Consequences of impaired purine recycling in dopaminergic neurons.

A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction.

Study of antibody titres after measles vaccination: fever within 7 days of vaccination and efficacy of booster doses.

We investigated seroconversion rates in febrile children after measles vaccination. Among 6364 vaccinees, 501 children had a temperature of 37.5 degrees C or higher within 7 days of vaccination. The seroconversion rate assessed by a haemagglutination-inhibition assay was 76.6% in 501 febrile children but 95.2% in 84 afebrile controls. Measles vaccination has been reported to provide immunity in at least 95% of cases. The number of patients infected with measles has dramatically decreased since the introduction of measles vaccination. However, problems remain, including primary vaccine failure (PVF), failure to develop immunity after vaccination, and secondary vaccine failure (SVF), that is, the development of infection because of waning antibodies after vaccination. In this study, we investigated the effect of febrile upper respiratory tract infection (URTI) after vaccination and found a lower rate of seroconversion to measles and a lower mean antibody titre in those who developed a fever within 7 days of measles vaccination.

Serum sodium levels in patients with Kawasaki disease.

The purpose of this study was to assess the hypothesis that lower serum sodium levels are associated with cardiovascular sequelae in patients with Kawasaki disease (KD). We used the database of the 16th nationwide survey of KD in Japan. We investigated the distribution of serum sodium levels and the relationship between serum sodium levels and cardiovascular sequelae. Of the reported cases, serum sodium levels were reported in 13,569 patients (89%). The proportion of patients with serum sodium levels 130 mEq/L or less, was greater in complete cases than in incomplete cases. The proportion of patients with serum sodium levels 130 mEq/L or less was increased with age. The largest proportion of patients with serum sodium levels 130 mEq/L or less was found in the category of 3-5 days since onset of illness. A serum sodium of level 135 mEq/L or less was an independent risk factor for cardiovascular sequelae (odds ratio, 1.79, 95% confidence interval, 1.42-2.26). Among patients with KD, there are significant differences in serum sodium levels between diagnostic categories, age, and days since the onset of illness. The sodium level may be a simple predictor of cardiovascular sequelae.

Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch-Nyhan disease.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is an enzyme that catalyses the conversion of hypoxanthine and guanine into their respective nucleotides. Inherited deficiency of the enzyme is associated with a loss of striatal dopamine in both mouse and man. Although HPRT is not directly involved in the metabolism of dopamine, it contributes to the supply of GTP, which is used in the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). Since BH4 is required as a cofactor for tyrosine hydroxylase in the synthesis of dopamine, any limitation in the supply of GTP could interfere with the synthesis of dopamine. The current studies were designed to address the hypothesis that the reduced striatal dopamine in mice with HPRT deficiency results from reduced availability of BH4. The mutant mice had small reductions in striatal BH4, with normal BH4 levels in other brain regions. Liver BH4 was normal in HPRT-deficient mutant mice, and a phenylalanine challenge test failed to reveal any evidence for impaired hepatic phenylalanine hydroxylase, another BH4-dependent enzyme. Although striatal BH4 content is not normal, supplementation with BH4 or L-dopa failed to correct the striatal dopamine deficiency of the mutant mice, suggesting that BH4 limitation is not responsible for the dopamine loss.

Percutaneous and laparoscopic approaches of radiofrequency ablation treatment for liver cancer.

BACKGROUND/PURPOSE: Radiofrequency ablation (RFA) and microwave coagulation therapy (MCT) have been gaining acceptance as a standard method in the management strategy of liver cancer, for reasons of minimally invasive techniques and effective results. We present our experience of RFA and MCT in patients with liver cancer, and analyze retrospectively the advantages and disadvantages of both of the percutaneous and laparoscopic approaches. METHODS: Thirty-two consecutive patients (23 men and 9 women) with 19 hepatocellular carcinomas (HCC), 12 metastatic liver cancers, and recurrent cholangiocellular carcinoma (CCC), were enrolled in this study. Out of these 32 patients, as a prior laparotomy, 19 underwent hepatectomy, colectomy, gastrectomy or cholecystectomy, and 15 were treated with the laparoscopic approach, 17 treated with the percutaneous approach, and 2 treated with the combined approach of those two. All of these procedures were carried out under general anesthesia with ultrasound guidance. Seven and 30 days after these procedures, an assessment helical computed tomography was done. RESULTS: No sign of the residual tissues was noted in all patients except only one case. CONCLUSIONS: The percutaneous approach was thought to be a more practical and less invasive method regardless previous laparotomy. For the laparoscopic approach, tumors located at the hepatic surface or margin were preferable candidates.

Soluble forms of the selectin family in children with Kawasaki disease: prediction for coronary artery lesions.

AIM: To investigate the relationship between the plasma levels of soluble forms of the selectin family and the incidence of coronary artery lesions (CALs) in patients with Kawasaki disease (KD). METHODS: Thirty-three patients with KD, including group A patients (n = 22) who had no CALs and group B patients (n = 11) who had CALs, as well as age-matched febrile (n = 10) and afebrile controls (n = 11), were studied. RESULTS: Peak plasma E-selectin levels (172.0 +/- 58.6 ng ml(-1)) occurred during the acute phase of KD, while peak plasma P-selectin levels (260.3 +/- 43.2 ng ml(-1)) occurred during the subacute phase of the illness (p<0.05). Plasma L-selectin levels (1757.3 +/- 244.3 ng ml(-1)) during the convalescent phase tended to be higher than in either the acute or the subacute phase (not significant). Before intravenous immunoglobulin treatment, the plasma levels of E- (225.1 +/- 46.8 ng ml(-1)) and P-selectin (259.4 +/- 76.2 ng ml(-1)) of patients with CALs (n = 11) were significantly higher than those of patients (n = 22) with no CALs (E-selectin, 131.6 +/- 36.9 ng ml(-1); P-selectin, 184.9 +/- 84.6 ng ml(-1); p < 0.05). When a plasma E-selectin value before immunoglobulin treatment of >184.7 ng ml(-1) was used as the cut-off point, the sensitivity and specificity for the incidence of CALs were 81.8% and 90.9%, respectively. These findings demonstrate the relationship between plasma levels of selectins and disease severity of Kawasaki vasculitis. CONCLUSION: Higher plasma levels of E-selectin may have potential as a predictor of the incidence of coronary artery lesions in Kawasaki disease patients.

Assessment of the ability of myocardial contrast echocardiography with harmonic power Doppler imaging to identify perfusion abnormalities in patients with Kawasaki disease at rest and during dipyridamole stress.

The aim of our study was to assess the ability of myocardial contrast echocardiography (MCE) with harmonic power Doppler imaging (HPDI) to identify perfusion abnormalities in patients with Kawasaki disease at rest and during pharmacological stress imaging with dipyridamole. Results were compared with those of 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) imaging as the clinical reference standard. MCE with HPDI was performed on 20 patients with a history of Kawasaki disease. Images were obtained at baseline and during dipyridamole infusion (0.56 mg x kg(-1)) in the apical two- and four-chamber views. Myocardial opacification suitable for the analysis was obtained in all patients. Nine patients with stenotic lesions had a reversible defect after dipyridamole infusion detected by both MCE with HPDI and SPECT, and 3 patients with a history of myocardial infarction had a partially or completely irreversible defect detected by both methods. Three patients with coronary aneurysm without stenotic lesion, 4 patients with regressed coronary aneurysm, and 2 patients with normal coronary artery in acute phase also had normal perfusion at rest and after pharmacological stress by both methods. A 96% concordance (kappa = 0.87) was obtained when comparing the respective segmental perfusion scores using the two methods at baseline, and an 86% concordance (kappa = 0.81) was obtained at postdipyridamole infusion. After combining baseline and postdipyridamole images, each segment was labeled as having normal perfusion, irreversible defects, or reversible defects. Using these classifications, concordance for the two methods was 92% (kappa = 0.87). MCE with HPDI is a safe and feasible method by which to detect asymptomatic ischemia due to severe stenotic lesion, and it may be an important addition to the modalities used to identify patients at risk for myocardial infarction as a complication of Kawasaki disease.

Solid and papillary tumor of the pancreas complicating agenesis of the dorsal pancreas.

We report the first documented case of a solid and papillary tumor of the pancreas (SPT) complicating agenesis of the dorsal pancreas. A 28-year-old female patient was referred to our hospital for a pancreatic tumor detected at a local hospital. The laboratory findings were all within normal limits. Diagnostic images revealed absence of the dorsal pancreas and the presence of a tumor located in the head of the pancreas. The tumor was solid, well demarcated, noncalcified, and hypovascular. Fine-needle aspiration cytology revealed that larger cell clumps often had a branching papillary appearance, with multiple layers of tumor cells surrounding central vascular stalks; a preoperative diagnosis of SPT was made. At surgery, on February 10, 1999, the tumor was found to have clear margins, and it showed no signs of direct invasion of adjacent structures. No metastases were found in the liver or the local lymph nodes. Accordingly, partial resection of the pancreas, including the entire tumor, was performed, and, thus, almost the entire head of the pancreas could be saved. Microscopic examination of the resected specimen yielded findings compatible with SPT. No recurrences, and no impairment of pancreatic endocrine or exocrine function have been noted since the operation.

A clinical evaluation of lymphangioma of the large intestine: a case presentation of lymphangioma of the descending colon and a review of 279 Japanese cases.

With the development and widespread use of colonoscopy, lymphangioma of the large intestine has recently been reported frequently. This paper presents some findings from a review of 279 cases of this disease in Japan, including a typical case that we encountered. A 69-year-old female was diagnosed as having lymphangioma of the descending colon based on the findings of a barium enema and a colonoscopy, and the lesion was successfully removed by an endoscopic resection. In the published reports, the etiology of this disease is not clear yet but the age at onset range shows a tendency toward a higher incidence in comparatively older patients and the male-to-female ratio indicates a higher incidence in males. If there is no complication, endoscopic treatment seems to be the preferable procedure for this disease.

Complete cure of malignant lymphoma of the stomach with a huge adrenal lesion achieved by preoperative chemotherapy and surgery: report of a case.

We report herein the case of a 53-year-old woman with malignant lymphoma of the stomach who was successfully treated by preoperative chemotherapy and surgery. The patient consulted our hospital with the chief complaint of upper abdominal pain. Endoscopy demonstrated a protruding lesion at the antral posterior wall of the stomach, and a post-biopsy pathological diagnosis of diffuse large cell type B-cell lymphoma was established. Moreover, abdominal ultrasonography, computed tomography, and magnetic resonance imaging demonstrated a tumor measuring approximately 10cm in diameter in the left adrenal gland. A total of three courses of chemotherapy using the CHOP regimen were given preoperatively. The CHOP regimen consisted of 100mg of prednisolone administered for 8 days together with 1.9mg of vincristine, 1,000mg of cyclophosphamide, and 60mg of epirubicin administered intravenously on the first day. This resulted in tumor shrinkage, and a distal gastrectomy, lymph node dissection, and left adrenalectomy were subsequently performed. Since the pathological findings of the resected tissue specimen demonstrated complete elimination of the malignant lymphoma, this combination of procedures was defined as having resulted in a complete response. The postoperative course of this patient was uneventful. She is still alive without any sign of tumor recurrence 6 years after her operation, and is being followed up at the outpatient clinic.

Evaluation of the prognostic factors after thymoma resection.

We discuss the prognostic factors of thymoma clinicopathologically. Regarding the survival rate by the clinical stage classification of Masaoka, significant correlation was made between stage I and stage III (P < 0.05) and stage I and stage IVa (P < 0.03). The tumor resectability was classified into complete and incomplete resection, and a significant difference was shown by the survival rate of the complete resection at P < 0.0001. Regarding the survival rate by the invasive organ of the tumor, significant correlation was made between no invasion and the great vessel invasion (P < 0.0004) and between invasion except for the great vessel and great vessel invasion (P < 0.004). As for the histological type, the tendency in which the epithelial cell type predominancy increased with the progress of the clinical stage was shown. A significant correlation was not shown in the evaluation by adjuvant therapy. However, recently we have done chemotherapy and/or radiotherapy periodically for invasive thymoma.

Successful removal of a stone and an expandable metallic stent from the biliary tract of a patient with acute occlusive pyogenic cholangitis.

We removed a biliary stone and the metallic stent placed two years previously in a patient with benign biliary strictures. An 80-year-old woman who had been inplanted with an expandable metallic stent (EMS) to prevent obstruction by a large common bile duct stone about two years before as an emergency measure in another hospital, was afficted with acute occlusive pyogenic cholangitis (AOPC) and hospitalized in our hospital. After treating the AOPC, we successfully removed the EMS with a cholangioscope and normal biopsy forceps through the percutaneous transhepatic channel under fluoroscopy. The type of the EMS was Accufulex stent. To remove it was easier than expected. Once it started to unravel, it was removed from the common bile duct within a few minutes.

Efficacy of a new formulation of lenograstim (recombinant glycosylated human granulocyte colony-stimulating factor) containing gelatin for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia.

The efficacy and safety of a new formulation of lenograstim (recombinant glycosylated granulocyte colony-stimulating factor) prepared by switching the stabilizer from human serum albumin (HSA) to gelatin was investigated for the treatment of neutropenia after consolidation chemotherapy in patients with acute myeloid leukemia (AML). The results obtained in the study using the gelatin-containing formulation (gelatin-lenograstim) were retrospectively compared to those obtained from a placebo-controlled double-blind randomized study (AML-DBT) using the HSA-containing formulation (HSA-lenograstim). The median time of neutrophil recovery to > or = 1000/mm3 was significantly shorter in the gelatin-lenograstim group (14 days) than in the placebo group (21 days, P = .0001), and there was no significant difference between the gelatin-lenograstim group and the HSA-lenograstim group (14.5 days of AML-DBT, P = .5462). The incidences of febrile neutropenia were significantly reduced in the gelatin-lenograstim group (24/43, 55.8%) compared to the placebo group (58/64, 90.6%, P < .0001). The incidence of fever and antibiotic use was also significantly lower in the gelatin-lenograstim group (69.8% and 83.7%, respectively) than in the placebo group (92.2%, P = .0034, and 96.9%, P = .0285, respectively). However, between the 2 groups there were no differences in the number of patients who had infectious episodes. No serious adverse drug reactions ascribed to gelatin-lenograstim were encountered. These results demonstrate that gelatin-lenograstim exerted beneficial effects in the acceleration of neutrophil recovery and in the reduction of fever, febrile neutropenia, and antibiotic use, and its efficacy was equivalent to HSA-lenograstim. Therefore, we concluded that the gelatin-lenograstim formulation, which offers no risk of virus contamination and can be stored at room temperature, is more beneficial than the HSA-lenograstim formulation.

Evaluation of prognostic factors and PCNA expression for pulmonary metastatic tumors of colorectal carcinoma.

The present study was conducted to evaluate clinicopathologically 26 patients whose primary colorectal carcinoma and resulting pulmonary metastatic tumors had been resected, and to determine the relationship between tumor progress and prognosis by PCNA immunostaining. Patients with solitary pulmonary metastasis were found to have much better prognoses than those with multiple metastasis. There was no correlation between tumor size of pulmonary metastasis and prognosis. Survival rates of patients with disease-free intervals (DFIs) of 2 years or longer were higher than for those with DFIs of less than 2 years. Mean PCNA expression of pulmonary metastatic lesions was significantly higher than that of primary lesions. It was suggested that the higher PCNA expression stemming from the relation between depth of tumor invasion and PCNA expression was greater with tumor progress.

Primary leiomyoma of the pancreas.

We report the first documented case of a primary leiomyoma of the pancreas. A 72-yr-old female patient was admitted to our hospital for the follow-up of a pancreatic tumor detected 2 yr previously at a different hospital. Diagnostic images revealed the presence of a tumor located in the head of the pancreas. The tumor was characterized by a clear margin, hypervascularity, and was a homogenous mass. Moreover, the tumor had not changed in size or characteristics since a previous computed tomography (CT) scan performed 2 yr previously. The tumor was preoperatively diagnosed as a nonfunctional islet-cell tumor or papillary cystic tumor. During the operation, the tumor was found to be encapsulated and showed no signs of direct invasion to neighboring structure. Tumorous lesions of the liver or swellings of the neighboring lymph nodes suggesting metastasis were not found. Instead of a pancreatoduodenectomy, the tumor was enucleated. Microscopically, immunohistochemical studies of a resected specimen indicated a myogenic origin, and neither mitotic activity nor hemorrhagic and necrotic findings were recognized. No signs of recurrence have been seen since its excision. Accordingly, the tumor was diagnosed as a primary leiomyoma of the pancreas.

Adrenal metastasis from hepatocellular carcinoma (HCC): report of 3 cases.

Although autopsy reports show that the adrenal gland is the second most common organ of hematogeneous metastasis from hepatocellular carcinoma (HCC), paradoxically there is found to be a very scarce number of the adrenal metastasis in clinical practice. We have recently experienced rare patients with right adrenal metastasis from HCC. Case 1: A 51 year-old man with a 5-year history of chronic hepatitis was admitted with hematemesis to Nippon Medical School Hospital. CT revealed a main tumor associated with a few daughter tumors in the hepatic posterior segment and in addition another tumor located between the right hepatic lobe and right kidney. The diagnosis of HCC with a right adrenal gland metastasis was made, and hepatectomy and right adrenalectomy was performed. Twenty months after operation he was alive and free of disease. Case 2: A 78 year-old man underwent resection of the lateral segment of the left hepatic lobe for HCC. Twelve months later, recurrent foci in the residual liver were found and those were treated with transarterial embolization (TAE). Right adrenal metastasis was found on CT 26 months after hepatectomy. TAE was done for the hepatic recurrent tumors and adrenal metastasis. Twelve months after, he survived in good condition. Case 3: A 47 year-old man presented with liver cirrhosis with a long history. He was diagnosed as having HCC with multiple intrahepatic metastases and was treated with TAE 4 times. Follow-up CT revealed right adrenal metastasis. TAE was done for hepatic recurrent tumor and right adrenal metastasis. Three months later the patient died of liver failure.

Spontaneous gastrointestinal perforation in patients with lymphoma receiving chemotherapy and steroids. Report of three cases.

Spontaneous gastrointestinal perforations in three patients with lymphoma were considered to be treatment-related conditions. All three were diagnosed as having malignant lymphoma by histological examination, and treated with chemotherapy and steroids. Four to 14 days after the start of chemotherapy, they complained of abdominal pain and plain roentgenograms revealed pneumoperitoneum. The interval between the onset of peritonitis and operation was almost 24 h. Emergency operations were carried out; one patient with a jejunal perforation underwent resection of the jejunum, another with a gastric perforation received a simple closure with omental patch, and the third with a gastric perforation underwent gastrectomy. Two patients recovered from the surgery, while the gastrectomy patient died due to sepsis. The favorable outcome of the surgical intervention is attributed to early diagnosis, prompt exploration, and selective operative procedures. We recommended a simple closure with omental patch for gastroduodenal perforation. Resection and primary anastomosis are possible only in the small bowel.

[Allogeneic peripheral blood stem cell transplantation in 30 patients with hematologic disorders].

Thirty patients (median age of 32 years; range, 6-61) with hematologic disorders received unmanipulated peripheral blood stem cell transplants from HLA-matched or one-antigen-mismatched related donors following myeloablative therapy for acute lymphoblastic leukemia (7), acute myelogenous leukemia (6), chronic myelogenous leukemia (8), myelodysplastic syndrome (3), or other disorders (6). Granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells were collected from donors in 1 to 3 aphereses. The apheresis products contained mean counts of 11.3 x 10(8) (range, 3.8-17.2) nucleated cells/kg and 6.7 x 10(6) (range, 1.3-16.7) CD34+ cells/kg. Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclosporin A plus methotrexate, or FK506 plus methotrexate. All patients received G-CSF following their transplant. Although 1 patient died of pneumonia 6 days after transplantation, the others demonstrated rapid engraftment. Median days to recovery to 500/microliter neutrophils and 20,000/microliter platelets were 13 (range, 8-21) and 14 (range, 1-23) days, respectively. The incidence of acute GVHD grade II-IV was 33%; chronic GVHD developed in 57% of the assessable patients. There were no episodes of graft failure or rejection. Nineteen patients (63%) were alive and in complete remission from 147 to 839 days following their transplant (median follow-up of 560 days). Further follow-up study will be required to assess the incidence of chronic GVHD and graft-versus-leukemia (GVL) effects.