Evaluation of cardiac effects of the new antineoplastic drug --dimethoxybenfluron--in the rabbit.

Cardiotoxicity ranks among the most serious adverse effects of some cytostatics. The cardiac effects of repeated i.v. administration of a new antineoplastic agent, dimethoxybenfluron (once a week, 10 administrations), were investigated in rabbits with respect to cardiac function and the release of cardiac troponin T (cTnT). Different doses of dimethoxybenfluron were administered to two groups of animals (12 mg/kg; n = 7 and 24 mg/kg; n = 6) and compared with either a control group (saline 1 ml/kg; n = 6) or a group with experimentally induced cardiomyopathy (daunorubicin 50 mg/m2; n = 13). In daunorubicin-induced cardiomyopathy, cTnT levels in animals with premature deaths were significantly higher (0.31 +/-0.11 microg/l) in comparison with the surviving animals (0.04 +/- 0.03 microg/l). However, cardiac TnT levels after the administration of dimethoxybenfluron in both doses were within the physiological range (lower than 0.1 microg/l) during the whole experiment as it was in the control group. The lack of cardiotoxicity of this new antineoplastic drug was supported by the absence of alterations in PEP:LVET ratio, left ventricle dP/dtmax or histological heart examination as well as by the fact that no premature death of animals occurred following repeated administration of dimethoxybenfluron. It is possible to conclude that no signs of cardiotoxicity were observed following repeated i.v. administration of dimethoxybenfluron.     

Renal injuries induced by chronic intoxication with microcystins

The microcystins (MCs) LR and YR are hepatotoxins produced by some species of freshwater cyanobacteria. Only a few reports on the acute nephrotoxicity of MCs have been published to date. Here we investigate the effects on rat kidneys of chronic administration of relatively low doses of MC LR and MC YR. Male Wistar rats were injected every second day for 8 months with MC LR (10 microg/kg i.p., n=5) and MC YR (10 microg/kg i.p., n=5). The control group was treated with vehicle, a mixture containing 0.8 % ethanol and 0.2 % methanol in 0.9 % saline (3.7 ml/kg i.p., n=5). We found that MCs could induce damage to the kidney cortex and medulla. The lesions mainly consisted of damaged and dilated tubuli filled with homogenous eosinophil material. We conclude that long-term exposure to relatively low doses of MCs poses a considerable risk for kidney injury.     

Effect of a platelet activating factor antagonist (CV6209) on shock caused by temporary hepatic inflow occlusion

Platelet activating factor (PAF) is a newly discovered inflammatory chemical mediator, which was reported to play a pivotal role in various types of shock. There is also a great possibility that PAF plays an important role in the shock caused by hepatic inflow occlusion. In the present study, the effect of CV6209, a PAF antagonist, on the shock caused by the occlusion was investigated. Intravenous 3 micrograms/kg of PAF caused hypotension in Wistar rats (n=6), and pretreatment with intravenous 3 mg/kg of CV6209 significantly (p less than 0.01) prevented the hypotension (n=6). Forty-five minutes of hepatic inflow occlusion caused hypotension in rats during the occlusion period, and the hypotension continued even after restoration of blood flow in control group (pretreated with saline i.v. only, n=5). In contrast, this hypotension was significantly (p less than 0.01) reversed in PAF antagonist group (pretreated with 3 mg/kg of CV6209 i.v., n=5). In sham-operated rats (n=6), arterial pressure remained unchanged and not hypotensive during the monitoring period. The survival rate of rats 90 minutes after declamp was 30% in control group (n=20), and that was significantly (p less than 0.05) improved to be 65% in PAF antagonist group (n=20). In conclusion, PAF plays an important role in the shock and death caused by temporary hepatic inflow occlusion, and a PAF antagonist could be a therapeutic drug against temporary hepatic inflow occlusion.     

Plasma thromboxane and prostacyclin: comparison during normal pregnancy and pregnancy complicated by hypertension

Plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolites of two prostanoids with opposing biological effects, TXA2 and prostacyclin, were measured by radioimmunoassay in normal pregnancy (controls) and pregnancy complicated by hypertension (PIH) from 32 to 36 (Period 1; P1) and from 36 to 40 (Period 2; P2) weeks of gestation. The plasma concentration of each compound in the control subjects was 265.6 +/- 58.4 (TXB2), 132.4 +/- 16.5 (6-keto-PGF1 alpha) for P1 (n = 10) and 142.6 +/- 11.8 (TXB2), 68.5 +/- 5.2 (6-keto-PGF1 alpha) for P2 (n = 10) respectively (pg/ml, mean +/- s.e). In the patients with PIH, TXB2 concentrations increased moderately for P1 (419.2 +/- 21.2; n = 7) and significantly (p less than 0.005) for P2 (452.8 +/- 31.0; n = 7) respectively (pg/ml, mean +/- s.e), while the plasma levels of 6-keto-PGF1 alpha revealed a slight to moderate decrease both for P1 (84.5 +/- 4.0; n = 7) and P2 (59.7 +/- 8.1; n = 7) respectively (pg/ml, mean +/- s.e). The physiological balance of TXB2 to 6-keto-PGF1 alpha was significantly greater (p less than 0.005) in the patients with PIH, where the TXB2/6-keto-PGF1 alpha ratio was 5.2 +/- 0.7 for P1 and 9.4 +/- 2.3 for P2 respectively (mean +/- s.e) compared with that of the controls, where it was 2.4 +/- 0.4 for P1 and 2.0 +/- 0.2 for P2 respectively (mean +/- s.e).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic effects of magnesium and vitamin E in rat spinal cord radiation damage: evaluation based on lipid peroxidation levels

This study investigated the neuroprotective effects of magnesium sulfate prophylaxis and vitamin E prophylaxis in a rat model of spinal cord radiation injury. Groups were subjected to different treatment conditions for 5 days prior to irradiation, and outcomes were evaluated on the basis of lipid peroxidation levels in cord tissue. Four groups of rats were investigated: no radiation/treatment (n = 4), intraperitoneal (i.p.) saline 1 ml/day (n = 6), i.p. vitamin E 100 mg/kg/day (n = 6), and i.p. magnesium sulfate 600 mg/kg/day (n = 6). The thoracic cord of each non-control rat was exposed to 20 Gy radiation in a LINAC system using 6 MV x-rays, and malondialdehyde (MDA) levels (reflecting lipid peroxidation level) were determined 24 hours post-irradiation. The MDA levels in thoracic cord segments from the control rats were used to determine baseline lipid peroxidation. The mean levels in the control, saline-only, vitamin E, and magnesium sulfate groups were 12.12 +/- 0.63, 27.0 +/- 2.81, 17.71 +/- 0.44, and 14.40 +/- 0.47 nmol/mg tissue, respectively. The MDA levels in the saline-only group were significantly higher than baseline, and the levels in the vitamin E group were significantly lower than those in the saline group (P < 0.05 for both). The levels in the magnesium sulfate group were dramatically lower than those in the saline group (P < 0.001). The results indicate that i.p. magnesium sulfate has a marked neuroprotective effect against radiation-induced oxidative stress in the rat spinal cord.     

Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer

Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.     

Combination of gemcitabine and docetaxel regresses both gastric leiomyosarcoma proliferation and invasion in an imageable patient-derived orthotopic xenograft (iPDOX) model

Gastric leiomyosarcoma is a recalcitrant cancer and the chemotherapy strategy is controversial. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of gastric leiomyosarcoma to identify an effective therapeutic regimen to develop individualized precision medicine for this disease. The gastric leiomyosarcoma obtained from a patient was first grown in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP) to stably label the tumor stroma. The RFP-expressing tumor was then passaged orthotopically in the gastric wall of non-transgenic nude mice to establish an imageable PDOX (iPDOX) model. The bright fluorescent tumor was readily imaged over time to determine drug efficacy. Four weeks after implantation, 70 PDOX nude mice were divided into 7 groups: control without treatment (n = 10); doxorubicin (DOX) (2.4 mg/kg, intraperitoneally (i.p.), once a week for 2 weeks, n = 10); gemcitabine (GEM)/ docetaxel (DOC) (GEM: 100 mg/kg, DOC: 20 mg/kg, i.p., once a week for 2 weeks, n = 10); cyclophosphamide (CPA) (140 mg/kg, i.p., once a week for 2 weeks, n = 10); temozolomide (TEM) (25 mg/kg, orally, daily for 14 consecutive days, n = 10); yondelis (YON) (0.15 mg/kg, i.v., once a week for 2 weeks, n = 10); pazopanib (PAZ) (100 mg/kg, orally, daily for 14 consecutive days, n = 10). On day 14 from initiation of treatment, all treatments except PAZ significantly inhibited tumor growth compared with untreated control (DOX: p < 0.01, GEM/DOC: p < 0.01, CPA: p < 0.01, TEM: p < 0.01, YON: p < 0.01) on day 14 after initiation. In addition, only GEM/DOC was more significantly effective than DOX (p < 0.05). GEM/DOC could regress the leimyosarcoma in the PDOX model and has important clinical potential for precision individual treatment of leiomyosarcoma patients.     

A comparison of maximal squat strength and 5-, 10-, and 20-meter sprint times, in athletes and recreationally trained men

The purpose of this study was to identify whether there was a relationship between relative strength during a 1 repetition maximum (1RM) back squat and 5-, 10-, and 20-m sprint performances in both trained athletes and recreationally trained individuals. Professional rugby league players (n = 24) and recreationally trained individuals (n = 20) participated in this investigation. Twenty-meter sprint time and 1RM back squat strength, using free weights, were assessed on different days. There were no significant (p ≥ 0.05) differences between the well-trained and recreationally trained groups for 5-m sprint times. In contrast, the well-trained group's 10- and 20-m sprint times were significantly quicker (p = 0.004; p = 0.002) (1.78 + 0.06 seconds; 3.03 + 0.09 seconds) compared with the recreationally trained group (1.84 + 0.07 seconds; 3.13 + 0.11 seconds). The athletes were significantly stronger (170.63 + 21.43 kg) than the recreationally trained individuals (135.45 + 30.07 kg) (p = 0.01); however, there were no significant differences (p > 0.05) in relative strength between groups (1.78 + 0.27 kg/kg; 1.78 + 0.33 kg/kg, respectively). Significant negative correlations were found between 5-m sprint time and relative squat strength (r = -0.613, power = 0.96, p = 0.004) and between relative squat strength and 10- and 20-m sprint times in the recreationally trained group (r = -0.621, power = 0.51, p = 0.003; r = -0.604, power = 0.53, p = 0.005, respectively). These results, indicating that relative strength, are important for initial sprint acceleration in all athletes but more strongly related to sprint performance over greater distances in recreationally trained individuals.     

Antinociceptive effects of the essential oil of Alpinia zerumbet on mice.

Alpinia zerumbet (Pers.) Burtt. et Smith is an aromatic plant that is distributed widely in the tropical and sub-tropical regions of the world. In Brazil, where A. zerumbet is called "colonia", it is used widely in folk medicine for the treatment of various diseases, including hypertension. In the present study, the antinociceptive effects of the orally administered essential oil of A. zerumbet (EOAz) were evaluated in male Swiss mice (20-25 g each). In the acetic acid-induced writhing test, EOAz (30, 100 and 300 mg/kg body wt.; n = 10, n = 13 and n = 15, respectively) was effective at all doses. In the hot-plate test, EOAz significantly increased the latency at doses of 100 and 300 mg/kg body wt., but not at 30 mg/kg body wt., at all observation times up to the 180th min (n = 10 for each dose). In the formalin test, EOAz significantly reduced paw licking time in the second phase of the test at 100 mg/kg body wt. (n = 10), but decreased it in both phases at 300 mg/kg body wt. (n = 10). At 30 mg/kg body wt., the effect of EOAz did not differ from control values in either phase of the formalin test (n = 10). Pretreatment with naloxone (5 mg/kgbodywt., i.p.) caused a significant reversal of the analgesic effect of 300 mg/kg body wt. EOAz (n = 8) that was complete for the first phase, but only partial for the second phase of the formalin test. The data show that orally administered OEAz promotes a dose-dependent antinociceptive effect, with a mechanism of action which probably involves the participation of opiate receptors.     

Effects of calcium channel blockers on bupivacaine-induced toxicity

The purpose of this study was to investigate the influence of calcium channel blockers on bupivacaine-induced acute toxicity. For each of the three tested calcium channel blockers (diltiazem, verapamil and bepridil) 6 groups of mice were treated by two different doses, i.e. 2 and 10 mg/kg/i.p., or an equal volume of saline for the control group (n=20); 15 minutes later, all the animals were injected with a single 50 mg/kg/i.p. dose of bupivacaine. The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was significantly increased by the three different calcium channel blockers. The convulsant activity of bupivacaine was not significantly modified but calcium channel blockers decreased the time of latency to obtain bupivacaine-induced convulsions; this effect was less pronounced with bepridil.     

Anaphe venata larva extract-induced purposeless chewing in rats: the role of cholinergic, GABAergic and opioid systems

Seasonal ataxia was reported in humans following the consumption ofAnaphe venata larva as protein supplement in diet and altered motor function in rodents when the extract was administered intraperitoneally. In this study we investigated the effect of the crude aqueous and Phosphate Buffer Saline (PBS) extracts of this larva on altered spontaneous rat behavior in a novel environment particularly chewing behaviour, with a view to determine the mechanism(s) involved in these behavioural alteration. Animals were randomly assigned into four groups (n = 6-12 per group) and graded doses of aqueous and PBS extracts (100-400 mg/kg) were administered dissolved in saline intraperitoneally (i.p.) to each animal in the experimental groups. The control group received an equivalent volume of saline. Behavioral scores were recorded for a period of 30 minutes after the administration of saline or extract. The role of various receptors in the extract induced chewing was evaluated using known receptor agonist/antagonists. Results revealed a significant increase in purposeless chewing (F (7, 95) = 7.85; p <0.05) by the aqueous extract compared to saline control at all dose levels, which was significantly attenuated by scopolamine (3 mg/kg, i.p) and thiamine (1 mg/kg, i.p) respectively (p <0.05); while flumazenil (2 mg/kg, i.p) and naloxone (2.5 mg/kg, i.p) did not alter the induced purposeless chewing behaviour. Also, administration of PBS induced a significant (F (7, 95) = 6.11; p <0.05) increase in chewing behaviour but only at 400 mg/kg dose level which was attenuated by scopolamine (3 mg/kg, i.p); while flumazenil (2 mg/kg, i.p), naloxone (2.5 mg/kg, i.p), and thiamine (1 mg/kg, i.p) potentiated purposeless chewing behaviour respectively. It may therefore be concluded from this study that Anaphe extract-induced purposeless chewing behaviour in rat is mediated via the activation of cholinergic neurotransmission which is modulated by GABAergic and opioid receptor systems.     

Potent convulsant actions of the adenosine receptor antagonist, xanthine amine congener (XAC)

The convulsant properties of xanthine amine congener (XAC, 8-(4-(2-aminoethyl)-aminocarboxylmethyloxy)phenyl-1,3-dipropylxant hine) are compared to those of caffeine. Male Swiss albino mice were infused with convulsants through a lateral tail vein. Convulsion thresholds (i.e. the amount of convulsants required to elicit convulsions) of 39.8 +/- 2.0 mg/kg (n = 10) and 109.8 +/- 2.3 mg/kg (n = 10) were calculated for XAC and caffeine respectively. Pretreatment of animals with the adenosine receptor agonists 2-chloroadenosine, N6-cyclohexyladenosine or 5'-N-ethylcarboxamido-adenosine (1 mg/kg, i.p., 20 minutes prior to infusion) significantly decreased the seizure threshold of both XAC and caffeine. The adenosine uptake blockers, 6-nitrobenzylthioinosine or dipyridamole (0.25 mg/kg, i.p., 20 minutes prior to infusion) did not significantly affect the seizure threshold to either XAC or caffeine. The benzodiazepine agonist diazepam (5 mg/kg, i.p., 20 minutes prior to infusion) significantly increased the seizure threshold to both XAC (p less than 0.05) and caffeine (p less than 0.01), whereas the benzodiazepine antagonist Ro 15-1788 (10 mg/kg, i.p., 20 minutes prior to infusion) significantly increased the seizure threshold to caffeine (p less than 0.01), but not XAC. The results suggest that actions at benzodiazepine receptors may be a tenable hypothesis to explain the convulsant actions of caffeine, but not those of XAC.     

一氧化氮合酶抑制剂L-NAME对大鼠脑缺血耐受诱导的影响

采用大鼠四血管闭塞全脑缺血耐受模型和脑组织切片形态学方法,观察应用一氧化氮合酶(NOS)抑制剂L—NAME对大鼠海马CAl区脑缺血耐受(BIT)诱导的影响,在整体水平探讨一氧化氮(NO)在BIT诱导中的作用。54只Wistar大鼠凝闭双侧推动脉后分为6组：(1)假手术组(n＝6);分离双侧颈总动脉,但不阻断脑血流;(2)损伤性缺血组(n＝6)：全脑缺血10min;(3)预缺血 损伤性缺血组(n＝6)：脑缺血预处理(CIP)3min,再灌注72h后行全脑缺血10min;(4)L—NAME组;分别于CIP前1h和后1、12及36h腹腔注射L—NAME(5mg／kg),每个时间点6只动物,其余步骤同预缺血 损伤性缺血组;(5)L—NAME L—精氨酸组(n＝6)：于CIP前1h腹腔注射L—NAME(5mg／kg)和L—精氨酸(300mg／kg),其它步骤同L—NAME组;(6)L—NAME 损伤性缺血组(n＝6)：于腹腔注射L—NAME(5mg／kg)72h后行全脑缺血10min。实验结果表明,(1)单纯10min全脑缺血可使海马CAl区组织学分级增加(表明损伤加重),神经元密度降低(P＜0．01);(2)预缺血 损伤性缺血组的海马CAl区组织学分级、神经元密度与假手术组相比,无显著性差别(P＞0．05);(3)L—NAME组中,应用L—NAME后海马CAl区组织学分级增加,神经元密度降低,与预缺血 损伤性缺血组相比有显著性差异(P＜0．05),表明L—NAME可阻断CIP对神经元的保护作用;(4)L—NAME L—精氨酸组与L—NAME组相比,海马CAl区组织损伤明显减轻(P＜0．05),但与预缺血 损伤性缺血组相比仍有显著性差别(P＜0．05),提示L-精氨酸可部分逆转L—NAME的作用;(5)L—NAME 损伤性缺血组的组织学表现与损伤性缺血组相同(P＞0．05)。这些结果表明,在整体情况下N0参与BIT的诱导。与CIP前1h及后1、12h给予L—NAME组相比,CIP后36h给予L—NAME对CIP保护作用的阻断效应明显减弱,提示N0在CIP后较早阶段即开始参与BIT的诱导。     

900 MHz pulse-modulated radiofrequency radiation induces oxidative stress on heart, lung, testis and liver tissues

Oxidative stress may affect many cellular and physiological processes including gene expression, cell growth, and cell death. In the recent study, we aimed to investigate whether 900 MHz pulse-modulated radiofrequency (RF) fields induce oxidative damage on lung, heart and liver tissues. We assessed oxidative damage by investigating lipid peroxidation (malondialdehyde, MDA), nitric oxide (NOx) and glutathione (GSH) levels which are the indicators of tissue toxicity. A total of 30 male Wistar albino rats were used in this study. Rats were divided randomly into three groups; control group (n = 10), sham group (device off, n = 10) and 900 MHz pulsed-modulated RF radiation group (n = 10). The RF rats were exposed to 900 MHz pulsed modulated RF radiation at a specific absorption rate (SAR) level of 1.20 W/kg 20 min/day for three weeks. MDA and NOx levels were increased significantly in liver, lung, testis and heart tissues of the exposed group compared to sham and control groups (p < 0.05). Conversely GSH levels were significantly lower in exposed rat tissues (p < 0.05). No significantly difference was observed between sham and control groups. Results of our study showed that pulse-modulated RF radiation causes oxidative injury in liver, lung, testis and heart tissues mediated by lipid peroxidation, increased level of NOx and suppression of antioxidant defense mechanism.     

Insulin sensitivity is mediated by the activation of the ACh/NO/cGMP pathway in rat liver

The hepatic parasympathetic nerves and hepatic nitric oxide synthase (NOS) are involved in the secretion of a hepatic insulin sensitizing substance (HISS), which mediates peripheral insulin sensitivity. We tested whether binding of ACh to hepatic muscarinic receptors is an upstream event to the synthesis of nitric oxide (NO), which, along with the activation of hepatic guanylate cyclase (GC), permits HISS release. Male Wistar rats (8-9 wk) were anesthetized with pentobarbital sodium (65 mg/kg). Insulin sensitivity was assessed using a euglycemic clamp [the rapid insulin sensitivity test (RIST)]. HISS inhibition was induced by antagonism of muscarinic receptors (atropine, 3 mg/kg i.v.) or by blockade of NOS [NG-nitro-L-arginine methyl ester (L-NAME), 1 mg/kg intraportally (i.p.v.)]. After the blockade, HISS action was tentatively restored using a NOdonor [3-morpholynosydnonimine (SIN-1), 5-10 mg/kg i.p.v.] or ACh (2.5-5 microg.kg(-1).min(-1) .i.p.v.). SIN-1 (10 mg/kg) reversed the inhibition caused by atropine (RIST postatropine 137.7 +/- 8.3 mg glucose/kg; reversed to 288.3 +/- 15.5 mg glucose/kg, n = 6) and by L-NAME (RIST post-L-NAME 152.2 +/- 21.3 mg glucose/kg; reversed to 321.7 +/- 44.7 mg glucose/kg, n = 5). ACh did not reverse HISS inhibition induced by L-NAME. The role of GC in HISS release was assessed using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 nmol/kg i.p.v.), a GC inhibitor that decreased HISS action (control RIST 237.6 +/- 18.6 mg glucose/kg; RIST post-ODQ 111.7 +/- 6.2 mg glucose/kg, n = 5). We propose that hepatic parasympathetic nerves release ACh, leading to hepatic NO synthesis, which activates GC, triggering HISS action.     

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.     

Serum Cardiac Troponin-I is Superior to Troponin-T as a Marker for Left Ventricular Dysfunction in Clinically Stable Patients with End-Stage Renal Disease

Background

Serum troponin assays, widely used to detect acute cardiac ischemia, might be useful biomarkers to detect chronic cardiovascular disease (CVD). Cardiac-specific troponin-I (cTnI) and troponin-T (cTnT) generally detect myocardial necrosis equally well. In dialysis patients however, serum cTnT levels are often elevated, unlike cTnI levels. The present study aims to elucidate the associations of cTnI and cTnT with CVD in clinically stable dialysis patients.

Methods

Troponin levels were measured using 5^th generation hs-cTnT assays (Roche) and STAT hs-cTnI assays (Abbott) in a cohort of dialysis patients. Serum troponin levels were divided into tertiles with the lowest tertile as a reference value. Serum troponins were associated with indicators of CVD such as left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and the presence of coronary artery disease (CAD). Associations were explored using regression analysis.

Results

We included 154 consecutive patients, 68±7 years old, 77% male, 70% hemodialysis. Median serum cTnT was 51ng/L (exceeding the 99^th percentile of the healthy population in 98%) and median serum cTnI was 13ng/L (elevated in 20%). A high cTnI (T3) was significantly associated with a higher LVMI (Beta 31.60; p=0.001) and LVEF (Beta -4.78; p=0.005) after adjusting for confounders whereas a high serum cTnT was not. CAD was significantly associated with a high cTnT (OR 4.70 p=0.02) but not with a high cTnI. Unlike cTnI, cTnT was associated with residual renal function (Beta:-0.09; p=0.006).

Conclusion

In the present cohort, serum cTnI levels showed a stronger association with LVMI and LVEF than cTnT. However, cTnT was significantly associated with CAD and residual renal function, unlike cTnI. Therefore, cTnI seems to be superior to cTnT as a marker of left ventricular dysfunction in asymptomatic dialysis patients, while cTnT might be better suited to detect CAD in these patients.     

Increased expression of hypothalamic NADPH-diaphorase neurons in mice with iron supplement

Iron deficiency is known as the most important nutritional problem in the world. The loss of appetite is a common characteristic of iron deficiency. Iron-containing heme is required as a cofactor for nitric oxide synthase (NOS) which produces nitric oxide (NO). NOS in the central nervous system has been suggested to regulate food intake. Hence, we examined the expression of hypothalamic NOS at various levels of dietary iron. ICR mice (n = 30) were randomly divided into three groups based on the level of dietary iron and fed experimental diets for 4 weeks: the normal-iron diet group (7 mg/kg diet, n = 10), the low-iron diet group (21 mg/kg diet, n = 10) and the high-iron diet group (42 mg/kg diet, n = 10). Expression of NOS in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) of hypothalamus was examined by histochemistry for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-diaphorase). The high-iron diet mice showed significantly higher staining intensity of NADPH-diaphorase-positive neurons in the PVN and LHA than the normal- and low-iron diet mice.