious puberty. Neuroimaging disclosed a suprasellar mass in continuity with the hypothalamus, and a diagnosis of hypothalamic hamartoma was made. After surgical resection of the hamartoma, the seizures were completely alleviated, and the epileptic EEG discharges disappeared. Improvement of mental function was also noted.     

Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities.

Cognitive function was examined in 227 patients three months after admission to hospital for ischaemic stroke, and in 240 stroke-free controls, using 17 scored items that assessed memory, orientation, verbal skills, visuospatial ability, abstract reasoning, and attentional skills. After adjusting for demographic factors with standardised residual scores in all subjects, the fifth percentile was used for controls as the criterion for failure on each item. The mean (SD) number of failed items was 3.4 (3.6) for patients with stroke and 0.8 (1.3) for controls (p < 0.001). Cognitive impairment, defined as failure on any four or more items, occurred in 35.2% of patients with stroke and 3.8% of controls (p < 0.001). Cognitive domains most likely to be defective in stroke compared with control subjects were memory, orientation, language, and attention. Among patients with stroke, cognitive impairment was most frequently associated with major cortical syndromes and with infarctions in the left anterior and posterior cerebral artery territories. Functional impairment was greater with cognitive impairment, and dependent living after discharge either at home or nursing home was more likely (55.0% with, v 32.7% without cognitive impairment, p = 0.001). In a logistic model examining the risks related to dependent living after stroke, cognitive impairment was a significant independent correlate (odds ratio, OR = 2.4), after adjusting for age (OR = 5.2, 80 + v 60-70 years) and physical impairment (OR = 3.7, Barthel index < or = 40 v > 40). It is concluded that cognitive impairment occurs frequently after stroke, commonly involving memory, orientation, language, and attention. The presence of cognitive impairment in patients with strike has important functional consequences, independent of the effects of physical impairment. Studies of stroke outcome and intervention should take into account both cognitive and physical impairments.     

Thinning of ventricular septum in tetralogy of Fallot]

Cross sectional echocardiography was used to evaluate the thickness of the ventricular septum in tetralogy of Fallot (TOF). Forty-six patients with TOF and 20 patients with pseudo-truncus arteriosus underwent echocardiography during a five-year period beginning in 1984. Thicknesses of the right ventricular anterior wall (RVAWT), trabecular septum (IVST) and left ventricular posterior wall (LVPWT) were measured in end diastole on parasternal short axis view at the level of the tips of papillary muscles. The ratios of IVST to RVAWT and IVST to LVPWT were assessed. The ratio of IVST to RVAWT was 1.09 +/- 0.15 in the group aged less than 7 years (less than 7 y.o.) and 0.94 +/- 0.15 in the group aged of 7 years or more (greater than = 7 y.o.). The ratios of IVST to LVPWT were 1.10 +/- 0.14 (less than 7 y.o.) and 0.90 +/- 0.15 (greater than = 7 y.o.), respectively. Both ratios were significantly different (p less than 0.01) in the two age groups, and relative thinning of the septum was demonstrated in the older patients. It is speculated that thinning of the interventricular septum is caused by the lower systolic wall stress of the ventricular septum compared with that of the free walls, which is produced under equal systolic pressure of the two ventricles. It is suggested that this thinning is one of the factors that reduces left ventricular function after repair of TOF.     

Surgical strategies for treatment of giant or large intracranial aneurysms: our experience with 139 cases.

Giant or large intracranial aneurysms are the vascular neurosurgeon's greatest challenge. At our department, we have treated one hundred and thirty nine patients with giant or large intracranial aneurysms between 1975 and 2001. These included 37 partially thrombosed giant aneurysms. 75 aneurysms were giant (> 2.5 cm) and 64 were large aneurysms (2-2.5 cm). Three-dimensional computed tomography angiograms were performed in patients besides MRI angiography and digital subtraction angiography. These were found to be very valuable in the preoperative assessment of surgical anatomy of the aneurysm with respect to the branch arteries and perforators origin besides knowing the relations to the skull base. With our experience in surgical treatment of these 139 cases, we find that the basic technique is trapping and evacuation and not just clipping of the aneurysm neck but also reconstruction of the artery bearing the aneurysm, especially with wide-necked aneurysms. Use of multiple clipping, tandem clipping or dome clipping as per the intraoperative situation, is very helpful in dealing with giant aneurysms as also is the use of different types of clips like fenestrated clip with straight clip (combination clipping), booster clip, dome clips etc. While selecting surgical strategy for partially thrombosed giant aneurysm, securing the neck is most important. If the neck is too narrow to reconstruct, aneurysmectomy with anastomosis is one of the surgical strategies. An extracranial intracranial bypass should be considered in cases where clipping or parent artery ligation is expected to be associated with compromise of cerebral circulation.