Thoracoscopic radical surgery for a morbidly obese patient with early lung cancer after laparoscopic sleeve gastrectomy: a case report.

BACKGROUND: We experienced a case of early stage lung cancer involving a morbidly obese patient. Obesity is associated with a higher incidence of surgical complications. We examined the effectiveness of laparoscopic sleeve gastrectomy as a primary weight loss procedure in a morbidly obese patient who required oncological surgery. CASE PRESENTATION: A 64-year-old morbidly obese female with a body mass index of 43.5 kg/m2 was referred to our hospital to undergo weight loss. A right-sided lung mass was found incidentally on computed tomography conducted in preparation for laparoscopic sleeve gastrectomy, which was performed prior to tumor surgery. As a result, weight loss was achieved within 2.5 months after the laparoscopic sleeve gastrectomy, and the patient's type-2 diabetes, hypertension, and dyslipidemia, which are linked to obesity, were markedly ameliorated. After a quick intraoperative pathological inspection revealed that the tumor was malignant, thoracoscopic right lung superior lobe resection was performed safely. CONCLUSIONS: Laparoscopic sleeve gastrectomy proved to be a powerful approach in a case in which a morbidly obese patient with early stage cancer needed to lose weight rapidly.

[A case report of curative resection for gastric cancer with peritoneal dissemination successfully treated by combined chemotherapy of S-1 and paclitaxel].

The patient was a 54-year-old female with gastric cancer. As laparotomy showed diffuse peritoneal dissemination, only laparotomy was performed and chemotherapy was conducted with a combination of S-1 80 mg/m(2) (2 weeks administration and 1 week rest) and paclitaxel (PTX) 50 mg/m(2) (day 1, 8). After 5 courses of this regimen, endoscopy showed the tumor was reduced in size and PET-CT revealed no evidence of metastasis. She underwent total gastrectomy with D2 lymph node dissection and Roux-en Y reconstruction. Peritoneal metastasis histologically disappeared, and the final findings were T1, N0, H0, P0, CY0, M0, Stage I A, Cur A. The only adverse effect was grade 1 stomatitis during this chemotherapy. CT showed no findings of recurrence 11 months after the operation. The S-1/PTX combination chemotherapy was thought to be effective for gastric cancer with peritoneal dissemination and made curative operation possible in this case.

Preventive effect of a traditional herbal medicine, Hochu-ekki-to, on immunosuppression induced by surgical stress.

PURPOSE: To examine the effect of preoperative administering of a Japanese traditional herbal medicine, Hochu-ekki-to (TJ-41), on immunosuppression induced by surgical stress in patients with gastrointestinal malignancies. METHODS: To monitor the immune functions, the mitochondrial membrane potential (MMP) and natural killer (NK) cell activity prior to and following operation were measured in peripheral blood lymphocytes (PBL) in patients with (n = 20) or without (n = 27) the preoperative administering of TJ-41 for 7 days. The plasma catecholamine and interleukin (IL)-6 levels were also analyzed prior to and following the operation. RESULTS: The numbers of MMP-high CD56-positive cells (NK cells) and NK cell activities in the TJ-41-treated group were significantly higher than those in the control group (P = 0.026 and P = 0.037, respectively). An elevation of plasma noradrenaline and IL-6 following surgery was also inhibited by the preoperative administering of TJ-41 (P = 0.023 and P = 0.039, respectively). A positive correlation between MMP-high CD56-positive cell numbers and NK cell activity in PBL treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) in vitro suggested that MMP measurement in CD56-positive cells can serve as a convenient alternative to evaluate the NK cell activity. CONCLUSION: Our findings suggest that the preoperative administering of TJ-41 prevents surgical stress-induced immunosuppression by maintaining the NK cell activity and inhibiting the elevation of stress mediators.

Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice.

Parkinson's disease is characterized by loss of nigral dopaminergic neurons and presence of Lewy bodies, whose major component is alpha-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residue number: 1-130) in dopaminergic neurons. Notably, dopaminergic neurons were selectively diminished in the substantia nigra pars compacta of Syn130m, while transgenic mice that expressed comparable amount of full-length human alpha-synuclein did not develop such pathology. Therefore, the truncation of human alpha-synuclein seems to be primarily responsible for the loss of nigral dopaminergic neurons. The nigral pathology resulted in impairment of axon terminals in the striatum and concomitant decrease in striatal dopamine content. Behaviorally, spontaneous locomotor activities of Syn130m were reduced, but the abnormality was ameliorated by treatment with L-DOPA. The loss of nigral dopaminergic neurons was not progressive and seemed to occur during embryogenesis along with the onset of expression of the transgene. Our results indicate that truncated human alpha-synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.

Dopamine receptor agonists reverse behavioral abnormalities of alpha-synuclein transgenic mouse, a new model of Parkinson's disease.

Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.

Accumulation of phosphorylated alpha-synuclein in dopaminergic neurons of transgenic mice that express human alpha-synuclein.

Parkinson's disease is neuropathologically characterized by the presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice that expressed human alpha-synuclein carrying an Ala53Thr point mutation (halpha-syn140m) under the control of the rat tyrosine hydroxylase promoter and found that halpha-syn140m was localized not only in the cytoplasm but also in the nuclei of mesencephalic dopaminergic neurons. In the present study, we carried out immunohistochemical analysis of the brain of Tg mice using anti-PSer129, an antibody that specifically recognizes alpha-synuclein phosphorylated at Ser129. The antibody detected only phosphorylated halpha-syn140m, whereas phosphorylation of endogenous alpha-synuclein, if any, was below the detection limit of the method employed. The analysis showed that approximately one-third of the halpha-syn140m-positive neurons in the midbrain of heterozygous Tg mice were concomitantly reactive to anti-PSer129. The ratio almost doubled in homozygotes, indicating that the phosphorylation level depends directly on the amount of substrate. In addition, the ratio did not change at least up to 48 weeks of age. These data strongly suggest that halpha-syn140m underwent constitutive phosphorylation and that the phosphorylation level was maintained to a certain level until the aged stages. Remarkably, halpha-syn140m localized in the nuclei seemed to be preferentially phosphorylated compared with that in the cytoplasm. Among kinases that have been reported to be involved in the phosphorylation of alpha-synuclein, the beta subunit of casein kinase-2 was detected in the nuclei by immunohistochemistry. These data imply that at least casein kinase-2 is involved in the phosphorylation of halpha-syn140m in the Tg mice.

Increased glia-specific transgene expression with glial fibrillary acidic protein promoters containing multiple enhancer elements.

The ability to direct transgene expression to astrocytes has become increasingly important as the roles for these cells continue to expand. Promoters consisting of the 5'-flanking region of the human or mouse glial fibrillary acidic protein (GFAP) gene have generally proved satisfactory. However, a more powerful promoter would be advantageous for several applications, such as expression of dominant negative RNAs or proteins, or for gene therapy. We investigated the possibility of increasing the transcriptional activity of the human GFAP promoter by inserting into it one or three additional copies of putative GFAP enhancer regions. The promoters enhanced with three additional copies gave 75-fold higher LacZ expression levels upon plasmid transfection into GFAP-expressing U251 cells than the parental gfa2 promoter. Surprisingly, in a transgenic mouse model, the enhanced promoters resulted in no or only very low expression of marker genes, probably caused by toxicity. When various cell lines were infected with replication-deficient adenoviral vectors, the enhanced promoters gave LacZ expression levels that were approximately 10-fold higher than those with the parental gfa2 promoter, while retaining specificity for GFAP-expressing cells. Injection of the adenoviral vectors carrying the enhanced promoters into nude mouse brain showed that LacZ expression was limited to GFAP-positive cells. We conclude that gfa2 enhanced promoters are useful for production of short-term, glia-specific, high expression levels of genes in an adenoviral context. Adenoviral vectors containing these enhanced promoters may be useful in glioma gene therapy.

Role of bcl-2 mRNA in homeostatic proliferation in circulating T-cells in human liver transplant patients after T-cell depletion.

BACKGROUND: Prolonged T-cell depletion after liver transplantation leads to life-threatening infections. Members of the anti-apoptotic Bcl-2 gene family can maintain T-cell viability. T-cell numbers and their Bcl-2 expression following living donor liver transplantation (LDLT) were analyzed in 108 surviving and 13 deceased recipients. MATERIALS AND METHODS: Bcl-2 mRNA levels and phenotypic changes of T-cells were examined by quantitative PCR and by measuring expression of CD45RO and CCR7. RESULTS: Based on the restoration of peripheral T-cell numbers, the 108 surviving recipients were classified into three groups. All recipients showed T-cell depletion, down to approximately 30% of pretransplant levels within 3 h of graft reperfusion. In Group I, the T-cell numbers were rapidly restored to pretransplant levels, within 5 days, with a rapid decrease in Bcl-2 mRNA levels immediately after LDLT. In Group II, the T-cell numbers were restored to normal levels by 19 days, with down-regulation of Bcl-2 mRNA. In Group III, the T-cell numbers were maintained at low levels for much longer, with high levels of Bcl-2 mRNA. In all three groups of recipients, there was statistically significant (r = -0.78) inverse correlation between T-cell numbers and Bcl-2 mRNA. CONCLUSIONS: For successful transplantation, homeostatic restoration of T-cells must occur as soon as possible. Evaluation of peripheral T-cell numbers and of Bcl-2 expression may have therapeutic potential in identifying those transplant patients who face increased risk of infection.

Changes in pH increase perfusion pressure of coronary arteries in the rat.

Stricture of coronary arteries is closely related to ischemic heart disease. The purpose of this study was to examine whether changes in pH caused contraction of rat coronary arteries, as determined using Langendorff perfused hearts. Changing the pH of the perfusate increased perfusion pressure as an indication of the contractile state of coronary arteries. Alkaline pH-induced increase of perfusion pressure in Wistar Kyoto rats (WKY) was almost identical to that of spontaneously hypertensive rats (SHR), whereas acidic pH-induced increase in SHR was much greater than that in WKY. Acidic pH-induced increase in perfusion pressure was inhibited by verapamil, cromakalim, and adenosine. Feeding WKY with N(G)-nitro-L-arginine resulted in hypertension followed by enhanced acidic pH-induced increase in perfusion pressure. These results suggest that acidic-pH induced contraction of rat coronary arteries is caused by Ca(2+) influx through voltage-dependent Ca(2+) channels and the contraction is enhanced by hypertension.

Functional evaluation of the postoperative gastrointestinal tract using kinematic MR imaging: Quantitative assessment of peristaltic activity.

The purpose of this study is to demonstrate the feasibility of kinematic MR imaging in visualizing peristaltic activity in the reconstructed gastrointestinal tract with quantitative measurements. Sixteen patients with gastrointestinal reconstruction were studied with kinematic MR imaging using HASTE and/or true FISP. Peristaltic waves were noted in the retrosternal gastric segment after gastric pull through (frequency = 3.0 +/- 0.5 times/min, velocity = 2.6 +/- 0.6 mm/s) and in the residual antrum after cardiectomy (frequency = 3 times/min, velocity = 4.0 mm/s). Peristaltic waves were not apparent in the residual fundus after distal gastrectomy and in the reconstructed jejunum after pancreatoduodenectomy and gastrojejunostomy.

Inhibition of tumor necrosis factor-induced apoptosis in transgenic mouse liver expressing creatine kinase.

BACKGROUND: The mitochondrion acts as a pivotal decision center in many types of apoptotic responses. To clarify the effects of the enhanced mitochondrial function on tumor necrosis factoralpha (TNFalpha)-induced apoptosis, we studied hepatic injuries in transgenic mice whose livers express creatine kinase (CK). METHODS: Mice fed a diet containing 10% creatine, came to accumulate phosphocreatine and to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation activities. TNFalpha-mediated hepatic apoptosis in normally fed and Cr-feeding CK transgenic mice were assessed. RESULTS: TNFalpha and actinomycin D cause severe liver failure in normally fed transgenic mice, and in the wild-type mice. In contrast, no significant elevations in transaminase levels after injection were observed in Cr feeding transgenic mice. The disruption of the mitochondrial transmembrane potential at 2 h after TNFalpha injection, prior to ATP depletion, activation of caspase 3 like protease, and DNA fragmentation at 4-6 h after injection, were observed in normally fed transgenic mice. These were fully suppressed in Cr feeding transgenic mice. However, anti-Fas antibody-induced apoptosis was not inhibited in both groups. CONCLUSIONS: The results indicate that TNFalpha-induced apoptosis was inhibited in CK transgenic mice livers by maintaining mitochondrial function.

Usefulness of 99mTc-sestamibi scintigraphy in suggesting the therapeutic effect of chemotherapy against gastric cancer.

PURPOSE: Imaging with (99m)Tc-sestamibi ((99m)Tc-MIBI) has been used to assess 170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in several types of malignancy, such as breast and lung cancers. The purpose of this study was to evaluate the relationship between (99m)Tc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients. EXPERIMENTAL DESIGN: Thirty-six patients with advanced gastric cancer underwent (99m)Tc-MIBI scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and the expression of P-gp or multidrug resistance-associated protein was analyzed by immunohistochemical staining. The relationship between the accumulation of (99m)Tc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined. RESULTS: Higher accumulation of (9m)Tc-MIBI in tumors was observed in 25 and 23 of 36 gastric cancer patients at the early (30 min) and delayed (120 min) images, respectively. Accelerated accumulation of (99m)Tc-MIBI negatively correlates with increased expression of P-gp, but not of multidrug resistance-associated protein, as determined by immunohistochemistry in gastric cancer tissues. The response rate to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with high (99m)Tc-MIBI accumulation (15.4%) was much lower than that in patients with low (99m)Tc-MIBI accumulation (54.5%). In contrast, patients with high (99m)Tc-MIBI accumulation show a higher response rate (41.7%) to chemotherapy with epirubicin, which is known to be a substrate of P-gp transporter. CONCLUSIONS: (99m)Tc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.

Change in mitochondrial membrane potential in peripheral blood lymphocytes, especially in natural killer cells, is a possible marker for surgical stress on the immune system.

There is accumulating evidence that surgical stresses cause impairment of systemic immune responses, which may promote susceptibility to infection as well as growth of remnant cancer cells in cancer patients. Although alterations in numbers, populations, and functions of lymphocytes have been extensively studied to assess modulation of the immune system, the precise mechanisms of immunosuppression caused by surgical stresses have not been identified, nor have methods been developed to estimate the magnitude of surgical stresses on the immune system. In the present study, to evaluate the effects of surgical procedures on the immune system, the mitochondrial membrane potential (Delta Psi(m)) of peripheral blood lymphocytes (PBL) from 25 patients who underwent various types of operation was measured by flow cytometry using 3,3'-dihexiloxacarbocyanine iodide (DiOC(6)(3)) on the day before operation and on postoperative day (POD) 1, POD 3, and POD 7. The Delta Psi(m) in PBL, especially in natural killer (NK) cell population, was reduced after major surgery. In particular, the reduction of Psi Delta(m) in NK cells appeared to be proportional to the severity of the surgical procedures and reflected the impairment of cellular function. Interestingly, the Delta Psi(m) in NK cells was also negatively correlated with the level of plasma noradrenaline after major surgery, suggesting that the reduction of Delta Psi(m) in NK cells induced by surgical stresses may be mediated, at least in part, by the accompanying increase in plasma noradrenaline. Monitoring of Delta Psi(m) in PBL after operation may be one of the useful markers for estimating the magnitude of surgical stresses on the immune system.

Quantitative PCR to evaluate small amounts of BCL2 mRNA in human peripheral T cells: implication of equimolar target and competitor end products.

BACKGROUND: It is difficult to reliably and reproducibly quantitate small amounts of mRNA by conventional PCR. The method we describe here enabled us to more accurately quantitate a small amount of BCL2 mRNA in human peripheral T cells. METHODS: The sample was amplified in four tubes containing three-fold serial dilutions of competitor so that when the PCR products in the four tubes were totaled, the number of target and competitor components were approximately equal. An unknown concentration of target molecules should be assessed only within a narrow range, requiring that several reactions be performed for each sample. RESULTS AND CONCLUSION: With this method, conventional PCR machines can be used to perform quantitative PCR on very small amounts of BCL2, and would be especially useful for samples that contain substance(s) that affect PCR amplification efficiency.

Surgical stress during operation for gastrointestinal cancer increases plasma thioredoxin levels and decreases mitochondrial membrane potential in peripheral blood lymphocytes.

Surgical stress is difficult to evaluate quantitatively. It has been reported that mitochondrial membrane potential (delta psi(m)) in the peripheral blood lymphocytes (PBLs) is decreased by surgical stress. Thioredoxin (TRX), a small protein with redox-active dithiol/disulfide in the active site, is induced by a variety of oxidative stresses and secreted from the cells. Accumulating evidence shows that plasma levels of TRX are elevated in oxidative stress-associated disorders. In the present study, we examined plasma levels of TRX in cases undergoing operations for gastrointestinal cancer. Plasma levels of TRX were significantly elevated on the first postoperative day compared with the pre-operative levels. The changes in the plasma TRX levels tended to show an inverse relationship with the changes in delta psi(m) in PBLs, which shows a significant decrease caused by surgical stress. Plasma TRX levels as well as delta psi(m) in PBLs are valuable markers to evaluate surgical stress.

Mitochondrial membrane potential is reduced in peripheral natural killer cells following partial hepatectomy.

The mechanism underlying immunosuppression after partial hepatectomy remains unclear. Hepatectomy induces lymphopenia, which is related to immunomodulation. The aim of this study was to determine whether peripheral blood lymphocytes (PBL) are susceptible to mitochondria-mediated apoptosis after hepatic resection. We compared the changes in mitochondrial membrane potential in lymphocytes from hepatectomized patients with metastatic liver tumor with the corresponding changes in lymphocytes from cholechystectomized patients, because changes in mitochondrial membrane potential have been reported to frequently occur during the early stages of apoptosis. Mitochondrial membrane potential, subpopulation, and apoptosis of lymphocytes were estimated with flow cytometry. Hepatectomy significantly (P<0.001) reduced postoperative mitochondrial membrane potential, while cholecystectomy slightly decreased it. Apoptosis of lymphocytes was increased on post-hepatectomy day, and this increase was correlated with the extent of mitochondrial membrane potential reduction. The major subset of lymphocytes with low mitochondrial membrane potential consisted of CD56(+) natural killer (NK) cells, and NK cell activity and cell counts significantly decreased after hepatectomy. Mitochondrial membrane potential of PBL was reduced after hepatectomy, and some lymphocytes underwent apoptosis through the mitochondrial pathway, which was one of the causes for lymphopenia. NK cells were more responsible for the decrease of mitochondrial membrane potential after hepatectomy than other lymphocytes, and the reduction in mitochondrial membrane potential in NK cells appeared to reflect modulation of the innate immune system.