Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity.

Phosphatidylinositol (PI) 3-kinase plays an important role in various metabolic actions of insulin including glucose uptake and glycogen synthesis. Although PI 3-kinase primarily functions as a lipid kinase which preferentially phosphorylates the D-3 position of phospholipids, the effect of hydrolysis of the key PI 3-kinase product PI 3,4,5-triphosphate [PI(3,4,5)P3] on these biological responses is unknown. We recently cloned rat SH2-containing inositol phosphatase 2 (SHIP2) cDNA which possesses the 5'-phosphatase activity to hydrolyze PI(3,4,5)P3 to PI 3,4-bisphosphate [PI(3,4)P2] and which is mainly expressed in the target tissues of insulin. To study the role of SHIP2 in insulin signaling, wild-type SHIP2 (WT-SHIP2) and 5'-phosphatase-defective SHIP2 (Delta IP-SHIP2) were overexpressed in 3T3-L1 adipocytes by means of adenovirus-mediated gene transfer. Early events of insulin signaling including insulin-induced tyrosine phosphorylation of the insulin receptor beta subunit and IRS-1, IRS-1 association with the p85 subunit, and PI 3-kinase activity were not affected by expression of either WT-SHIP2 or Delta IP-SHIP2. Because WT-SHIP2 possesses the 5'-phosphatase catalytic region, its overexpression marked by decreased insulin-induced PI(3,4,5)P3 production, as expected. In contrast, the amount of PI(3,4,5)P3 was increased by the expression of Delta IP-SHIP2, indicating that Delta IP-SHIP2 functions in a dominant-negative manner in 3T3-L1 adipocytes. Both PI(3,4,5)P3 and PI(3,4)P2 were known to possibly activate downstream targets Akt and protein kinase C lambda in vitro. Importantly, expression of WT-SHIP2 inhibited insulin-induced activation of Akt and protein kinase C lambda, whereas these activations were increased by expression of Delta IP-SHIP2 in vivo. Consistent with the regulation of downstream molecules of PI 3-kinase, insulin-induced 2-deoxyglucose uptake and Glut4 translocation were decreased by expression of WT-SHIP2 and increased by expression of Delta IP-SHIP2. In addition, insulin-induced phosphorylation of GSK-3beta and activation of PP1 followed by activation of glycogen synthase and glycogen synthesis were decreased by expression of WT-SHIP2 and increased by the expression of Delta IP-SHIP2. These results indicate that SHIP2 negatively regulates metabolic signaling of insulin via the 5'-phosphatase activity and that PI(3,4,5)P3 rather than PI(3,4)P2 is important for in vivo regulation of insulin-induced activation of downstream molecules of PI 3-kinase leading to glucose uptake and glycogen synthesis.

Intracellular signalling pathways of okadaic acid leading to mitogenesis in Rat1 fibroblast overexpressing insulin receptors: okadaic acid regulates Shc phosphorylation by mechanisms independent of insulin.

Okadaic acid is a powerful inhibitor of serine/threonine protein phosphatases 1 and 2A. Although it is known as a potent tumour promoter, the intracellular mechanism by which okadaic acid mediates its mitogenic effect remains to be clarified. We investigated the effect of okadaic acid on the activation of mitogenesis in Rat1 fibroblasts overexpressing insulin receptors. As previously reported, insulin induced Shc phosphorylation, Shc-Grb2 association, MAP kinase activation, and BrdU incorporation. Okadaic acid also stimulated tyrosine phosphorylation of Shc and its subsequent association with Grb2 in a time- and dose-dependent manner without affecting tyrosine phosphorylation of insulin receptor beta-subunit and IRS. However, to a lesser extent, okadaic acid stimulated MAP kinase activity and BrdU incorporation. Interestingly, preincubation of okadaic acid potentiated insulin stimulation of tyrosine phosphorylation of Shc (213% of control), Shc-Grb2 association (150%), MAP kinase activity (152%), and BrdU incorporation (148%). These results further confirmed the important role of Shc, but not IRS, in cell cycle progression in Rat1 fibroblasts. Furthermore, serine/ threonine phosphorylation appears to be involved in the regulation of Shc tyrosine phosphorylation leading to mitogenesis by mechanisms independent of insulin signalling.

[Abdominal organ infarction encountered immediately after surgery of primary lung cancer].

Very rare cases of abdominal organ infarction after surgery of primary lung cancer were reported. Case 1: Patient 1 was a 70-year-old man who underwent left upper lobectomy and ND 2a in June 1999 based on the clinical diagnosis of stage IA lung cancer. On the 4th postoperative day, the patient developed fever and right flank pain. Abdominal computed tomography (CT) demonstrated a specific finding compatible with renal infarction. The etiology could not be determined. The patient was treated conservatively. However, severe atrophy of right kidney was demonstrated by following CT performed 3 years later. Case 2: Patient 2 was a 70-year-old woman who underwent left upper lobectomy and ND 2a in December 2002 based on the clinical diagnosis of stage IA lung cancer. On the 4th postoperative day, the patient developed abdominal pain in the left upper quadrant, nausea and vomiting which had lasted for 10 days. Abdominal CT demonstrated a wedge-shaped filling defect at spleen compatible with splenic infarction. The etiology could not be determined. The patient was treated conservatively with prophylactic antibiotic therapy and followed closely. Partial atrophy of spleen was demonstrated by following CT performed 4 months later.

Tyrosine phosphorylation-dependent and -independent role of Shc in the regulation of IGF-1-induced mitogenesis and glycogen synthesis.

To examine the functional role of Shc tyrosine phosphorylation in IGF-1 signaling, wild-type (WT)-Shc and Y239,240,317F (3F)-Shc were transiently transfected into L6 myoblasts. IGF-1 signaling was compared among the transfected cells. IGF-1-induced tyrosine phosphorylation of Shc and its subsequent association with Grb2 were increased in WT-Shc cells, whereas they were decreased in 3F-Shc cells compared with those in parental L6 cells. Consistent with their changes, IGF-1-induced MAPK activation and thymidine incorporation were enhanced in WT-Shc cells, whereas they were again decreased in 3F-Shc cells. It is possible that Shc and insulin receptor substrate (IRS)-1 can interact competitively, via their phosphotyrosine binding (PTB) domains, with the activated IGF-1 receptor. In this regard, IGF-1-induced tyrosine phosphorylation of IRS-1 was decreased by overexpressing both WT-Shc and 3F-Shc cells. Consistent with the decrease, IGF-1-induced IRS-1 association with the p85 subunit of PI3K and activation of PI3K and Akt were reduced in both WT-Shc and 3F-Shc cells. As a result, IGF-1-induced glycogen synthesis was also decreased in both cells. Furthermore, expression of Shc PTB domain alone inhibited IGF-1 stimulation of Akt and glycogen synthesis. These results indicate that tyrosine phosphorylation of Shc is important for IGF-1 stimulation of MAPK leading to mitogenesis and that Shc, via its PTB domain, negatively regulates IGF-1-induced glycogen synthesis by competing with IRS-1, which is not relevant to Shc tyrosine phosphorylation.

Evidence for functional roles of Crk-II in insulin and epidermal growth factor signaling in Rat-1 fibroblasts overexpressing insulin receptors.

We examined the potential role of Crk-II in insulin and epidermal growth factor (EGF) signaling in Rat-1 fibroblasts overexpressing insulin receptors. Crk is an SH2 and SH3 domain-containing adaptor protein that has been reported to associate with p130cas, paxillin, c-cbl, c-abl, Sos, and C3G in vitro. Insulin- and EGF-induced association of Crk-II with these molecules was assessed by immunoblotting of anti-Crk-II precipitates in Rat-1 fibroblasts overexpressing insulin receptors. Neither insulin nor EGF treatment induced Crk-II association with either Sos or C3G. Basal tyrosine phosphorylation of c-abl and its constitutive association with Crk-II were not further increased by insulin or EGF. p130cas and paxillin were heavily tyrosine phosphorylated in the basal state. Both insulin and EGF stimulated their dephosphorylation, followed by p130cas-Crk-II dissociation and paxillin-Crk-II association, although the magnitude of these effects was greater with insulin than with EGF. Interestingly, EGF, but not insulin, stimulated tyrosine phosphorylation of c-cbl and its association with Crk-II. To investigate the functional roles of Crk-II in mitogenesis and cytoskeletal rearrangement, we performed microinjection analysis. Cellular microinjection of anti-Crk-II antibody inhibited EGF-induced, but not insulin-induced, DNA synthesis. Insulin, but not EGF, stimulated cytoskeletal rearrangement in the cells, and microinjection of anti-Crk-II antibody effectively inhibited insulin-induced membrane ruffling, suggesting that Crk-II is involved in insulin-induced cytoskeletal rearrangement. These results indicate that Crk-II functions as a multifunctional adaptor molecule linking insulin and EGF receptors to their downstream signals. The presence of c-cbl-Crk-II association may partly determine the signal specificities initiated by insulin and EGF.

Role of the Src homology 2 (SH2) domain and C-terminus tyrosine phosphorylation sites of SH2-containing inositol phosphatase (SHIP) in the regulation of insulin-induced mitogenesis.

To examine the role of SHIP in insulin-induced mitogenic signaling, we used a truncated SHIP lacking the SH2 domain (deltaSH2-SHIP) and a Y917/1020F-SHIP (2F-SHIP) in which two tyrosines contributing to Shc binding were mutated to phenylalanine. Wild-type (WT)-, deltaSH2-, and 2F-SHIP were transiently transfected into Rat1 fibroblasts overexpressing insulin receptors (HIRc). Insulin-stimulated tyrosine phosphorylation of WT-SHIP and deltaSH2-SHIP, whereas tyrosine phosphorylation of 2F-SHIP was not detectable, indicating that 917/1020-Tyr are key phosphorylation sites on SHIP. Although SHIP can bind via its 917/1020-Tyr residues and SH2 domain to Shc PTB domain and 317-Tyr residue, respectively, insulin-induced SHIP association with Shc was more greatly decreased in 2F-SHIP cells than that in deltaSH2-SHIP cells. Insulin stimulation of Shc association with Grb2, which is important for p21ras-MAP kinase activation, was decreased by overexpression of WT- and 2F-SHIP. Importantly, insulin-induced Shc x Grb2 association was not detectably reduced in deltaSH2-SHIP cells. In accordance with the extent of Shc association with Grb2, insulin-induced MAP kinase activation was relatively decreased in both WT-SHIP and 2F-SHIP cells, but not in deltaSH2-SHIP cells. To examine the functional role of SHIP in insulin's biological action, insulin-induced mitogenesis was compared among these transfected cells. Insulin stimulation of thymidine incorporation and bromodeoxyuridine incorporation was decreased in WT-SHIP cells compared with that of control HIRc cells. Expression of 2F-SHIP also significantly reduced insulin-induced mitogenesis, whereas it was only slightly affected by overexpression of deltaSH2-SHIP. Furthermore, the reduction of insulin-induced mitogenesis in WT-SHIP cells was partly compensated by coexpression of Shc. These results indicate that SHIP plays a negative regulatory role in insulin-induced mitogenesis and that the SH2 domain of SHIP is important for its negative regulatory function.

Synergistic role of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase cascade in the regulation of insulin receptor trafficking.

To examine the molecular mechanism of insulin receptor trafficking, we investigated the intracellular signaling molecules that regulate this process in Rat1 fibroblasts overexpressing insulin receptors. Cellular localization of insulin receptors was assessed by confocal laser microscopy with indirect immunofluorescence staining. Insulin receptors were visualized diffusely in the basal state. Insulin treatment induced the change of insulin receptor localization to perinuclear compartment. This insulin-induced insulin receptor trafficking was not affected by treatment of the cells with PI3-kinase inhibitor (wortmannin), whereas treatment with MEK [mitogen-activated protein (MAP) kinase-Erk kinase] inhibitor (PD98059) partly inhibited the process in a dose-dependent manner. Interestingly, treatment with both wortmannin and PD98059 almost completely inhibited insulin receptor trafficking. The functional importance of PI3-kinase and MAP kinase in the trafficking process was directly assessed by using single cell microinjection analysis. Microinjection of p85-SH2 and/or catalytically inactive MAP kinase ([K71A]Erk1) GST fusion protein gave the same results as treatment with wortmannin and PD98059. Furthermore, to determine the crucial step for the requirement of PI3-kinase and MAP kinase pathways, the effect of wortmannin and PD98059 on insulin receptor endocytosis was studied. Insulin internalization from the plasma membrane and subsequent insulin degradation were not affected by treatment with wortmannin and PD98059. In contrast, insulin receptor down-regulation from the cell surface and insulin receptor degradation, after prolonged incubation with insulin, were markedly impaired by the treatment. These results suggest that PI3-kinase and MAP kinase pathways synergistically regulate insulin receptor trafficking at a step subsequent to the receptor internalization.

Comparison of the insulin and insulin-like growth factor 1 mitogenic intracellular signaling pathways.

We compared the intracellular insulin-like growth factor-1 (IGF-1) and insulin signaling pathways in Rat1 fibroblasts expressing the equivalent number of insulin receptors and endogenous IGF-1 receptors. Insulin and IGF-1 stimulated tyrosine phosphorylation of IRS-1 and Shc in a similar dose- and time-dependent manner. The time course of Shc phosphorylation by both IGF-1 and insulin was slower than that of IRS-1. Both phosphorylated IRS-1 and Shc associated with Grb2.Sos complexes, leading to p21ras activation. To compare the functional importance of p21ras for IGF-1-and insulin-induced DNA synthesis, single cell microinjection studies were performed. BrdU incorporation into newly synthesized DNA was measured by immunofluorescence microscopy to assess the functional importance of p21ras. Both IGF-1 and insulin stimulated BrdU incorporation, but the effect of IGF-1 was greater. Microinjection of anti-p21ras antibody completely inhibited both IGF-1-and insulin-induced DNA synthesis, indicating the central role of p21ras in signaling by both hormones. Signal transduction from these receptors to Grb2.Sos complexes can occur through IRS-1 and/or Shc. To assess these two possible pathways, we performed Western blots for Grb2 in anti-Shc and anti-IRS-1 immunoprecipitates and found that 5-fold more Grb2 was associated with Shc than with IRS-1 after either IGF-1 or insulin stimulation. Microinjection of anti-Shc antibody inhibited IGF-1 and insulin stimulation of DNA synthesis by 78% and 74%, respectively. By microinjecting Shc subdomains of GST fusion proteins, we found that Shc N-terminus, but not the Shc SH2, was the functionally important domain through which Shc interacts with IGF-1 and insulin receptors. Insulin stimulation caused hyperphosphorylation and decreased electrophoretic mobility of Sos, and a similar effect was seen with IGF-1, although the time course was delayed compared with insulin. Finally, IGF-1 activated mitogen-activated proten kinase activity more effectively than insulin. These data indicate that Shc, rather than IRS-1, appears to be the predominant functional link to Grb2.Sos complexes from the IGF-1 receptor, as it is from the insulin receptor. Although IGF-1 and insulin stimulate cell cycle progression with similar coupling mechanisms from the receptor to Shc, to Grb2.Sos, to p21ras, the delayed IGF-1 induced mobility shift of Sos could lead to, at least in part, more efficient coupling to mitogen-activated protein kinase. These findings might explain the greater mitogenic activity of IGF-1 compared with insulin.

Glucosamine enhances platelet-derived growth factor-induced DNA synthesis via phosphatidylinositol 3-kinase pathway in rat aortic smooth muscle cells.

Vascular smooth muscle cells play a key role in the development of atherosclerosis. Culture of vascular smooth muscle A10 cells with high glucose for 4 weeks enhanced platelet-derived growth factor (PDGF)-induced BrdU incorporation. Since a long period of high glucose incubation was required for the effect, and it was inhibited by co-incubation with azaserine, the role of hexosamine biosynthesis in the development of atherosclerosis in diabetes was studied in A10 cells. Addition of glucosamine to the culture media enhanced PDGF-stimulated BrdU incorporation, and PDGF-induced tyrosine phosphorylation of the PDGF beta-receptor was increased by glucosamine treatment. Of the subsequent intracellular signaling pathways, PDGF-induced PDGF beta-receptor association with PLC gamma was not affected, whereas tyrosine phosphorylation of Shc, subsequent association of Shc with Grb2, and MAP kinase activation were relatively decreased. In contrast, PDGF-induced PDGF beta-receptor association with the p85 regulatory subunit of PI3-kinase and PI3-kinase activation were increased by 20% (P<0.01) and 36% (P<0.01), respectively. The intracellular signaling molecules responsible for the glucosamine effect were further examined using pharmacological inhibitors. Pretreatment with PLC inhibitor (U73122) had negligible effects, and MEK1 inhibitor (PD98059) showed only a slight inhibitory effect on the PDGF-induced BrdU incorporation. In contrast, pretreatment with PI3-kinase inhibitor (LY294002) significantly inhibited glucosamine enhancement of PDGF-induced BrdU incorporation. These findings suggest that glucosamine is involved in the development of atherosclerosis by enhancing PDGF-induced mitogenesis specifically via the PI3-kinase pathway.

The dominant negative effect of a kinase-defective insulin receptor on insulin-like growth factor-I-stimulated signaling in Rat-1 fibroblasts.

To study the interaction between insulin receptor (IR) and insulin-like growth factor-I (IGF-I) receptor (IGF-IR) tyrosine kinases, we examined IGF-I action in Rat-1 cells expressing a naturally occurring tyrosine kinase-deficient mutant IR (Asp 1048 IR). IGF-I normally stimulated receptor autophosphorylation, IRS-I phosphorylation, and glycogen synthesis in cells expressing Asp 1048 IR. However, the Asp 1048 IR inhibited IGF-I-stimulated thymidine uptake by 45% to 52% and amino acid uptake (aminoisobutyric acid [AIB]) by 58% in Asp 1048 IR cells. Furthermore, IGF-I-stimulated tyrosine kinase activity toward synthetic polymers, Shc phosphorylation, and mitogen-activated protein (MAP) kinase activity was inhibited. The inhibition of mitogenesis and AIB uptake was restored with the amelioration of the impaired tyrosine kinase activity and Shc phosphorylation by the introduction of abundant wild-type IGF-IR in Asp 1048 IR cells. These results suggest that the Asp 1048 IR causes a dominant negative effect on IGF-IR in transmitting signals to Shc and MAP kinase activation, which leads to decreased IGF-I-stimulated DNA synthesis, and that the kinase-defective insulin receptor does not affect IGF-I-stimulated IRS-I phosphorylation, which leads to the normal IGF-I-stimulated glycogen synthesis.

Effect of glimepiride (HOE 490) on insulin receptors of skeletal muscles from genetically diabetic KK-Ay mouse.

A new sulfonylurea, glimepiride (HOE 490), has been developed for the glycemic control in non-insulin-dependent diabetes mellitus. We examined the effect of glimepiride on glucose and insulin levels in KK-Ay mice, an animal model of non-insulin-dependent diabetes mellitus, which is characterized by hyperglycemia and hyperinsulinemia. Administration of glimepiride (0.5 mg/kg/day) for 8 weeks to KK-Ay mice resulted in decrease in glucose (297 +/- 36 to 250 +/- 51 mg/dl) and insulin (76 +/- 14 to 41 +/- 14 microU/ml) levels. To clarify the mechanism of the agent, we examined the effect of this new drug on insulin receptors in the skeletal muscles. There was no difference in insulin binding to the receptors from both glimepiride-treated and -untreated KK-Ay mice muscles. The insulin-stimulated autophosphorylation of insulin receptors from KK-Ay mice was decreased compared to that from normal mice (5 +/- 1 vs. 39 +/- 13% over basal). Glimepiride did not ameliorate impaired insulin-stimulated insulin receptor autophosphorylation. To determine the effect of glimepiride on post-insulin receptor signaling pathway, we measured 2-[3H]glycerol incorporation into diacylglycerol in the cultured rat fibroblast cell line overexpressing human insulin receptors. Glimepiride (100 microM) as well as insulin (10 nM) significantly stimulated diacylglycerol production. These results suggest that glimepiride has a potent extrapancreatic effect on glucose metabolism and may directly stimulate glucose transport activity through phospholipid signaling pathway, but not through insulin receptor kinase signaling pathway.

I-123 MIBG imaging of metastatic carcinoid tumor from the rectum.

I-131 MIBG, a specific radiopharmaceutical agent for scintigraphic imaging and treatment of pheochromocytoma and neuroblastoma may be useful for detection of apudomas. Scintigraphy with I-123 radiolabeled MIBG was performed in a patient with metastatic carcinoid tumor from the rectum. I-123 MIBG scintigraphic findings showed multiple areas of abnormal tumor uptake of hepatic and bone metastases from the rectal carcinoid. Bone scintigraphy demonstrated multiple metastatic lesions. Computed tomography revealed multiple solid tumors of the liver. This report describes accumulation of I-123 MIBG in the liver and bone metastases from the rectal carcinoid. Radioiodine MIBG scintigraphy may be useful for detecting metastatic lesions, for evaluating postoperative recurrence, and also for the treatment of the carcinoid tumor.

[Simultaneous spontaneous pneumomediastinum caused by vocal exercise; report of 2 cases].

Two cases of spontaneous pneumomediastinum caused by vocal exercise were reported. Two 18-year-old men were admitted to our hospital simultaneously in April 2003, because of cervical discomfort and chest pain after vocal exercise of self introduction as a event of freshman in their college. Their chest X-ray film and chest computed tomography (CT) demonstrated typical pneumomediastinum. One of them also showed thoracic epidural emphysema without any particular neurological deficit. Both cases completely recovered by only conservative therapy within 5 days. Spontaneous pneumomediastinum which occurs frequently in young men is thought to be a relatively rare disease showing a good prognosis. It seems important to consider this rare condition when the young man complaints chest pain and discomfort around their neck. We thought that there must be a high possibility of this disease being overlooked as a mere chest pain in young man of unknown reason until now. It is our conclusion that spontaneous pneumomediastinum is a really benign condition that requires no specific examination nor therapy.

[Diplopia and blepharoptosis associated with orbital emphysema following thoracotomy with lung cancer; report of a case].

BACKGROUND: Orbital emphysema is a common complication of trauma and fracture of orbital bones. However, subcutaneous emphysema also can rarely lead to orbital emphysema. We reported the clinical and radiological findings in a patient with diplopia and blepharoptosis following thoracotomy for lung cancer. CASE: A 76-year-old man had undergone left inferior lobectomy and ND 2 a in October 2002, based on the clinical diagnosis of stage IB lung squamous cell carcinoma. He presented with diplopia and blepharoptosis several days following thoracotomy. Chest X-ray demonstrated extensive subcutaneous emphysema, and physical examination also revealed diffuse subcutaneous emphysema including face and palpebrae. Head computed tomography (CT) revealed subcutaneous emphysema in the infratemporal fossa bilaterally. His diplopia and blepharoptosis gradually resolved, and he was discharged with no visual complaints on the fourteenth postoperative day. CONCLUSIONS: Subcutaneous emphysema can lead to diplopia and orbital emphysema in the absence of orbital trauma. Early surgical intervention for air leakage is highly recommended to avoid both the orbital emphysema and the visual complications in the event that subcutaneous emphysema should get to including face or palpebrae.

[A clinical evaluation of the practical reliability in video-assisted thoracic surgery for right primary lung cancer].

Recently, lobectomy by video-assisted thoracic surgery (VATS lobectomy: VL) has been widely applied to peripheral lung cancer because of its less invasive approach compared to standard thoracotomy (ST). However, the appropriate approach in VL still remains to be solved. The aim of this study was to evaluate the practical reliability of our technical devices in VL for right primary lung cancer. For the VATS procedures, a mini-thoracotomy measuring about 6-7 cm was made in the fourth or fifth intercostal space (ICS) under the auscultatory triangle without rib resection. Two access holes 12 mm in size were also made in the fourth ICS at the anterior axillary line and in the seventh ICS at the posterior axillary line, respectively. These access holes were used for insertion of thoracoscope, endoscopic stapler or retracting instrument according to operative procedure. After stapling of the vessels and bronchus, the resected pulmonary lobe was removed from the thorax using a plastic retrieval bag. The present study showed the technical feasibility of this unique thoracoscopic approach in the standard lobectomy with systematic nodal dissection for right lung cancer.

[Conservative therapy for recurrent bronchial stump fistula occurred after surgery for lung cancer with cerebrovascular disease].

BACKGROUND: Although pyrothorax caused by bronchial stump fistula is 1 of the most severe respiratory complications frequently encountered after surgery for lung cancers, it is very difficult to prevent the development of pyrothorax. However, conservative treatment for bronchial stump fistula occurred after surgery for lung cancer was successfully performed in 1 of our elderly lung cancer patients with a history of cerebrovascular events. CASE: Patient was a 74-year-old man who developed cerebral infarction in October 2000, and was continuously undergoing rehabilitation for left hemiplegia. Chest computed tomography (CT) demonstrated a tumorous lesion in the right S6. Clinical diagnosis of stage IA squamous cell carcinoma was made. His performance status (PS) was degree IV, and he required complete assistance. In addition, since several abnormal florae were detected by preoperative examinations of sputum, the development of postoperative respiratory complications was suspected. In April 2001, thoracoscopy-assisted right inferior lobectomy and nodal dissection 1 (ND 1) were performed. Although the patient developed bronchial stump fistula on the 6th hospital day, it was successfully treated by conservative procedures after second surgery. CONCLUSION: Conservative therapy under nutritional management mainly consisting of central venous nutrition may be useful for some surgically treated lung cancer patients with bronchial stump fistula when they have mild inflammation and the reduction of pyrothorax cavity can be expected by re-expansion of the residual lobes of the lung.

[Assessment of ability to withstand lung resections and post-operative survival in patients with respiratory disorders and bronchogenic carcinoma].

Of 1192 lung resections in patients with bronchogenic carcinoma since 1952, the early post-operative mortality averaged 3.9%, whereas during the last ten years, it was 2.6% of 730 lung resections, including 159 (22%) pneumonectomies, 76 (10%) bilobectomies, 492 (67%) single lobectomies and 3 (0.4%) partial lung resections. In the latter, 352 (48.2%) and 75 (10%) had airway obstructive failure of FEV1.0 less than 70% and 55%, respectively, and, 56 (7.7%) and 9 (1%) represented preoperative hypoxia of PaO2 less than 70 torr and 60 torr, respectively. The ratios of pneumonectomies in these, being similar to those with better lung functions, the perioperative mortality was also similar. Our previously reported indices preoperatively to prove ability to withstand curative lung resections, being supported by these data, we attempted in a certain limited group of patients, extendingly to clear patients with critically poor predicted pulmonary vascular reserve pf 710-930 dyne . cm-5 . sec/m2 for lung resections, resulting in six elevenths of over one year survival. One must extend benefit of lung resection to patients with coexistence of bronchogenic carcinoma and respiratory disorder apparently severe enough to preclude resection surgery by critical assessment of the predicted pulmonary vascular reserve after lung resection.

[New quantitative method for non-invasive monitoring of tissue blood oxygenation by near infrared spectrophotometry].

The near infrared absorption spectra was measured with the transmitted light through rat brain under the various condition. The absorbance changes below 780 nm were attributable to hemoglobin (Hb) in the brain tissue, whereas those above 780 nm were associated with both Hb and cytochrome oxidase. To eliminate possible interference from cyt. oxidase, two wavelengths, 750 nm and 780 nm, were used to measure Hb oxygenation in the tissue. The absorbance changes in human blood cell suspensions were measured with changes in hematocrit values in the optical cuvette. At two wavelengths 750 nm and 780 nm, there was a linear relationship between absorbance changes and hematocrit values. Through these in vitro studies, the following equation (1) and (2) were obtained to monitor quantitatively the changes of oxy-Hb content (delta Hb O2) and total-Hb content (delta Hb Vol.) in the living tissue. These are (1) delta Hb O2 = -1.15 delta A 750 + 1.39 delta A 780, (2) delta Hb Vol. = -0.29 delta A 750 + 0.59 delta A 780. The studies using these equations showed that the oxy-Hb content in the brain was decreased as the O2 concentration in inspired gas was lowered with a half of Hb deoxygenated at 7% O2. The reliability of these equations was examined under the various conditions in situ such as CO2 inhalation, intravenous injection of Ca2+-blocker nicardipine, hemorrhage and retransfusion. These results confirmed that these equations derived from in vitro studies, were successfully applied to the in situ measurements of the oxygenation state of Hb in the living tissues.

[Non-invasive assessment of mitochondrial function in rat brain during and after hemorrhagic shock].

Brain oxygen metabolism was studied noninvasively by the simultaneous measurement of hemoglobin (Hb) oxygenation, and cytochrome oxidase (aa3) redox state in the brain of a rat, using our near-infrared (NIR) transmission spectrophotometer. Redox state of cyt. aa3 was measured using a wavelength pair of 830-940 nm. The changes of oxy- and total (oxy + deoxy) Hb content in the rat brain could be monitored quantitatively by expressions of -1.15 delta A750 + 1.39 delta A780 and -0.29 delta A750 + 0.59 delta A780, respectively (delta A750, delta A780: absorbance changes at wavelength 750 and 780 nm). An application of NIR-Spectrophotometry for the studies of brain metabolism in acute hemorrhagic shock in rats was presented. Tissue hypoxia was induced in 20 rats by rapid withdrawal of arterial blood to a mean blood pressure of 30 mmHg. This level of shock pressure was maintained for 30 minutes in group A (n = 8), and for 70 minutes in group B (n = 10), then the removed blood was returned by infusion. Blood oxygenation level, relative blood volume and cyt. aa3 redox state in the rat brain were monitored during shock, and for two more hours after the reinfusion. Group A had a high survival rate while group B had a poor survival rate. In both groups with the onset of hypotension, there occurred a rapid deoxygenation of brain blood and a rapid and progressive shift of cyt. aa3 towards a more reduced state.(ABSTRACT TRUNCATED AT 250 WORDS)