Sitagliptin, a dipeptidyl peptidase-4 inhibitor, increases the number of circulating CD34⁺CXCR4⁺ cells in patients with type 2 diabetes.

We investigated the effects of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on the number of circulating CD34(+)CXCR4(+)cells, a candidate for endothelial progenitor cells (EPCs), plasma levels of stromal cell-derived factor (SDF)-1α, a ligand for CXCR4 receptor and a substrate for DPP-4, and plasma levels of interferon-inducible protein (IP)-10, for a substrate for DPP-4, in patients with type 2 diabetes. We studied 30 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea. Thirty diabetic patients were randomized in a 2:1 ratio into a sitagliptin (50 mg/day) treatment group or an active placebo group (glimepiride 1 mg/day) for 12 weeks. Both groups showed similar improvements in glycemic control. The number of circulating CD34(+)CXCR4(+) cells was increased from 30.5 (20.0, 47.0)/10(6) cells at baseline to 55.5 (31.5, 80.5)/10(6) cells at 12 weeks of treatment with 50 mg/day sitagliptin (P = 0.0014), while showing no significant changes in patients treated with glimepiride. Plasma levels of SDF-1α and IP-10, both physiological substrates of endogenous DPP-4 and chemokines, were significantly decreased at 12 weeks of sitagliptin treatment. In conclusion, treatment with sitagliptin increased the number of circulating CD34(+)CXCR4(+) cells by approximately 2-fold in patients with type 2 diabetes.

Localization of acupuncture points on the Lung Meridian using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances.

Using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances, it is possible to draw on the surface of the human body several points similar to the acupuncture points of Traditional Chinese Medicine-TCM with the help of histological slides of 12 organs of the main TCM Meridians, using the method first described by Yoshiaki Omura Sc.D. M.D. To determine the relationship of the Lung Meridian of TCM and the points drawn with a histological human Lung slide by BDORT, it was mapped the upper limb in 41 healthy individuals. There were almost identical matches in all points in 26 subjects (63.4%). In 15 subjects there were no identical matches at any point (36.5%). In all cases of no identical matches of the points, the new Lu1 point is displaced in the direction of midpoint of thorax below the clavicle. On the arm there was a medially deviation in comparison to the line obtained from the TCM points, for example the new Lu9 point was located on the midpoint of the wrist.

A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. METHODS: Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor kappaB (NF-kappaB) activation was assessed by reporter gene assay. RESULTS: Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-kappaB activation. We therefore examined the effect of liraglutide on TNFalpha-induced NF-kappaB activation and NF-kappaB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-kappaB activation and TNFalpha-induced IkappaB degradation. It also reduced TNFalpha-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-kappaB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. CONCLUSIONS/INTERPRETATION: Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-kappaB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.

Glimepiride upregulates eNOS activity and inhibits cytokine-induced NF-kappaB activation through a phosphoinoside 3-kinase-Akt-dependent pathway.

AIMS: Several studies suggest increased mortality postcoronary angioplasty in patients on sulphonylureas. However, a theoretical reduction in cardiac risk has been suggested with the newer sulphonylurea agents, which differ from the first-generation agents. In the present study, we investigated whether a third generation of sulphonylurea, glimepiride, might stimulate nitric oxide (NO) production and thereby inhibit cytokine-induced nuclear factor (NF)-kappaB activation in endothelial cells compared with the classical sulphonylurea glibenclamide. METHODS AND RESULTS: We demonstrated that glimepiride, but not glibenclamide, induces NO production in human umbilical vein endothelial cells (HUVEC). A significant increase in endothelial NO synthase (eNOS) activity, measured in terms of citrulline production, was observed with glimepiride treatment. Akt phosphorylation followed by phosphorylation of eNOS (Ser1177) was observed with glimepiride treatment in HUVEC. Moreover, two phosphoinoside 3-kinase inhibitors, wortmannin and LY294002, significantly inhibited glimepiride-induced NO production. We also demonstrated inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation in HUVEC treated with glimepiride, which was attenuated by pretreatment with N(omega)-nitro-L-arginine methyl ester. We also demonstrated a marked increase in p65 in nuclear extracts from untreated HUVEC following stimulation with TNFalpha, which was dose dependently inhibited by glimepiride, but not by glibenclimide in association with NF-kappaB levels. CONCLUSION: These data suggest that glimepiride might be a preferable sulphonylurea agent in the setting of type 2 diabetes and vascular disease because it may have protective effects on vascular endothelial cells.

Membranous glomerulonephritis associated with diffuse malignant pleural mesothelioma: report of a case.

Membranous glomerulonephritis is associated with a variety of malignant neoplasms. However, an association between membranous glomerulonephritis and pleural mesothelioma is very rare. We report herein a case of pleural mesothelioma associated with membranous glomerulonephritis. A 52-year-old man with severe proteinuria was diagnosed to have diffuse malignant pleural mesothelioma. A left extrapleural pneumonectomy was thus performed. The proteinuria resolved postoperatively. However, 6 months postoperatively, the proteinuria recurred. A renal biopsy revealed membranous glomerulonephritis. Simultaneously, a recurrence of the mesothelioma in the left pleural cavity was confirmed. Although rare, membranous glomerulonephritis appears to be one type of paraneoplastic syndrome associated with malignant pleural mesothelioma.

Lymphoepithelial cyst of the pancreas: a preoperatively diagnosed case based on an aspiration biopsy.

This paper reports an extremely rare case of lymphoepithelial cyst of the pancreas. The patient, a 58-year-old man with no subjective symptoms, was found to have a pancreatic tumor during a physical examination. He visited our clinic and was admitted for a follow-up examination. Based on the ultrasonographic findings, superselective angiography, and aspiration biopsy, an epidermoid cyst was diagnosed. Enucleation was easily performed. Macroscopically, this cyst resembled an atheroma. Histologically, the cavity of the cyst was lined with a squamous epithelium with a nucleated layer and below that, lymphatic tissue. No malignancy was found. Tumors of the pancreas with a squamous epithelial covering are extremely rare; only a few such cases have been reported in the literature. As of 1991, only 12 cases, including the present case, had been reported. With the advances in diagnostic techniques, the detection of pancreatic tumors is expected to improve. This paper reports a case in which the use of an aspiration biopsy and superselective angiography proved to be useful in making an accurate diagnosis.

[Clinical evaluation of adriamycin ointment in advanced or local recurrent breast cancer].

For the purpose of local therapy for advanced and recurrent breast cancer, we have applied a new Adriamycin (ADR) ointment. This new ADR ointment has been prepared by the technique of a two-factor composite experimental design and includes PEG: 25%, CVP: 0.65%, HPC: 1.35% and ADR: 0.04%. We have applied it to three patients with advanced breast cancer and six patients with locally recurrent breast cancer. By using this ointment, the skin ulcers have become dry, bleeding has stopped and the sense of heat has been lost. In some cases, the neoplastic ulcers have diminished in size. Some problems with this ointment are easy bleeding at the time of removing the gauze and an unstable effect in diminishing the size of the neoplasm. We therefore think that the use of this ointment alone is very effective for controlling the symptoms of the local lesion, but not so effective for diminishing the size of the neoplasm.