Masaaki Isaka

Plasma adrenomedullin in diabetes

Vol 350 • November 15, 1997 1449 had secondary DVT and six cancers were diagnosed among these patients during their hospital stay (1·2%). When thrombosis was idiopathic, the rate of occult cancer was significantly higher (3·9%, p<0·02). Among the 64 patients with bilateral DVT, 41 (64%) had secondary bilateral DVT and two cancers were diagnosed (4·9%). When bilateral DVT was idiopathic, the rate of cancer was significantly higher than when it was not (35%, p<0·001). To our knowledge, this is the first study to establish the increased risk of occult cancer in bilateral DVT. The low rate of bilateral DVT probably explains the lack of data in the published research. However, this was a retrospective study with possible bias. We cannot rule out the possibility that clinical examination was more meticulous in patients with bilateral DVT. It is also possible that screening tests were more extensive in patients with bilateral venous thrombosis. However, most cancers are diagnosed by clinical examination, chest radiography, or standard biological screening tests, which were routinely done in all our patients. Further followup will be required to determine the rate of undiagnosed cancers. The rate of known cancers in our series (13%) and the rate of occult cancers found during the hospital stay (3·2%) were similar to those in other studies. Symptomatic pulmonary embolism was more common in patients with bilateral DVT than in those with unilateral DVT. The bilateral thrombosis can explain an increased risk of PE. The presence of PE and the location of DVT (proximal versus inferior vena cava) were not associated with the risk of occult cancer. Our study shows an increased rate of occult cancers in bilateral DVT (mainly in idiopathic bilateral DVT), with malignant disease in one-third of the patients. These data call for an extensive search for occult cancer in this situation, that concerns less than 10% of patients with DVT.

Long-term effects of eicosapentaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II diabetes mellitus

The present study was undertaken to investigate the efficacy of a new, highly purified (purity greater than 91%), ethyl esterification product from natural eicosapentaenoic acid (EPA-E, C20:5 omega 3) in patients with type II diabetes mellitus (NIDDM). Hemodynamic changes were assessed at the level of the dorsalis pedis artery using an ultrasonic color Doppler duplex system before and after oral administration of EPA-E at a dose of 1800 mg/day for 48 weeks. The cross-sectional area of the dorsalis pedis artery increased significantly from 2.5 +/- 0.2 to 3.9 +/- 0.4 mm2 (48 weeks, mean +/- SE, p < 0.05). Moreover, EPA-E improved the clinical symptom (coldness, numbness) as well as the vibration perception threshold sense of the lower extremities [from 32.1 +/- 8.5 to 16.1 +/- 4.8 (48 weeks) microns]. A significant decrease of serum triglycerides was also noted by EPA-E administration. Furthermore, significant decrease of the excretion of albumin in urine [from 24.4 +/- 3.3 to 13.9 +/- 1.8 (48 weeks) mg/g.Cr, p < 0.05]. The results of this study suggest that EPA-E has significant beneficial effects on diabetic neuropathy and serum lipids as well as other diabetic complications such as nephropathy and macroangiopathy.

High glucose and hyperosmolarity increase platelet-derived growth factor mRNA levels in cultured human vascular endothelial cells.

We investigated the effects of high glucose and hyperosmolality on platelet-derived growth factor (PDGF) production and PDGF-B chain mRNA levels in cultured human umbilical vein endothelial cells. Under an excess of ambient glucose (13.8 and 27.5mM) and a hyperosmolar condition (22.0mOsm/L with mannitol), PDGF concentrations in the culture medium were both significantly increased (10.3 +/- 6.0%, 36.2 +/- 7.2%, 48.5 +/- 9.0% increase respectively compared with 5.5mM glucose). Parallel to protein secretion levels, PDGF-B chain mRNA levels showed a significant increase (57.7%, 103.7%, 210.8% increase), while no change of beta-actin mRNA levels was observed. Thus, elevated PDGF released from endothelium by high glucose may play an important role in the pathogenesis of diabetic angiopathy.

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs—eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)—in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system

cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice. LKO mice demonstrated up-regulation of hepatic Srebf2 and its corresponding target genes. No phenotypic differences were observed between IKO and floxed mice. Severe liver injury was observed in LKO mice fed a methionine-choline deficient diet, a model for non-alcoholic steatohepatitis. These results provide new evidence regarding the hepatic CREB3L3 role in plasma triglyceride metabolism and hepatic and intestinal CREB3L3 contributions to cholesterol metabolism.

Norepinephrine Responsiveness in Patients with Borderline Hypertension Under Three Different Sodium Balances

The pressor effects of intravenous norepinephrine (NE) infusion (100 and 200 ng/kg/min for 15 min) were examined in 17 patients with borderline hypertension (BHT) and 15 age-matched normotensive subjects (NT) under three different sodium balances; the regular customary diet, treatment with diuretics, and the high-sodium diet. Treatment with diuretics decreased and high sodium diet increased the pressor response to NE in both groups but there were no significant differences in NE reactivity between the groups. The increments in mean blood pressure after NE infusion (200 ng/kg/min) during the three experimental periods correlated significantly with the preinfusion plasma NE concentration in both BHT and NT: r = -0.58 (p less than 0.01) and r = -0.54 (p less than 0.01), respectively. Neither the slopes nor the intercepts differed between the two groups. Thus, evidence presented indicates that BHT do not have increased pressor responsiveness to NE, and that NE pressor response depends upon basal sympathetic tone.

Effects of Ketanserin on Systemic and Regional Haemodynamics in Patients with Essential Hypertension

Serotonin (5-hydroxytryptamine) has long been studied as a potent vasoactive agent. Because of its multiple and complex action on the cardiovascular system, however, its role in the pathogenesis and/ or maintenance of human essential hypertension has been controversial (Vanhoutte 1983). Recently, the first relatively specific Srserotonergic antagonist, ketanserin, has been introduced (Vanhoutte et at. 1983); it lowers blood pressure in hypertensive patients (Fagard et at. 1984; Van Nueten et at. 1987; Wenting et at. 1982, 1984; Woittiez et at. 1986). This antihypertensive effect of ketanserin may suggest a close relationship between serotonin and increased vascular resistance in essential hypertension, but its precise mode of action remains unclear (Robertson et at. 1987). Therefore, to clarify the role of serotonin in the pathophysiology of essential hypertension, the effects of ketanserin on systemic and regional circulation were investigated in 10 patients with mild to moderate essential hypertension.

Haemodynamic Changes Associated with Long Term Antihypertensive Therapy with Ketanserin

Ketanserin is a new serotonergic receptor-blocking agent which has specific inhibitory action on the serotonin S2-receptors (Leysen et al. 1981) but is devoid of partial agonistic properties. Experimental and clinical studies ofketanserin have been conducted in patients with pathological conditions in which serotonin is considered to playa role, and the efficacy and safety of the drug have been reported (Janssen 1983). The antihypertensive effect of ketanserin has been clearly demonstrated in both animals and humans (Wenting et al. 1984). The mechanism of action ofketanserin as an antihypertensive agent is complex and remains to be fully clarified, but there is a possibility that ketanserin acts synergistically at S2-serotonergic and (XI-adrenergic receptors to lower blood pressure. Another feature ofketanserin is that it does not have partial agonistic action on serotonin Sl-receptors or cause troublesome central nervous system side effects (Pettersson et al. 1985), which have been observed with conventional antiserotonin agents. Since increases in peripheral vascular resistance are often seen in patients with essential hypertension. the use of a drug with vasodilatory action is a desirable approach to correct some cardiodynamic abnormalities. This study examined the haemodynamic and endocrinological effects of administration of ketanserin for 12 weeks to ambulatory patients with essential hypertension. 1. Subjects and Methods