Vasorelaxing cell permeant phosphopeptide mimetics for subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to vasospasm resulting in delayed cerebral ischemia. Therapeutic options are currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy. Nitric oxide (NO) modulates cerebral blood flow through activation of the cGMP-Protein Kinase G (PKG) pathway. Our hypothesis is that SAH results in downregulation of signaling components in the NO-PKG pathway which could explain why treatments for vasospasm targeting this pathway lack efficacy and that treatment with a cell permeant phosphopeptide mimetic of downstream effector prevents delayed vasospasm after SAH. Using a rat endovascular perforation model, reduced levels of NO-PKG pathway molecules were confirmed. Additionally, it was determined that expression and phosphorylation of a PKG substrate: Vasodilator-stimulated phosphoprotein (VASP) was downregulated. A family of cell permeant phosphomimetic of VASP (VP) was wasdesigned and shown to have vasorelaxing property that is synergistic with nimodipine in intact vascular tissuesex vivo. Hence, treatment targeting the downstream effector of the NO signaling pathway, VASP, may bypass receptors and signaling elements leading to vasorelaxation and that treatment with VP can be explored as a therapeutic strategy for SAH induced vasospasm and ameliorate neurological deficits.

Coenzyme Q10 attenuates platelet integrin αIIbß3 signaling and platelet hyper-reactivity in ApoE-deficient mice.

Coenzyme Q10 (CoQ10) exists in a wide variety of foods and has promising cardiovascular benefits. However, its effects on platelets and integrin αIIbß3 signaling during atherosclerosis have not been previously explored. Here, apolipoprotein E-deficient (ApoE-/-) mice were fed a standard diet, high-fat diet (HFD) or CoQ10-supplemented HFD for 12 weeks. We found that CoQ10 supplementation in ApoE-/- mice significantly alleviated formation of HFD-induced atherosclerotic lesions, and attenuated platelet hyper-aggregation and granule secretion, including CD62P, CD63 and CD40 ligand (CD40L) expression and platelet factor-4, ß-thromboglobulin and activation normal T cell expressed and secreted (CCL5) release. CoQ10 supplementation decreased soluble fibrinogen and JON/A binding to αIIbß3 on activated platelets, indicating that αIIbß3-mediated inside-out signaling was attenuated. Additionally, CoQ10 down-regulated platelet αIIbß3 outside-in signaling including decreasing phosphorylation of the ß3 intracellular tail, cellular and sarcoma tyrosine-protein kinase (c-Src), and myosin light chain (MLC), and consistently attenuating platelet spreading and clot retraction. Importantly, platelet-monocyte aggregation that was primarily mediated by αIIbß3 and can be blocked using an αIIbß3-specific antagonist tirofiban was also markedly diminished by CoQ10. Thus, CoQ10 supplementation attenuates platelet hyper-reactivity via down-regulating both αIIbß3 inside-out and outside-in signaling, which may play important preventive roles in atherothrombosis.

Coenzyme Q10 Upregulates Platelet cAMP/PKA Pathway and Attenuates Integrin αIIbß3 Signaling and Thrombus Growth.

SCOPE: Platelet integrin αIIbß3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat-soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbß3 signaling and thrombosis, the major cause of cardiovascular diseases. METHODS AND RESULTS: Using a series of platelet functional assays in vitro, it is demonstrated that CoQ10 reduces human platelet aggregation, granule secretion, platelet spreading, and clot retraction. It is further demonstrated that CoQ10 inhibits platelet integrin αIIbß3 outside-in signaling. These inhibitory effects are mainly mediated by upregulating cAMP/PKA pathway, where CoQ10 stimulates the A2A adenosine receptor and decreases phosphodiesterase 3A phosphorylation. Moreover, CoQ10 attenuates murine thrombus growth and vessel occlusion in a ferric chloride (FeCl3 )-induced thrombosis model in vivo. Importantly, the randomized, double-blind, placebo-controlled clinical trial in dyslipidemic patients demonstrates that 24 weeks of CoQ10 supplementation increases platelet CoQ10 concentrations, enhances the cAMP/PKA pathway, and attenuates αIIbß3 outside-in signaling, leading to decreased platelet aggregation and granule release. CONCLUSION: Through upregulating the platelet cAMP/PKA pathway, and attenuating αIIbß3 signaling and thrombus growth, CoQ10 supplementation may play an important protective role in patients with risks of cardiovascular diseases.

Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma.

BACKGROUND: Selenium is an essential trace element obtained through diet that plays a critical role in DNA synthesis and protection from oxidative damage. Selenium intake and polymorphisms in selenoproteins have been linked to the risk of certain cancers though data for glioma are sparse. METHODS: In a case-control study of glioma, we examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathway with the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study. RESULTS: None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70). CONCLUSION: The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome.

Complementary therapy and survival in glioblastoma.

BACKGROUND: Complementary therapy (CAM) is common in cancer patients. We undertook this study to assess the association of complementary therapy usage with mortality in glioblastoma (GBM) patients. METHODS: The analysis was based on 470 patients. Information on current use of CAM was collected in structured interviews conducted a median of 6 weeks following GBM diagnosis. Proportional hazards regression was used to estimate hazard ratios (HRs) for GBM-related death according to the use of individual supplements with multivariate adjustment for known prognostic factors including age, KPS, and extent of tumor resection (ESR). RESULTS: Use of CAM agents was common, with 77% of the cohort reporting CAM usage. No mortality association was observed with the use of multivitamins (HR = 0.91; P = .40) or omega-3 fatty acids (HR = 1.07; P = .69). Patients taking vitamin D as an individual supplement (containing higher dosages than in a multivitamin) had reduced mortality when compared with nonusers (age-adjusted HR = 0.68; P = .02). However, the association was diminished after adjustment for KPS and ESR (HR = 0.74; P = .09). Use of herbal supplements was also associated with reduced mortality (HR = 0.58; P = .04). Vitamin E users had a nonsignificantly higher mortality when compared with nonusers (HR = 1.54; P = .09). CONCLUSIONS: Use of CAM is common in GBM patients. These exploratory analyses suggest no mortality association with the use of multivitamins or omega-3 fatty acids. Associations observed with vitamins D and E merit further investigation.

The long-term effectiveness of clozapine and lamotrigine in a patient with treatment-resistant rapid-cycling bipolar disorder.

The challenges in the management of treatment-resistant rapid-cycling bipolar disorder are multifaceted and represent a significant burden to the patient. There is a need for more exploration into the potential utility of various combination therapies in the setting of severe affective states. A 52-year-old woman with a history of severe treatment-resistant rapid-cycling bipolar affective disorder (BPAD) was hospitalized for the treatment of a severe mixed episode. The introduction of lamotrigine and clozapine in combination proved remarkably effective and well tolerated in both the acute management and in subsequent maintenance. The patient has remained asymptomatic during the 5-year follow-up without any further mood disturbance. Lamotrigine and clozapine are among the less-prescribed agents for BPAD and there is as yet little research into their use in combination. It is possible that these agents have complementary modes of action on various facets of the affective pathology, resulting in superior mood stabilization in this patient.

Impact of a standard medication chart on prescribing errors: a before-and-after audit.

OBJECTIVES: (1) To develop and implement a standard medication chart, for recording prescribing (medication orders) and administration of medication in public hospitals in Queensland. (2) To assess the chart's impact on the frequency and type of prescribing errors, adverse drug reaction (ADR) documentation and safety of warfarin prescribing. (3) To use the chart to facilitate safe medication management training. DESIGN, SETTING AND PARTICIPANTS: The medication chart was developed through a process of incident analysis and work practice mapping by a multidisciplinary collaborative. Observational audits by nurse and pharmacist pairs, of all available prescriptions before and after introduction of the standard medication chart, were undertaken in five sites. RESULTS: Similar numbers of both patients (730 pre-implementation and 751 post-implementation; orders, 9772 before and 10 352 after) were observed. The prescribing error rate decreased from 20.0% of orders per patient before to 15.8% after (Mann-Whitney U test, p = 0.03). Previous ADRs were not documented for 19.5% of 185 patients before and 11.2% of 197 patients after (chi(2), p = 0.032). Prescribing errors involving selection of a drug to which a patient had had a previous ADR decreased from 11.3% of patients before to 4.6% after (chi(2), p = 0.021). International normalised ratios (INRs) >5 decreased from 1.9% of 14 405 INRs in the 12 months before to 1.45% of 15 090 INRs after (chi(2), p = 0.004). After minor modifications, the chart was introduced into all hospitals statewide, which enabled standardised medication training and safer rotation of staff. The chart also formed the basis for the National Inpatient Medication Chart. CONCLUSION: Introduction of a standard revised medication chart significantly reduced the frequency of prescribing errors, improved ADR documentation and decreased the potential risks associated with warfarin management. The standard chart has enabled uniform training in medicine management.

Integrated care improves risk-factor modification after stroke: initial results of the Integrated Care for the Reduction of Secondary Stroke model.

OBJECTIVE: Despite evidence demonstrating that risk-factor management is effective in reducing recurrent cerebrovascular disease, there are very few structured care programmes for stroke survivors. The aim was to implement and evaluate an integrated care programme in stroke. METHODS: 186 patients with stroke were randomised to either the treatment (integrated care) or control (usual care) group and were followed up over 12 months. The Integrated Care for the Reduction of Secondary Stroke (ICARUSS) model of integrated care involved collaboration between a specialist stroke service, a hospital coordinator and a patient's general practitioner. The primary aim was to promote the management of vascular risk factors through ongoing patient contact and education. RESULTS: In the 12 months poststroke, systolic blood pressure (sBP) decreased in the treatment group but increased in controls. The group difference was significant, and remained so when age, sex, disability and sBP at discharge were accounted for (p = 0.04). Treatment patients also exhibited better modification of body mass index (p = 0.007) and number of walks taken (p<0.001) than controls. Rankin scores indicated significantly reduced disability in treatment patients relative to controls in the year poststroke (p = 0.003). CONCLUSIONS: Through an integrated system of education, advice and support to both patient and GP, the ICARUSS model was effective in modifying a variety of vascular risk factors and therefore should decrease the likelihood or recurrent stroke or vascular event.

Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazin.

Stargazin is membrane bound protein involved in trafficking, synapse anchoring and biophysical modulation of AMPA receptors. A quantitative trait locus in chromosome 7 containing the stargazin gene has been identified as controlling the frequency and duration of absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Furthermore, mutations in this gene result in the Stargazer mouse that displays an absence epilepsy phenotype. GAERS stargazin mRNA expression is increased 1.8 fold in the somatosensory cortex and by 1.3 fold in the thalamus. The changes were present before and after the onset of absence seizures indicating that increases are not a secondary consequence of the seizures. Stargazin protein expression was also significantly increased in the somatosensory cortex after the onset of spontaneous seizures. The results are of significant importance beyond the GAERS model, as they are the first to show that an increase in stargazin expression may be pro-epileptic.

Effect of celecoxib and novel agent LC-1 in a hamster model of lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompanying inhibition of NF-kappaB, were investigated. MATERIALS AND METHODS: Syrian golden hamsters (n = 140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were randomized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treatments were given via orogastric lavage for 32 wk. Immunohistochemistry was used to determine COX-2 expression and NF-kappaB activity. Ki-67 labeling was used as an index of proliferation. COX activity was measured by prostaglandin E(2) enzyme-linked immunosorbent assay. RESULTS: BOP successfully induced lung adenocarcinoma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-kappaB. Prostaglandin E(2) levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activity, but no decrease in NF-kappaB was seen as measured by immunohistochemistry in the tumors. There was no significant difference in tumor size, tumor incidence, or tumor proliferation index between placebo and treatment groups. CONCLUSIONS: Carcinogen exposure results in increased COX-2 and NF-kappaB expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer development when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-kappaB activity will need to be explored to determine the viability of this approach to prevent lung cancer development.

Electro-sensitisation of mammalian cells and tissues to ultrasound: a novel tumour treatment modality.

This study demonstrates that mammalian cell targets (erythrocytes and tumour cells) may be sensitised to ultrasound using electric pulses and this combination treatment results in destruction of those cells in vitro. It further demonstrates that when a tumour mass is treated in vivo using combined electric field and ultrasound therapy, significant retardation of tumour growth has been observed using a mouse tumour model. We suggest that combined electric field and ultrasound (CEFUS) therapy may provide a novel, drug-free treatment modality for cancer.

Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children.

The clinical efficacy and pharmacokinetics of long-term epidural ropivacaine infusion were investigated in 18 postoperative children aged between 0.3 and 7.3 yr. A lumbar or thoracic epidural catheter was inserted after the anaesthetic induction. Sixty minutes following a bolus dose of ropivacaine 1 mg kg-1, 0.2% ropivacaine was infused at a fixed rate of 0.4 mg kg-1 h-1 for a mean of 61.3 h (range 36-96 h). Clinical evaluation comprised hourly recording of pain, sedation, motor block, nausea/vomiting, pruritus-scores, SpO2, pulse and respiratory rates, and recording of non-invasive arterial pressure every 4 h. Total and free plasma concentrations were measured by high-performance liquid chromatography at 0, 1, 6, 12, 24, 36, 48, 72 and 96 h. Analgesia was of high quality and side effects were minor. No clinical signs of local anaesthetic toxicity were seen. Total (100-3189 micrograms litre-1) and free (10-56 micrograms litre-1) ropivacaine concentrations were within the range reported to be 'safe' in previous studies in adults. Mean (95% CI) volume of distribution was 3.1 litre kg-1 (2.1-4.2 litre kg-1), total clearance was 8.5 ml kg-1 min-1 (5.8-11.1 ml kg-1 min-1), free clearance was 220 ml kg-1 min-1 (170-270 ml kg-1 min-1) and elimination half-life was 4.9 h (3.0-6.7 h).

Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats.

We explored the possibility that silymarin (SY), a fraction from Silybum marianum, might protect against the effects of in utero exposure to ethanol upon subsequent social memory function. Three groups of 8 pregnant female Sprague-Dawley rats each were provided with a liquid diet containing 35% ethanol derived calories (EDC). One experimental group received a daily subcutaneous injection of 400 mg/kg SY, the second, a 400 mg/kg oral dose of SY, a third group was maintained on the 35% EDC diet. A fourth group served as the pair-fed control group. The liquid diet regimen was maintained throughout pregnancy. Rats pups were fostered by dams in a fifth group that had been maintained on rat chow. At 90 days the pups were tested for social memory. Social recognition scores recorded for the ethanol pups were significantly poorer than those observed in both SY/ethanol groups and the chow group.

Diazepam-induced neuroprotection: dissociating the effects of hypothermia following global ischemia.

Global cerebral ischemia produces hippocampal CA1 neuronal loss which in turn leads to deficits in memory related tasks. Previous studies have shown that the benzodiazepine diazepam is effective at attenuating this cell death and the related behavioural impairments. However these studies have been confounded by diazepam-induced hypothermia. In this study we sought to determine the neuroprotective efficacy of diazepam in the absence of hypothermia. Diazepam (10 mg/kg) was administered to two groups of gerbils at 30 and 90 min following a 5-min ischemic insult. In one group the brain temperature was monitored for 24 h post-ischemically but not regulated. In the second group, post-ischemic brain temperature was maintained at 36.5 degrees C to counteract the hypothermia produced by diazepam. Both behaviour (open field performance) and CA1 cell counts from these groups were compared to those from sham/normal, no drug ischemic and vehicle ischemic groups at 10 days survival. In animals treated with diazepam without temperature regulation, there was significant histological and behavioural protection at 10 days compared to untreated ischemic animals. Preventing hypothermia in diazepam-treated animals resulted in a decrease in the number of cells surviving (from 41.2 to 31.6% of sham) and abolished behavioural protection. Diazepam appears to have limited ability to attenuate neuronal loss and its neuroprotective efficacy is augmented by the concurrent hypothermic actions of the drug itself.

Breakfasts high in monoglyceride or triglyceride: no differential effect on appetite or energy intake.

OBJECTIVE: To test whether isoenergetic isoenergetically-dense doses of dietary 1-monoglyceride or triglyceride differentially influence appetite and meal-to-meal energy intake in man. DESIGN: Six men and six women were each studied twice in a 2 d protocol. On day 1 (maintenance day) they were fed a medium fat (MF) maintenance diet (MF: 40% fat, 47% carbohydrate and 13% protein by energy) calculated at 1.6 x resting metabolic rate (RMR). On day 2 (manipulation day) at 08.30 h subjects consumed a high-fat breakfast designed to contain 80-85% of RMR, composition 10% protein, 56% fat and 34% carbohydrate by energy, with 65% of energy for fat derived as either 1-monoglyceride or triglyceride. Food and energy intake were monitored at lunch (given at 12.30pm) and throughout the remainder of the day. During this time subjects had ad libitum access to isoenergetic, isoenergetically dense MF (40:47:13) foods (550kJ/100g), until 22.30pm). Subjective hunger and satiety were tracked hourly, during waking hours. RESULTS: There was no significant effect of fat type on food or energy intake at lunch or during the ad libitum period. There was no diet effect on subjective hunger (F(1,10)0.00; P= 0.975) in the inter-meal periods of morning or afternoon, nor during the whole day. Subjects found both diets to be similarly pleasant (F(1,61)0.84;P= 0.364). Men and women responded similarly, except that men ate more on all occasions than women. CONCLUSIONS: This study suggests that when a large dose of l-monoglyceride or triglyceride is incorporated into a breakfast meal, it behaves in a manner that is very similar to triglyceride in terms of the effects on hunger, appetite or feeding behaviour.

Reducing pain after inguinal hernia repair in children: caudal anesthesia versus ketorolac tromethamine.

BACKGROUND: The optimal method to achieve analgesia after inguinal hernia repair in children is unknown. This study compared the analgesic efficacy, adverse events, and the costs associated with supplementation of local anesthesia (infiltration of the wound) with either intravenous ketorolac or caudal analgesia in children having inguinal hernia repair. METHODS: With parental consent and institutional review board approval, children aged 2-6 yr having elective, outpatient inguinal hernia repair were studied in this randomized, single-blinded investigation. Anesthesia was induced by inhalation with nitrous oxide and halothane or intravenously with propofol. Anesthesia was maintained with nitrous oxide and halothane. Patients were randomly assigned to receive caudal analgesia (1 ml/kg 0.20% bupivacaine with 1/200,000 epinephrine) or intravenous ketorolac (1 mg/kg) immediately after induction of anesthesia. Both groups received field blocks with 0.25% bupivacaine administered by the surgeon under direct vision during operation. Patients were assessed for 24 h. In-hospital pain was assessed using a behavior-based pain score. Parents assessed pain with a visual linear analog pain scale with anchors of 0 (no pain) and 100 (worst pain imaginable). RESULTS: The authors studied 164 children, with 84 patients in the ketorolac group. The groups had similar demographic data. In-hospital analgesic requirements and pain scores were almost identical in both groups. Pain at home was significantly less in the ketorolac group, with visual linear analog pain scale scores of 10 (0-80) compared with 20 (0-80) (median [range]) for ketorolac versus caudal (P = 0.002 by the Mann-Whitney U test). The ketorolac group also had a lower incidence of vomiting, ambulated more rapidly, and micturated earlier (P < 0.05). CONCLUSION: The use of intravenous ketorolac to supplement local anesthesia infiltrated by the surgeon during pediatric inguinal hernia repair is superior to supplementation with caudal analgesia.

Influence of penicillin prophylaxis on antimicrobial resistance in nasopharyngeal S. pneumoniae among children with sickle cell anemia. The Ancillary Nasopharyngeal Culture Study of Prophylactic Penicillin Study II.

PURPOSE: To evaluate the consequences of prolonged prophylactic penicillin use on the rates of nasopharyngeal colonization with Streptococcus pneumoniae and the prevalence of resistant pneumococcal strains in children with sickle cell anemia. METHODS: Nasopharyngeal specimens were obtained from children with sickle cell anemia (Hb SS or Hb S beta degrees thalassemia) at 10 teaching hospitals throughout the United States. These patients were participating in a prospective, randomized, placebo-controlled trial in which they were prescribed prophylactic penicillin before their fifth birthday and were randomized to prophylactic penicillin or placebo after their fifth birthday (PROPS II). The specimens were cultured for S. pneumoniae, and isolates were analyzed for antimicrobial susceptibility to nine commonly prescribed antimicrobial agents. RESULTS: Of the 226 patients observed, an average of 8.4 specimens were collected per patient. From 1,896 individual culture specimens, 5.5% of the specimens were positive for S. pneumoniae; 27% of patients had at least one positive culture. Nine percent of the study patients had at least one isolate of penicillin intermediate or resistant pneumococci. There was no significant difference in the percent of positive cultures for S. pneumoniae in those patients given penicillin prophylaxis after 5 years of age (4.1%) compared with those patients given placebo after 5 years of age (6.4%). Likewise, there was no significant difference (p = 0.298) in the percent of patients with at least one positive culture for S. pneumoniae in the group given prophylactic penicillin after 5 years of age (21.8%) compared with the group given placebo after 5 years of age (28.3%). There was no difference between the penicillin and placebo groups in the proportion of patients with penicillin intermediate or resistant pneumococci, but there was a trend toward increased carriage of multiply drug-resistant pneumococci in children > 5 years of age receiving prophylactic penicillin compared to children > 5 years of age receiving placebo. The increased colonization rate with multiply drug-resistant organisms of children > 5 years of age receiving penicillin prophylaxis is not statistically significant. CONCLUSIONS: The potential for continued penicillin prophylaxis to contribute to the development of multiply resistant pneumococci should be considered before continuing penicillin prophylaxis in children with sickle cell anemia who are older than 5 years of age. Added to the published data from PROPS II, which demonstrated no apparent advantage to continue prophylaxis, the data support the conclusion that, for children with no history of invasive pneumococcal disease, consideration should be given to discontinue prophylactic penicillin after their fifth birthday.

Selenium content of Brazil nuts from two geographic locations in Brazil.

Brazil nuts (Bertholletia excelsa) natively contain very high concentrations of selenium. Since dietary selenium, including Brazil nuts, have been associated with protection against tumor development in laboratory animal studies, it was of interest to determine the selenium content of the nuts from different nut-growing regions of Brazil. In the work reported, 162 nuts from each of two regions (Acre-Rondonia and Manaus-Belem) were individually analyzed for selenium. The average +/- standard deviation and range of selenium concentrations in ppm, fresh weight for nuts from Acre-Rondonia and Manaus-Belem regions were, respectively, 3.06 +/- 4.01 (0.03-31.7) and 36.0 +/- 50.0 (1.25-512.0). The toxicology of Brazil nut consumption is discussed.

Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their combination.

Seventy-four patients with chronic stable mild angina, mild coronary artery disease (83% had one- or two-vessel disease) and normal left ventricular function were studied to measure the response of treadmill exercise performance and painful and silent ischemia in the ambulatory setting to randomly assigned treatment with nifedipine or propranolol and their combination; titration to maximal tolerated dosages was performed in double-blind manner. At 3 months both nifedipine and propranolol reduced the weekly angina rate (p less than 0.05); during treadmill exercise testing, increases (p less than 0.05) were noted in time to angina and total exercise time and decreases in maximal ST depression at the end of exercise. There were no differences between the responses to nifedipine and propranolol and no significant additional changes were seen after another 3 months of therapy. The combination of nifedipine and propranolol reduced the number of patients with angina on exercise treadmill testing from 64% to 38% (p less than 0.05). During ambulatory electrocardiographic monitoring before treatment, there were 1.4 +/- 2.4 (mean +/- SD) episodes/24 h of painful ischemia and a very low silent ischemia frequency: mean 1.1 +/- 2.7 episodes/24 h, mean duration 16 +/- 25 min/24 h. Treatment with propranolol and nifedipine resulted in reduction of episodes and duration of painful and painless ischemia; approximately 77% of patients were free of all ischemic episodes. It is concluded that patients with chronic stable mild angina have a low incidence of silent ischemia. Nifedipine or propranolol alone, titrated to individualized maximally tolerated dosages, are equally effective in long-term control of painful and painless ischemia, anginal episodes and exercise-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial experience of intra-operative red cell salvage.

The use of red cell saving machines is described in 16 cases of aortic reconstruction. There were 3 deaths in the series, all unrelated to use of the technique. Salvaged autologous blood accounted for 45% of red cell requirements. Biochemical and haematologic parameters were monitored before, during and after operation. When large volumes of blood are salvaged, the system becomes cost effective and the risks of homologous transfusion are reduced.