Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. Cystatin C (CysC), an endogenous cysteine protease inhibitor, is a major protein component of Bunina bodies observed in the spinal motor neurons of sporadic ALS and is decreased in the cerebrospinal fluid of ALS patients. Despite prominent deposition of CysC in ALS, the roles of CysC in the central nervous system remain unknown. Here, we identified the neuroprotective activity of CysC against ALS-linked mutant Cu/Zn-superoxide dismutase (SOD1)-mediated toxicity. We found that exogenously added CysC protected neuronal cells including primary cultured motor neurons. Moreover, the neuroprotective property of CysC was dependent on the coordinated activation of two distinct pathways: autophagy induction through AMPK-mTOR pathway and inhibition of cathepsin B. Furthermore, exogenously added CysC was transduced into the cells and aggregated in the cytosol under oxidative stress conditions, implying a relationship between the neuroprotective activity of CysC and Bunina body formation. These data suggest CysC is an endogenous neuroprotective agent and targeting CysC in motor neurons may provide a novel therapeutic strategy for ALS.

Change in environmental bacterial flora in a new hospital building.

Microbial surveillance of environmental bacteria was performed in order to study the microbial changes in a newly established hospital building. Airborne bacteria and surface-associated bacteria on floors and sinks were systematically collected between 2002 and 2005. The number of isolates obtained from frequently used floors was significantly higher than that obtained from those floors used less often. A significant increase in Staphylococcus aureus, the appearance of Pseudomonas aeruginosa, and changes among species of Gram-negative bacilli were observed 8-11 months after the new building had been opened. Furthermore, pulsed-field gel electrophoresis (PFGE) typing of meticillin-resistant S. aureus (MRSA) and P. aeruginosa showed that strains of the same PFGE groups were isolated from different sinks, floors and the adjoining old buildings. The number of MRSA isolates obtained from the new building increased as time passed. The sinks from which P. aeruginosa strains of the same PFGE type were isolated are connected by the same drainage pipe. Human movement has considerable effects on bacterial flora and their subsequent spread.

Tetrahydrobiopterin in intestinal lumen: its absorption and secretion in the small intestine and the elimination in the large intestine.

In treating hereditary deficiency of tetrahydrobiopterin (BH(4)), supplementation with BH(4) might be the ultimate choice of therapy. Oral administration of BH(4) has been believed to be inefficient owing to poor absorption of BH(4) in the intestine. In this study, we found a considerable amount of BH(4) as well as its oxidized pterins in the ingredients of intestinal lumen of mice when they were served food that did not contain significant amounts of biopterin. Ligation of the biliary duct led to significant decrease in luminal biopterin. Supplementation of BH(4) either by intraperitoneal administration of sepiapterin or of 6RBH(4) ((6R)-L-erythro-5,6,7,8-tetrahydrobiopterin) increased the BH(4) content in the intestinal lumen with a slight delay after the rise of blood BH(4). In these mice, biopterin appeared in the large intestine, caecum and colon, 2 h after the administration. The appearance of BH(4) in the large intestine was accompanied by a large amount of pterin (2-amino-4-hydroxypteridine). The amounts of biopterin + pterin that appeared in the large intestine after intraperitoneal administration of BH(4) were not greater than those found after oral administration at the same dose. When the mice were treated with a large dose of antibiotics prior to the BH(4) administration, the amount of biopterin increased in the caecum but the amount of pterin decreased greatly. These results suggested that a large proportion of BH(4) administered moved to the large intestine, where most biopterin was decomposed presumably by enteric bacteria. Nonetheless, most of the orally administered biopterin was taken up by the small intestine and the amount of biopterin reaching the large intestine was almost the same as that which appeared after direct injection of 6RBH(4) into the peritoneal cavity.

Adenomatoid tumour of the liver.

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus.

BACKGROUND: Insulin resistance significantly correlated with a non-dipper type of essential hypertension. Thiazolidinediones (TZD), oral hypoglycaemic agents that act as insulin sensitizers, have been demonstrated in multiple in vivo and in vitro studies to possess antihypertensive properties. This study examined the efficacy of TZD therapy with pioglitazone at transforming the circadian rhythms of blood pressure from a non-dipper to a dipper type. MATERIALS: We examined 31 patients with type 2 diabetes mellitus during both a baseline period and a period of treatment with pioglitazone. Patients received 15 mg day(-1) pioglitazone for four weeks and 30 mg day(-1) for 12 weeks. Twenty-four hour ambulatory blood pressure monitoring (ABPM) and laboratory data (blood tests for cardiovascular risk factors) were obtained at the beginning and end of the study. RESULTS: In non-dippers (n = 16), but not dippers (n = 15), we observed a significant interaction between pioglitazone therapy and nocturnal falls in systolic and diastolic blood pressure. This examination indicated that the magnitude of the nocturnal blood pressure fall was affected by pioglitazone therapy. In non-dippers, but not dippers, a significant correlation was observed between the percent decrease in nocturnal BP and the homeostasis model assessment (HOMA) index (r = 0.774, P = 0.0007). CONCLUSIONS: The present study demonstrated that pioglitazone can restore the nocturnal BP declines in parallel to reductions in the HOMA index, suggesting that insulin resistance may play an important role in the genesis of circadian BP rhythms. TZD-based treatment may thus have the additional therapeutic advantage of reducing the risk of cardiovascular complications by transforming the circadian rhythm of BP.

The nutritional advantages of proximal gastrectomy for early gastric cancer.

BACKGROUND/AIMS: Total gastrectomy has generally been performed for the treatment of early gastric cancers involving the upper third of the stomach. However, proximal gastrectomy has also been used for the treatment of cardial early gastric cancer. METHODOLOGY: To compare the nutritional parameters after proximal gastrectomy with the parameters after total gastrectomy, and to also determine the advantages of the postoperative nutritional states, a retrospective analysis was made to evaluate the nutritional status of patients with early gastric cancer who underwent proximal gastrectomy with those undergoing total gastrectomy. Forty-nine patients were studied for one year after surgery; 9 underwent proximal gastrectomy while 40 had a total gastrectomy. RESULTS: Proximal gastrectomy allowed the patient to better maintain both their nutritional parameters and body weight. CONCLUSIONS: Proximal gastrectomy was thus found to be a beneficial modality for early gastric cancer patients regarding terms of the postoperative nutritional status, in comparison to total gastrectomy.

Direct hypogastric artery reconstruction for threatened lower limb ischemia: report of a case.

The hypogastric artery is one of the major collateral arteries in aortoiliac occlusive disease. This report describes a case of limb-threatening ischemia caused by acute arterial thrombosis of the right hypogastric artery. The external iliac and distal arteries were obstructed and the hypogastric artery was a major collateral artery. A diagnostic arteriogram taken after intra-arterial thrombolytic therapy revealed a stenotic lesion in the orifice of the hypogastric artery. Open thromboendarterectomy of the hypogastric artery and patch angioplasty, using an expanded polytetrafluoroethylene graft, were performed to salvage the limb. The hypogastric artery was successfully revascularized and ischemic rest pain was relieved.

Synthesis and stereostructure-activity relationship of three asymmetric center pyrethroids: 2-methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether and cyanohydrin ester.

2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and cyanohydrin ester 3, a couple of pyrethroids with three asymmetric centers, were synthesized. Of each of the four diastereomers of 2 and 3, only the (1R*,2R*,3R*)-2a and 3a showed significant insecticidal activities. Dual sets of enantiomers [(1R,2R,3R)-(-)-2a and (1S,2S,3S)-(+)-2a] and [(1R,2R,3R)-(-)-3a and (1S,2S,3S)-(+)-3a] were synthesized through the asymmetric cyclopropanation using the Aratani catalyst. Significant separations of insecticidal activities were observed between both the enantiomers against the tobacco cutworm (Spodoptera litura) and the common mosquito (Culex pipiens pallens); (1S,2S,3S)-(+)-2a and (+)-3a showed higher activities than their antipodes (1R,2R,3R)(-)-2a and (-)-3a. This result is the second example of such synthetic pyrethroids with three asymmetric centers.

Clinicopathological features of long-term survivors of scirrhous gastric cancer.

BACKGROUND/AIMS: Prognosis of scirrhous gastric cancer remains low. To determine the clinicopathological features that are correlated with prognosis, we studied long-term survivors of scirrhous gastric cancer (survival duration more than 5 years) in comparison with patients with short survival. METHODOLOGY: Among 2719 gastric cancer patients who underwent surgery at Matsuyama Red Cross Hospital, 211 cases were diagnosed as scirrhous type gastric cancer. Seventeen patients survived more than 5 years, and the rest had short survival (less than 5 years). Comparison of clinicopathological factors was done by chi 2 analysis. Multivariate analysis was done in order to focus on the prognostic factors. RESULTS: The 5-year survival of the total 211 patients was 12%. The 5-year survival of patients who underwent curative surgery (67 cases) was 30%, which was significantly higher than that of the non-curative surgery group (144 cases, 6%). Significant differences were noted in the following variables: peritoneal dissemination, hepatic metastasis, lymph node dissection, pattern of infiltrating growth, depth of invasion, histological lymph node metastasis, histological stage, and histological curability. Patients with either hepatic metastasis or peritoneal dissemination did not survive 5 years. Multivariate analysis revealed that the most significant independent prognostic factor was histological curability, followed by peritoneal dissemination. CONCLUSIONS: There is a possibility of long-term survival for patients with scirrhous gastric cancers without hepatic metastasis, peritoneal dissemination, or extensive lymph node metastasis. Curative surgery is important, suggesting that the extended operation is rational if possible.

Portal-systemic encephalopathy due to a congenital extrahepatic portosystemic shunt: three cases and literature review.

Extrahepatic portal-systemic encephalopathy due to congenital extrahepatic portosystemic shunt has so far been rarely reported in the literature. We herein report 3 such cases without liver cirrhosis or portal hypertension which were presented with the chief complaint being disturbance of consciousness and abnormal behavior. In all cases the brain computed tomography scan revealed no pathological findings, while electroencephalogram showed a diffuse slow activity with triphasic waves. The laboratory data revealed a high serum ammonia level. Percutaneous transhepatic portography demonstrated portosystemic shunts. After these shunts were surgically occluded, the serum ammonia level reached a normal range and encephalopathy disappeared. A liver biopsy also revealed neither fibrosis nor cirrhosis in any of the cases. The 23 previously reported cases are also discussed.

Superior mesenteric vein thrombosis due to diverticulitis and spontaneous thrombolysis after ilio-cecal resection. A case report.

Inflammation or infection is one of the major causes of superior mesenteric vein thrombosis. A case of secondary superior mesenteric vein thrombosis is presented, which was identified with enhanced CT. The mesenteric venous thrombosis was due to diverticulitis of the ileum, and ilio-cecal resection was performed. Because no findings of intestinal ischemia were present, thrombectomy was not attempted. After surgery, the patient was followed up by repeated CT scan, and spontaneous thrombolysis without thrombectomy or thrombolytic therapy was exhibited. The present case indicated abdominal inflammation or infection strongly related to the development and regression of mesenteric venous thrombosis.

[Efficacy of UFT in the treatment of para-aortic lymph node metastasis following gastric cancer surgery: case report].

The patient was a 68-year-old man who underwent pyloric gastrectomy for advanced stomach cancer on December 6, 1996. The histopathological diagnosis was poorly differentiated adenocarcinoma, ss, ly3, v1, n2 (+), and stage IIIa. Postoperative adjuvant chemotherapy consisted of short-term intravenous infusion of 5-FU, 320 mg/m2/day (= 480 mg/body) for 5 days beginning on postoperative day (POD) 1, and oral 5-FU, 200 mg/day, for 1 year beginning on POD 14. The preoperative CEA value was 316.2 ng, but it fluctuated below 10 ng postoperatively. About one year after the operation, the patient began to complain of epigastric pain, loss of appetite, and general malaise. CT of the upper abdomen revealed a 1.5-cm para-aortic lymph node, and the CEA value of 319.0 ng was abnormally high. 5-FU was stopped, oral UFT at 300 mg/day was started, and the patient's course was followed. Three months after the start of UFT, the lymph node had shrunk on CT (shrinkage rate: 66.7%), and the CEA value had decreased to 14.3 ng. As though corresponding to these changes there was a gradual decrease in the epigastric pain, general malaise, etc., and the patient's appetite also returned. There were no subsequent elevations in the CEA values or increases in the size of the para-aortic lymph nodes, and the patient's general condition was favorably maintained. UFT appeared to be effective against the lymph node metastasis around the aorta in this case.

[Changes of bone marrow arteries with aging].

The purpose of this study was to investigate the mechanism of so-called senile anemia. Using bone marrow tissue specimens prepared from 168 patients autopsied at the Second Department of Pathology of Tokyo Medical University, we measured the area of fatty marrow tissue and the luminal cross-sectional area of feeding arteries for the marrow to assess the relationship of these parameters with aging. Conversion to fatty marrow progressed with aging, and fatty marrow made up more than 50% of the overall bone marrow area in patients aged over 60 years. The nucleated cell count decreased significantly (p < 0.01) in patients aged over 60 years. Furthermore, the luminal cross-sectional area of bone marrow feeding arteries also decreased gradually with aging, declining by 18% to 26% in patients aged over 50 years compared with patients in their third decade. A significant negative correlation (r = -0.228; p < 0.001) was found between the area of fatty marrow and the luminal cross-sectional area of the bone marrow feeding arteries. In conclusion, we suggest that artherosclerotic changes associated with aging in the bone marrow have an impact on hematopoietic function and may be one of the factors involved in the development of senile anemia.

Laparoscopic splenectomy using a wall-lifting procedure.

A laparoscopic splenectomy using a hanger wall-lifting procedure is herein described. The patient is placed in the right lateral position. The left lower chest and left abdominal wall are then lifted by three wires in two directions, left laterally and vertical to the abdominal wall. The view of the operative field thus obtained is excellent. The lifting wires and bars do not hinder the movement of the forceps, since the angles of the instruments to approach the spleen are different from those of the wires. A laparoscopic splenectomy using this wall-lifting procedure avoids the usual complications associated with pneumoperitoneum while still being technically comparable to a procedure with pneumoperitoneum.

Pre-operative imaging can diagnose torsion of the gallbladder: report of a case.

Torsion of the gallbladder is a rare disease and pre-operative diagnosis of the disease is uncommon. About 400 cases have been reported, but only 4 were diagnosed by pre-operative imaging. We report on a case of gallbladder volvulus diagnosed pre-operatively using pre-operative imaging with ultrasound and computed tomography.

Duodenal metastasis from large cell carcinoma of the lung: report of a case.

Duodenal metastasis from primary lung cancer is extremely rare. It rarely shows any symptoms, and the prognosis for this condition is poor. We herein describe the case of a 46-year-old woman with primary lung cancer who underwent a left upper lobectomy. Severe anemia was observed about 20 days after lobectomy. Gastroduodenoscopy showed duodenal metastasis. Simultaneously, brain metastasis was also detected using magnetic resonance imaging. The patient underwent a local resection of the duodenum and a tumor resection of the brain. Postoperative irradiation of the brain metastases and systemic chemotherapy of the lung metastases were performed, and complete remission occurred. However, abdominal lymph node metastasis recurred, and the patient died 1 year after the lobectomy.

[Pathology and treatment of anemia in the elderly].

An important background characteristic of anemia in the elderly is decrease in hematopoiesis due to aging. Factors influencing hematopoiesis in the elderly include changes in the distribution of hematopoietic tissue, changes in hematopoietic stem cell density and changes in the hematopoietic inductive microenvironment. In the present study, in order to assess changes in the bone marrow with aging, the fat tissue area, uncleated cell-count and cellularity in the bone marrow, in addition to changes in the diameter of the vascular lumen which result primarily from sclerotic changes in the dorsomedial artery of the bone marrow were determined in different age groups. The results revealed that all of the aforementioned factors changed significantly with aging. We also describe on the results of assays of inflammatory cytokines (IL-1, IL-6, TNF-alpha), lactoferrin and transferrin receptors in cases of anemia of chronic disorders (ACD) which own secondary to chronic inflammatory diseases and is known to frequently afflict the elderly.

Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase.

While native human tyrosyl-tRNA synthetase (TyrRS) is inactive as a cell-signaling molecule, it can be split into two distinct cytokines. The enzyme is secreted under apoptotic conditions in culture where it is cleaved into an N-terminal fragment that harbors the catalytic site and into a C-domain fragment found only in the mammalian enzymes. The N-terminal fragment is an interleukin-8 (IL-8)-like cytokine, whereas the released C-domain is an endothelial-monocyte-activating polypeptide II (EMAP II)-like cytokine. Although the IL-8-like activity of the N-fragment depends on an ELR motif found in alpha-chemokines and conserved among mammalian TyrRSs, here we show that a similar (NYR) motif in the context of a lower eukaryote TyrRS does not confer the IL8-like activity. We also show that a heptapeptide from the C-domain has EMAP II-like chemotaxis activity for mononuclear phagocytes and polymorphonuclear leukocytes. Eukaryote proteins other than human TyrRS that have EMAP II-like domains have variants of the heptapeptide motif. Peptides based on these sequences are inactive as cytokines. Thus, the cytokine activities of split human TyrRS depend on highly differentiated motifs that are idiosyncratic to the mammalian system.