In Vivo Cardioprotection by N-Acetylcysteine and Isosorbide 5-Mononitrate in a Rat Model of Ischemia-Reperfusion

Aims: We evaluated the effect of N-acetylcysteine (NAC, infused i.v.), isosorbide 5-mononitrate (IS5MN, by gavage), or their combination on cardiac injury in an in vivo rat model of 30-min ischemia followed by 24 hours or 7 days of reperfusion. Results: When administered immediately prior to reperfusion with continuous infusion for 24 h, the combination of NAC + IS5MN reduced infarct size (29 ± 6 vs. 59 ± 4% area-at-risk, p < 0.01) and the infiltration of polymorphonuclear leukocytes (226 ± 15 vs. 315 ± 18 cells mm^–2 of area-at-risk, p = 0.002) and monocytes/macrophages (118 ± 8 vs. 194 ± 22 cells mm^–2, p = 0.012), compared to vehicle. NAC or IS5MN alone did not reduce infarct size at 24 hours of reperfusion. The same dose regimen of NAC and IS5MN did not reduce infarct size with permanent ischemia for 24 hours not followed by reperfusion. After 7 days of reperfusion (3 days of treatment with NAC + IS5MN or vehicle and 4 days of wash-out), infarct size was similar in the vehicle and NAC + IS5MN groups, but LV end-diastolic pressure and diastolic LV chamber wall stress were significantly lower in the animals treated with NAC + IS5MN (5 ± 1 mmHg and 62 ± 7 dyne mm^–2, respectively) compared to vehicle (9 ± 1 mmHg and 123 ± 18 dyne mm^–2, p < 0.05). Conclusion: We demonstrate in a rat model of cardiac ischemia-reperfusion treated with NAC and IS5MN, according to a regimen that mimicked a clinical situation (drugs started at time of reperfusion), that the short-term benefit seen after 24 h of reperfusion (51% reduction of infarct size) is maintained after one week, possibly through modulation of the inflammatory response to cardiac injury.     

Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI50 0.1 to <0.01 microg/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.     

More nurses: a proposal

This paper recognises the complexities of the current political, professional and economic agendas. Its chief concern is to maintain the quality of student learning while ensuring the development of competent practitioners and as such, while accepting the government and professional strategies, we suggest that students should exit the programme after less than three years if they achieve competency. In the words of former RCN assistant director of nurse education Sally Thomson (Alderman and Knight 1999): 'Quality is a better measure than quantity.' The profession has chosen to go down a competency based route; the amount of time taken, therefore, should become less significant. The approach suggested by the authors would maximise the number of students achieving registration without compromising standards or intensifying the existing stressors of registered staff. It should also ease the financial burden on many students and save public money, such as the 24 weeks of bursary for each student, and should increase the number of graduates as students are helped financially to complete the programme's degree component. Failure to consider this proposal seriously, we believe, might result in more students, less supervision, poorer quality placements, worse learning and less competence.     

Appraisal of the role of angiotensin II and aldosterone in ventricular myocyte apoptosis in adult normotensive rat

Despite previous observations on isolated ventricular myocytes, there are still few evidences that angiotensin II induces cardiomyocyte apoptosis in vivo. The possibility that aldosterone, the final hormone of the renin-angiotensin-aldosterone system under Ang II control, can stimulate cardiac apoptosis has not yet been explored. Angiotensin II or aldosterone (1mg/kg each) were infused in adult normotensive rats for different times, and the number of apoptotic ventricular myocyte nuclei was quantified by the TUNEL method, along with caspase-3 activation. The role of angiotensin II type 1 receptor in vivo was assessed by selective blockade with valsartan and ex vivo by binding experiments. In addition, myocytes in primary culture were incubated with Ang II or aldosterone in presence of spironolactone. Continuous infusion of Ang II induced a rapid, AT(1)-mediated increase of apoptotic cardiomyocyte nuclei (from 14+/-9 to 188+/-35 TdT-labeled nuclei/10(6) after 3h, P<0.005) and of activated caspase-3, that normalized after 24h. The normalization was associated with a down-regulation of myocardial AT(1) receptors. Aldosterone stimulated cardiomyocyte apoptosis both in vivo and in isolated cells, to a similar extent as Ang II. The maximal apoptotic rate reported here ( approximately 0.02%) and the transient effect of Ang II suggest that myocyte loss by apoptosis is limited in the present model. The data on aldosterone-induced ventricular myocyte apoptosis deserve further attention to delineate the role of aldosterone in cell death and offer possible mechanistic explanations on the benefits afforded by aldosterone receptor antagonists in heart failure.     

Intracarotid nitroprusside does not augment cerebral blood flow in human subjects.

BACKGROUND: The recent resurgence of interest in the cerebrovascular effects of nitroprusside can be attributed to the possibility of using nitric oxide donors in treating cerebrovascular insufficiency. However, limited human data suggest that intracarotid nitroprusside does not directly affect cerebrovascular resistance. In previous studies, physiologic or pharmacologic reactivity of the preparation was not tested at the time of nitroprusside challenge. The authors hypothesized that if nitric oxide is a potent modulator of human cerebral blood flow (CBF), then intracarotid infusion of nitroprusside will augment CBF. METHODS: Cerebral blood flow was measured (intraarterial (133)Xe technique) in sedated human subjects undergoing cerebral angiography during sequential infusions of (1) intracarotid saline, (2) intravenous phenylephrine to induce systemic hypertension, (3) intravenous phenylephrine with intracarotid nitroprusside (0.5 microg x kg(-1) x min(-1)), and (4) intracarotid verapamil (0.013 mg x kg(-1) x min(-1)). Data (mean +/- SD) were analyzed by repeated-measures analysis of variance and post hoc Bonferroni-Dunn test. RESULTS: Intravenous phenylephrine increased systemic mean arterial pressure (from 83 +/- 12 to 98 +/- 6 mmHg; n = 8; P < 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with intravenous phenylephrine or with concurrent infusions of intravenous phenylephrine and intracarotid nitroprusside. Intracarotid verapamil increased CBF (43 +/- 9 to 65 +/- 11 ml x 100 g(-1) x min(-1); P < 0.05). CONCLUSIONS: The authors conclude that, in humans, intracarotid nitroprusside sufficient to decrease mean arterial pressure during recirculation, does not augment CBF. Failure of intracarotid nitroprusside to augment CBF despite demonstrable autoregulatory vasoconstriction and pharmacologic vasodilation questions the significance of nitric oxide-mediated vasodilation in human cerebral circulation.     

Clinical trial of a novel surface cooling system for fever control in neurocritical care patients

OBJECTIVE: To compare the efficacy of a novel water-circulating surface cooling system with conventional measures for treating fever in neuro-intensive care unit patients. DESIGN: Prospective, unblinded, randomized controlled trial. SETTING: Neurologic intensive care unit in an urban teaching hospital. PATIENTS: Forty-seven patients, the majority of whom were mechanically ventilated and sedated, with fever > or =38.3 degrees C for >2 consecutive hours after receiving 650 mg of acetaminophen. INTERVENTIONS: Subjects were randomly assigned to 24 hrs of treatment with a conventional water-circulating cooling blanket placed over the patient (Cincinnati SubZero, Cincinnati OH) or the Arctic Sun Temperature Management System (Medivance, Louisville CO), which employs hydrogel-coated water-circulating energy transfer pads applied directly to the trunk and thighs. MEASUREMENTS AND MAIN RESULTS: Diagnoses included subarachnoid hemorrhage (60%), cerebral infarction (23%), intracerebral hemorrhage (11%), and traumatic brain injury (4%). The groups were matched in terms of baseline variables, although mean temperature was slightly higher at baseline in the Arctic Sun group (38.8 vs. 38.3 degrees C, p = .046). Compared with patients treated with the SubZero blanket (n = 24), Arctic Sun-treated patients (n = 23) experienced a 75% reduction in fever burden (median 4.1 vs. 16.1 C degrees -hrs, p = .001). Arctic Sun-treated patients also spent less percent time febrile (T > or =38.3 degrees C, 8% vs. 42%, p < .001), spent more percent time normothermic (T < or =37.2 degrees C, 59% vs. 3%, p < .001), and attained normothermia faster than the SubZero group median (2.4 vs. 8.9 hrs, p = .008). Shivering occurred more frequently in the Arctic Sun group (39% vs. 8%, p = .013). CONCLUSION: The Arctic Sun Temperature Management System is superior to conventional cooling-blanket therapy for controlling fever in critically ill neurologic patients.