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  • 1
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Analytical chemistry 67 (1995), S. 1437-1441 
    ISSN: 1520-6882
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 0942-0940
    Keywords: Subarachnoid haemorrhage ; chronic cerebral vasospasm ; calcium antagonist ; AT877 ; HA 1077
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The initial dose-escalating clinical trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage is reported. AT877 is characterized by its strong spasmolytic activity, its inhibition of intracellular calcium ion activity, and the inhibiton of several protein kinases. A total of 113 patients (Hunt and Hess grades I to IV) who had undergone surgery within 3 days of aneurysmal rupture entered the study. Patients were divided into 5 groups according to the total daily dose of AT877: I: 20 mg; II: 40 mg; III: 60 mg; IV: 90 mg; and V: 120–180 mg. AT877 was given by intravenous infusion over 30 min two or three times a day for 14 days after surgery. Although AT877 did not completely abolish angiographic vasospasm, severe vasospasm was seen less frequently in patients given higher doses. Vasospasm was the cause of a poor clinical outcome (Glasgow outcome scale rating 3 or greater) in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respectively. The results indicated a favourable clinical effect of AT877 at doses above 40 mg per day. Only mild hypotension was seen, even when 60 mg of AT877 was infused over 30 min. AT877 appears to be effective in patients with subarachnoid haemorrhage. Part of its effect may be attributable to protection of the brain from ischaemic insults due to chronic cerebral vasospasm. However, the drug still needs to be evaluated in a placebo-controlled double-blind trial (which is currently being carried out).
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Keywords Oxidized lipoprotein ; free radical ; atherosclerosis ; endothelial cells ; antioxidants.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Although oxidized low density lipoprotein (LDL) exists in plasma from diabetic patients, there are few studies on its biological activity. Thus, we investigated the biological potency of LDL plus intermediate density lipoprotein fraction isolated from 12 non-diabetic and 24 non-insulin-dependent diabetic subjects of similar age and body mass index, in order to induce monocyte chemoattractant protein-1 (MCP-1) mRNA expression in cultured human endothelial cells. MCP-1 mRNA content in the cells exposed to the lipoproteins isolated from the diabetic patients was significantly higher than that from the control subjects (p 〈 0.001). The increment of MCP-1 mRNA content was positively correlated with not only HbA1 c (r = 0.58, p 〈 0.0001) but also lysophosphatidylcholine (LPC) content in the lipoprotein (r = 0.46, p 〈 0.005) and was negatively correlated with diene formation lag time as a marker of oxidizability of the lipoprotein (r = – 0.33, p 〈 0.05). Treatments of the cells with either 50 μmol/l probucol, 50 μmol/l α-tocopherol, or 0.1 mmol/l deferoxamine suppressed the increase in MCP-1 mRNA content induced by diabetic lipoproteins, respectively. Furthermore, the diabetic lipoproteins activated nuclear transcription factor NF-kB in the cells, which was inhibited by pre-treatment of cells with 50 μmol/l probucol. These data indicate that oxidatively modified lipoproteins found in diabetic plasma stimulate MCP-1 gene expression in endothelial cells. The LPC content which reflects oxidative modification of lipoprotein is at least a possible marker of biological activity to increase an atherogenic cytokine in endothelial cells. [Diabetologia (1997) 40: 662–670]
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords OLETF ; xylose ; SGLT1 ; intestinal hypertrophy ; glucose absorption ; postprandial hyperglycaemia.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Otsuka Long-Evans Tokushima Fatty (OLETF) rats are reported to be obese Type II (non-insulin-dependent) diabetic rats with insulin resistance and impaired insulin secretion. To investigate the contribution of intestinal glucose absorption to postprandial hyperglycaemia, we determined the plasma xylose concentrations after an 0.8 g/kg oral xylose load which was used as a test of small intestinal glucose absorption in 6-week-old OLETF rats and weight-matched Long-Evans Tokushima Otsuka (LETO) rats. An oral glucose tolerance test showed that OLETF rats developed hyperglycaemia at 60 and 90 min after the glucose load, though the fasting plasma glucose concentration, insulin concentration and insulin-induced in vivo glucose utilization rate were similar. Consistently, in an oral D-xylose loading test, the peak concentration of plasma xylose in OLETF rats was increased by 58.7 % compared with that of LETO rats (p 〈 0.005). The disappearance rate of plasma xylose concentrations after intravenous xylose loading did not differ between the two strains. Co-treatment with 0.4 g/kg phlorizin, a specific inhibitor of sodium-dependent glucose transporter 1 (SGLT1), abolished both plasma glucose and xylose concentrations after the loads. Morphological studies showed that both the small intestinal wet weight and surface area were 30 % larger in the OLETF rats than in the LETO rats. Furthermore, the SGLT1 mRNA content of OLETF rats also increased compared with LETO rats. These results suggest that an increased SGLT1 expression concomitant with intestinal hypertrophy in OLETF rats is partly associated with postprandial hyperglycaemia before the onset of insulin resistance and hyperinsulinaemia. [Diabetologia (1998) 41: 1459–1466]
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Magnetic resonance, spectroscopy, imaging, neuropathic foot ulcers, fat, phosphocreatine, intracellular pH.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. We studied 36 Type II (non-insulin-dependent) diabetic patients without occlusive arterial diseases in the lower extremities and 12 age-matched and sex-matched non-diabetic subjects to clarify the association between diabetic polyneuropathy and foot ulcers using 1H- and 31P-magnetic resonance spectroscopy and imaging.¶Methods. The 36 diabetic patients consisted of 12 patients with superficial foot ulcers and 24 patients free from this disease. We measured fat to water and phosphocreatine to inorganic phosphate (PCr:Pi) ratios and calculated the intracellular pH of resting plantar muscles by depth-resolved surface-coil spectroscopy using an 1H-31P double tuned coil. Furthermore, foot vasculature, fat and PCr contents of plantar muscles were visualised by phase-contrast angiography, T1-weighted spin-echo imaging and 31P-chemical shift imaging.¶Results. The 12 foot ulcer patients showed a reduced PCr to Pi ratio (p 〈 0.001) and peripheral nerve functions (p 〈 0.01–0.001) but an increased fat to water ratio (p 〈 0.001) and intracellular pH (p 〈 0.001) compared with the 24 patients without ulcers. From stepwise multiple regression analyses, motor nerve function as well as severity of nephropathy was associated with both fat to water and PCr to Pi ratios. When these patients were categorised into three groups based on their level of motor nerve function, the frequency of foot ulcers of the lowest group was higher than that of the highest group.¶Conclusion/interpretation. Our findings indicated that motor nerve dysfunction in diabetic patients was closely associated with impaired energy metabolism, fatty infiltration and increased intracellular pH of plantar muscles and high frequency of foot ulcers. These new techniques could contribute to help clarify the predisposing factors for foot ulcers. [Diabetologia (2000) 43: 165–172]
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Keywords Euglycaemic insulin clamp ; insulin sensitizer ; isoxazolidinedione ; insulin signaling ; JTT-501
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg · kg–1· day–1) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40 % of non-treated) and hypertriglyceridaemia (23 % of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that this treatment increased the glucose infusion rate by 33 % during the last 30 min in SD rats. After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30 % and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects. [Diabetologia (1999) 42: 151–159]
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0533
    Keywords: Phytosterolemia ; Intradural xanthomatosis ; Denticulate ligaments ; Macrophage ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Multiple intradural xanthomatous tumors developed in 48-year-old female with familial phytosterolemia. These tumors were restricted to the spinal denticulate ligaments. Histological and immunohistocheimical findings were fundamentally similar to those of tendinous xanthomas. The major cellular component of these tumors were identified as of mono-histiocytic origin because they possessed myeloid histiocytic antigen (Mac 387), CD11c and lysozyme but not CD15. Sitosterols, campesterols and cholestanols were recovered from the extract of the tumors and the lesions were confirmed to be phytosterolemic xanthomas. Schwann cells stained with anti-S100 protein were confined to the perivascular small nerve bundles and did not show xanthomatous change. Although immunohistochemical preparation of epithelial membrane antigen and desmoplakin I+II revealed the presence of non-neoplastic meningothelial cells in the superficial portion of the tumors, they were too few to play a significant role in the development of these xanthomas.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    s.l. ; Stafa-Zurich, Switzerland
    Journal of metastable and nanocrystalline materials Vol. 24-25 (Sept. 2005), p. 577-580 
    ISSN: 1422-6375
    Source: Scientific.Net: Materials Science & Technology / Trans Tech Publications Archiv 1984-2008
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0942-0940
    Keywords: Calcium antagonist ; chronic cerebral vasospasm ; HA 1077 ; subarachnoid haemorrhage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effectiveness of calcium antagonists on a chronic cerebral vasospasm after an SAH is still under debate. Calcium channel blockers such as nimodipine, nefedipine etc. can dilate spastic arteries by intrathecal administration, but not by systemic (iv or po) use. HA 1077 is a novel and potent calcium antagonist vasodilator which is considered to act by employing different mechanisms from the usual calcium channel blockers since it inhibits 1. calcium ionophore A 23187 induced contraction in arterial strips and 2. phenylephrine induced contraction in calcium free media, suggesting that its site of action is in the intracellular space. HA 1077 is water soluble and relatively stable in light. In the present study, the efficacy of HA 1077 was evaluated on dogs by using the spiral arterial strips in vitro and by angiography in vivo. In the arterial strips from the control dogs, a 50% relaxation of KCl (15 mM) induced contraction was obtained by a 10−6 M HA 1077 for the “intracranial” basilar and middle cerebral arteries, while a 10−5 M was needed to obtain the same effect for the “extracranial” common carotid and vertebral arteries, indicating that HA 1077 is more effective for the intracranial arteries. A vasospasm was produced by the “two haemorrhage” model of Varsoset al. The average angiographic diameter of the basilar artery was reduced to 60% of the control on SAH day 7. Intravenous infusion of HA 1077 (0.5–3 mg/kg/30 min) significantly dilated the spastic basilar artery (up to 20–30%), for over 2 hours. A fall in the systemic BP remained less than 20% during this time. Such spasmolytic effects by intravenous administration could not have been obtained with the usual calcium channel blockers. HA 1077 may be suitable for the treatment of a vasospasm in humans as well.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0942-0940
    Keywords: HA1077 ; cerebral vasospasm ; subarachnoid haemorrhage ; cerebral blood flow ; calcium antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We examined the effects of the recently developed calcium antagonist HA1077 on cerebral haemodynamics during the chronic stage of the two-haemorrhage canine model system of vasospasm. Regional cerebral blood flow (rCBF), regional cerebral blood velocity and regional cerebral blood volume in the canine parietal cortex were measured by Laser-doppler flowmeter. On the 7th day after the initial injection of autogenous blood, subarachnoid haemorrhage (SAH) produced a significant decrease in rCBF (59% of control, p〈0.05) and Hood velocity (48% of control, p〈0.05), with no remarkable change in blood volume (108% of control). Bolus intravenous administration of HA1077 (0.1–0.3 mg/kg) dose-dependently increased the rCBF and blood velocity, without significantly changing the blood volume on Day 7 after SAH. HA1077 improves haemodynamic function manifested by an increase in rCBF and velocity in this SAH model, and may be suitable for the treatment of vasospasm in patients with SAH.
    Type of Medium: Electronic Resource
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