An efficient approach to gem-difluorocyclopropylstannanes via highly regio- and stereoselective hydrostannylation of gem-difluorocyclopropenes and their unique ring-opening reaction to afford ß-fluoroallylic alcohols.

Treatment of various gem-difluorocyclopropenes with 1.2 equiv. of n-Bu3SnH in the presence of 20 mol% of Et3B at 80 °C for 4 h led to the quantitative formation of the hydrostannylated products in a highly regio- and trans-selective manner. Additionally, the prepared trans-gem-difluorocyclopropylstannanes were treated with 1.5 equiv. of MeLi in THF at -78 °C for 5 min, followed by quenching the reaction with various agents, such as H2O, alcohols, carboxylic acids, and tosylamide, to give the corresponding ß-fluoroallylic alcohols, ethers, esters, and amides respectively with exclusive Z selectivity in acceptable yields.

Tofogliflozin, a novel sodium-glucose co-transporter 2 inhibitor, improves renal and pancreatic function in db/db mice.

BACKGROUND AND PURPOSE: Although inhibition of renal sodium-glucose co-transporter 2 (SGLT2) has a stable glucose-lowering effect in patients with type 2 diabetes, the effect of SGLT2 inhibition on renal dysfunction in type 2 diabetes remains to be determined. To evaluate the renoprotective effect of SGLT2 inhibition more precisely, we compared the effects of tofogliflozin (a specific SGLT2 inhibitor) with those of losartan (an angiotensin II receptor antagonist) on renal function and beta-cell function in db/db mice. EXPERIMENTAL APPROACH: The effects of 8-week tofogliflozin or losartan treatment on renal and beta-cell function were investigated in db/db mice by quantitative image analysis of glomerular size, mesangial matrix expansion and islet beta-cell mass. Blood glucose, glycated Hb and insulin levels, along with urinary albumin and creatinine were measured KEY RESULTS: Tofogliflozin suppressed plasma glucose and glycated Hb and preserved pancreatic beta-cell mass and plasma insulin levels. No improvement of glycaemic conditions or insulin level was observed with losartan treatment. Although the urinary albumin/creatinine ratio of untreated db/db mice gradually increased from baseline, tofogliflozin or losartan treatment prevented this increase (by 50-70%). Tofogliflozin, but not losartan, attenuated glomerular hypertrophy. Neither tofogliflozin nor losartan altered matrix expansion. CONCLUSIONS AND IMPLICATIONS: Long-term inhibition of renal SGLT2 by tofogliflozin not only preserved pancreatic beta-cell function, but also prevented kidney dysfunction in a mouse model of type 2 diabetes. These findings suggest that long-term use of tofogliflozin in patients with type 2 diabetes may prevent progression of diabetic nephropathy.

Heparin-induced thrombocytopenia complicated with massive thrombosis of the inferior vena cava after filter placement.

A 45-year-old man presented with deep vein thrombosis of the right leg and bilateral pulmonary embolism. Heparin was administered on the initial one and a half days. On the 3rd day, an inferior vena cava (IVC) filter was placed with a heparin flush, after which massive IVC thrombosis developed. The platelet count was 221000/mm3, decreased 42% from the initial level, but remained within the normal range. Heparin was replaced by argatroban on the 13th day. The platelet count increased to 355000/mm3 on the 15th day. The patient was positive for antibody against complexes of heparin and platelet factor 4, and was diagnosed as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). When thrombosis develops during heparin treatment, it is important to suspect HITTs and to assay for the associated antibodies, regardless of the actual platelet count.

Enhanced hydrolytic stability of dental composites by use of fluoroalkyltrimethoxysilanes.

The hydrolytic stability of a group of experimental composite materials was evaluated. Seven distinct composites were formed by the mixing of a resin monomer mixture with silica filler that had been pre-treated with one of 7 different ethanol solutions. In one case, the filler was treated with an ethanol solution that contained only 3-methacryloyloxypropyltrimethoxysilane. In 5 cases, it was treated with solution containing a mixture of 3-methacryloyloxypropyltrimethoxysilane and one of the following hydrophobic fluoroalkyltrimethoxysilanes: trifluoropropyl-, nonafluorohexyl-, tridecafluorooctyl-, heptadecafluorodecyl-, and henicosafluorododecyl-trimethoxysilane. The tensile strength, after being immersed in water for 1800 days, of 2 of the experimental composites, whose pre-treatment regimen had included a fluoroalkyltrimethoxysilane, was significantly higher than that of the composite whose pre-treatment regimen had not included a fluoroalkyltrimethoxysilane. Moreover, there was no significant difference between the tensile strength of fresh samples of these 2 composites and the tensile strength of identically produced samples that had remained under water for 1800 days or that had been subjected to 30,000 cycles of thermal stress.

Arginine as an exacerbating factor for glomerulonephritis in rats fed a methionine-threonine-supplemented low casein diet.

We previously demonstrated that a methionine-threonine-supplemented low (8.5%) casein diet (8.5CMT) reduced symptoms such as proteinuria in nephritic rats without severe protein malnutrition. In this study, we examined whether or not L-arginine supplementation to 8.5CMT would exacerbate proteinuria and other symptoms in nephritic rats. Male Wistar rats with glomerulonephritis induced by a single intravenous injection of nephrotoxic serum were fed either a 20% casein diet (control), 8.5% casein diet, 8.5CMT, or L-arginine-supplemented 8.5CMT (8.5CMTA) for 16 days. The 8.5CMTA, as compared with the 8.5CMT, aggravated proteinuria and glomerulonephritis. Administration of L-N(G)-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, to 8.5CMTA-fed nephritic rats by drinking water for 14 days canceled the adverse effect of L-arginine on proteinuria and histopathological damage in glomeruli. These results suggest that the supplementation of L-arginine makes exacerbation via nitric oxide production in glomerulonephritis.

Inhibitory effect of resveratrol on proteinuria, hypoalbuminemia and hyperlipidemia in nephritic rats.

The effect of resveratrol, a polyphenolic compound present in grapes and other plants, on proteinuria, hypoalbuminemia and hyperlipidemia was studied in rats with glomerulonephritis. The nephritis was induced by an intravenous injection of anti-rat kidney glomerular basement membrane rabbit antiserum. Nephritic rats were given oral intubation of resveratrol (5 mg/day/100 g body weight) for 14 days, while control nephritic rats as well as normal ones were similarly given vehicle alone. By resveratrol treatment, enlargement in liver and kidney due to nephritis induction was significantly reduced, together with partial restoration of nephritis-induced reduction in body weight gain. Both proteinuria and hypoalbuminemia, characteristic symptoms to nephrotic syndrome, were significantly remedied, that is, urinary protein excretion was suppressed and serum albumin concentration was increased by resveratrol treatment. Resveratrol also suppressed significantly hyperlipidemia incident to nephritis, the hypotriglyceridemic action being more prominent than the hypocholesterolemic one. From these results, resveratrol is suggested to be a potent anti-glomerulonephritic food factor capable of suppressing proteinuria, hypoalbuminemia and hyperlipidemia at the same time.

Primary hepatic choriocarcinoma--a case report.

A 65-year-old man experienced anorexia and abdominal enlargement and died suddenly 45 days after admission. Multiple necrotic and hemorrhagic tumors were present in the liver (6 kg). The fragile tumor ruptured and a large amount of blood accumulated in the peritoneal cavity. The tumor was composed of cytotrophoblast and syncytiotrophoblast cells. Neoplastic cells were positive for human chorionic gonadotropin and negative for alpha-fetoprotein and carcinoembryonic antigen. The huge tumor directly invaded the entire antrum of stomach. Neoplastic trophoblastic cells proliferated mainly in the serosa and propria muscular layer of the stomach, and tiny cancer nests were observed in many vessels of the submucosa and propria mucosa. The serum alpha and beta human chorionic gonadotropin subunits showed a very high level; 51 ng/mL and 820 ng/mL, respectively. No tumor, cyst or scar was observed in the testes, mediastinum and retroperitoneum, macroscopically and microscopically. Based on these autopsy findings, we diagnosed this patient as having primary hepatic choriocarcinoma.

[Complete remission in a case of sigmoid colon cancer with multiple liver metastases-treatment with arterial chemotherapy and percutaneous microwave coagulation therapy].

A 59-year-old man was admitted to our hospital for advanced sigmoid colon carcinoma with synchronous multiple liver metastases. The patient received sigmoidectomy with regional lymph node dissection on June 8, 1998. We started intra-arterial combination chemotherapy on July 1, 1998. MMC (4 mg/body) was administered via rapid intra-arterial infusion on day 1. After MMC administration, 5-day intra-arterial continuous infusion of 5-FU at 500 mg/body/day was performed with oral administration of LV (30 mg/body/day). The treatment cycle was defined as every three weeks. The patient was treated with 4 courses of chemotherapy. From September 30, he received intra-arterial infusion of bolus MMC 4 mg/body, LV 6 mg/body and 5-FU 1,000 mg/body/4 hrs every two weeks with oral administration of Tegafur-uracil 400 mg/day. After 4 intra-arterial chemotherapy sessions, the metastatic liver tumors disappeared except for a focus in the right lobe. Therefore we decided to give the remnant liver metastasis percutaneous microwave coagulation therapy (PMCT). He obtained a complete remission in the liver metastases after two PMCT (70 W, 60 sec) sessions. Intra-arterial chemotherapy is effective for unresectable metastatic liver tumors from colon cancer. If a patient shows a partial response on the metastatic tumors through the chemotherapy, one must consider other modalities such as PMCT.

CEA-producing mucin-negative gastric signet-ring cell carcinoma with neuroendocrine markers: a case report.

Biopsy and autopsy materials excised from a 69-year-old woman were investigated. Serum carcinoembryonic antigen (CEA) showed a high value of 955 ng/mL. A plateaulike tumor was located in the gastric cardia and fundus to the entire gastric body. It showed severe proliferation and infiltration from the mucosa to the serosa. The tumor was comprised of signet-ring cells and poorly differentiated adenocarcinoma cells, which spread into the submucosa of the pylorus, duodenum, and jejunum. Signet-ring cells had a large, eccentric vesicular nucleus and a pale cytoplasmic inclusion. Poorly differentiated adenocarcinoma cells had a pleomorphic nucleus, small eosinophilic nucleolus, and abundant eosinophilic cytoplasm. Both neoplastic cells were positive for CEA, epithelial membrane antigen, Leu-7 (CD57), and neuron-specific enolase, and were negative for cytokeratin, vimentin, and periodic acid-Schiff, Alcian blue, and mucicarmine stains. Electron microscopy showed endocrine granules with a limiting membrane measuring approximately 238 nm in diameter in the cytoplasm. The authors diagnosed this patient as having mucin-negative gastric signet-ring cell carcinoma with neuroendocrine markers, which is suggested to exist among poorly differentiated adenocarcinoma, undifferentiated carcinoma, and signet-ring cell carcinoma.

Coexisting primary early gastric plasmacytoma and sarcoidosis with hypercalcaemia.

We report on a 61-year-old woman with coexisting early stage primary gastric plasmacytoma and sarcoidosis with hypercalcaemia. Laboratory data on admission showed hypercalcaemia, with 12.8 mg/dl, parathyroid hormone-related peptide (PTHrP) 1.2 pmol/l, C-PTHrP 69.5 pmol/l, and 1,25-dihydroxyvitamin D3 46.7 pg/ml. Neoplastic plasma cells proliferated in the propria mucosa of the stomach, showed a monoclonal immunoglobulin of cytoplasmic IgA (lambda light chain) and were positive for leucocyte common antigen and epithelial membrane antigen on paraffin section prepared from a stomach biopsy specimen. Russel bodies were present, as were crystals. Abundant sarcoid granulomas were observed in many of the regional lymph nodes around the stomach and in the dermis of a skin nodule. The patient underwent subtotal gastrectomy with administration of antimyeloma chemotherapy. We suggest that the hypercalcaemia in this patient was due to PTHrP production by neoplastic plasma cells.

Use of a gastric juice-based PCR assay to detect Helicobacter pylori infection in culture-negative patients.

A gastric juice-based PCR assay was compared with culture, microscopy, and a rapid urease test with specimens from 114 subjects. The PCR and conventional tests were positive for 76 and 62% of the subjects, respectively. The prevalence of gastroduodenal disease and seropositivity for anti-Helicobacter pylori immunoglobulin G were similarly high among conventional-test-positive and PCR-only-positive subjects compared to all-negative ones. The PCR assay is recommended to confirm the H. pylori status of culture-negative peptic-ulcer patients.

Altered platelet alpha 2-adrenoceptors in patients with ischemic heart disease.

We evaluated the characteristics of platelet alpha 2-adrenoceptors in 12 patients with effort angina pectoris, 11 patients with variant angina pectoris and 11 normal control subjects. alpha 2-Adrenoceptors were quantified using a radioligand binding assay with radiolabelled rauwolscine, an alpha 2-selective antagonist. In addition, plasma norepinephrine concentrations were measured by high performance liquid chromatography. The mean value of the maximal number of binding sites (Bmax) in patients with effort angina (205.1 +/- 11.3 fmol/mg protein) was significantly lower than that in control subjects (293.0 +/- 10.2 fmol/mg protein). Bmax did not differ between patients with variant angina (322.9 +/- 45.4 fmol/mg protein) and control subjects. There was no significant difference in the dissociation constant (Kd) among the 3 groups. The plasma norepinephrine concentration tended to be higher in patients with effort angina or variant angina than in normal controls, but this difference was not statistically significant. In addition, studies in another group of young volunteers (n = 20) revealed a negative correlation (r = -0.50, p < 0.05) between the Bmax of 3H-rauwolscine binding to platelets and the percent change in the plasma norepinephrine concentration when subjects moved from the supine to the standing position. This suggests a functional correlation between platelet alpha 2-adrenoceptors and those located at presynaptic sites. If platelet alpha 2-adrenoceptors correlate with presynaptic alpha 2-adrenoceptors, the current findings of decreased alpha 2-adrenoceptor density in platelets from patients with effort angina could represent attenuated negative feedback of norepinephrine by presynaptic alpha 2-adrenoceptors.

Estudo dinâmico de Magnesia carbonica / Dynamic study of Magnesia carbonica

O referido trabalho visa o estudo e a compreensäo global do medicamento Magnesia carbonica, baseando-se no perfil psicodinâmico do experimentador e comparando-o com as características inerentes da substância em questäo

Demonstration of selective protein complexes of p53 with 73 kDa heat shock cognate protein, but not with 72 kDa heat shock protein in human tumor cells.

It has been demonstrated that p53, especially, mutant p53 (mp53), makes protein complexes with major heat shock proteins hsp72/hsc73. However, there is no direct evidence showing whether hsp72 or hsc73 could bind preferentially to p53. In the present study, using TYKnu human ovarial carcinoma cells and monoclonal antibodies reacting specifically to hsp72/hsc73, we were able to find the selective protein complex formation with p53, presumably mp53, and hsc73, but not in the case of p53 and hsp72. The p53-hsc73 protein complexes dissociate with the addition of ATP, indicating that the dissociation is dependent upon the ATP-hydrolysis. These data suggest that hsc73 rather than hsp72 plays an important role in the yet undefined mechanism of disregulated cell growth control by mp53.

Closure of ventricular septal rupture caused by acute myocardial infarction using a transaortic balloon catheter.

We report a case of successful transaortic closure of a postinfarction ventricular septal rupture using a Swan-Ganz catheter. The method markedly reduced a left-to-right shunt and the improved hemodynamic condition of the patient, an 81-year-old woman, was maintained for about a week before surgical treatment. Inflation of the balloon with water made the balloon visible via echocardiography and was effective in maintaining inflation and echocardiographic follow-up.

Protein interaction of retinoblastoma gene product pRb110 with M(r) 73,000 heat shock cognate protein.

Both the tumor suppressor gene products, the retinoblastoma sensitivity gene product pRb110 and p53, are found in oligomer complexes with the oncogene products of the DNA tumor viruses. It has been demonstrated that p53 binds to the M(r) 70,000 heat shock protein family. However, the protein association of pRb110 with the M(r) 70,000 heat shock protein family is not yet known. We analyzed the immunoprecipitates made with TYK-nu human ovarial carcinoma cell lysate and anti-pRb110 or anti-heat shock protein monoclonal antibodies. In this paper, we demonstrate that pRb110 is associated with the M(r) 73,000 heat shock cognate protein, but not with the M(r) 72,000 heat shock protein. This selective protein association was also detected in HeLa cervical carcinoma cells. Furthermore, the protein complexes of the M(r) 73,000 heat shock cognate protein and pRb110 were dissociated with the presence of ATP, but not with ADP and the nonhydrolyzable ATP analogue, ATP gamma S. This indicates that the dissociation is dependent on the ATP hydrolysis. These data may suggest an as yet undefined important role of M(r) 73,000 heat shock cognate protein in the cell growth control in collaboration with pRb110.