Significant inhibitory impact of dibenzyl trisulfide and extracts of Petiveria alliacea on the activities of major drug-metabolizing enzymes in vitro: An assessment of the potential for medicinal plant-drug interactions.

Dibenzyl trisulfide (DTS) is the major active ingredient expressed in Petiveria alliacea L., a shrub widely used for a range of conditions, such as, arthritis, asthma and cancer. Given its use alone and concomitantly with prescription medicines, we undertook to investigate its impact on the activities of important drug metabolizing enzymes, the cytochromes P450 (CYP), a key family of enzymes involved in many adverse drug reactions. DTS and seven standardized extracts from the plant were assessed for their impact on the activities of CYPs 1A2, 2C19, 2C9, 2D6 and 3A4 on a fluorometric assay. DTS revealed significant impact against the activities of CYPs 1A2, 2C19 and 3A4 with IC50 values of 1.9, 4.0 and 3.2µM, respectively, which are equivalent to known standard inhibitors of these enzymes (furafylline, and tranylcypromine), and the most potent interaction with CYP1A2 displayed irreversible enzyme kinetics. The root extract, drawn with 96% ethanol (containing 2.4% DTS), displayed IC50 values of 5.6, 3.9 and 4.2µg/mL respectively, against the same isoforms, CYPs 1A2, 2C19 and 3A4. These investigations identify DTS as a valuable CYP inhibitor and P. alliacea as a candidate plant worthy of clinical trials to confirm the conclusions that extracts yielding high DTS may lead to clinically relevant drug interactions, whilst extracts yielding low levels of DTS, such as aqueous extracts, are unlikely to cause adverse herb-drug interactions.

Facilitating the appropriate use of e-health solutions.

In this issue, the lead article proposes that e-health technologies should be used more broadly and that patients should have greater access to their information through such technologies. The Canadian Medical Protective Association (CMPA) agrees with this statement and suggests that to facilitate the timely and appropriate adoption of new technologies among healthcare providers to enhance patient care, barriers in the existing regulatory, legislative and legal frameworks must be addressed. While much of the discussion to date on e-health has focused primarily on high-level issues regarding regulatory compliance, "privacy by design" and the e-health "panacea," CMPA suggests that there needs to be a refocus on achieving more concrete change and gains through consideration of the specific impact on the drivers of healthcare delivery. An integrated or holistic approach is required involving healthcare providers, regulators, legislators, stakeholders, ministries of health, privacy commissioners and the courts. To better leverage potential advantages, efficiencies and enhanced, safer care for our healthcare system, all parties must work together to develop an acceptable and flexible approach to the "appropriate use" of e-health technologies that will facilitate adoption by healthcare professionals in a manner that is consistent with the expectations of the profession and applicable standards of practice.

Combined caffeine and bright light reduces dangerous driving in sleep-deprived healthy volunteers: a pilot cross-over randomised controlled trial.

AIM OF THE STUDY: To explore the effects of caffeine and bright light therapy on simulated nighttime driving in sleep-deprived healthy volunteers. PARTICIPANTS AND METHODS: Twelve male healthy volunteers aged 20 to 50 years participated in a randomized cross-over study of simulated nighttime driving at a sleep laboratory, followed by recovery sleep with polysomnography at home. The volunteers received variable combinations of caffeine 200mg (C+), caffeine placebo (C-), bright light 10,000 lux (L+), and bright light placebo<50 lux (L-), in four sessions (C+L+, C+L-, C-L+, C-L-), in random order with a wash-out period of 7 days. Treatments were given at 1 a.m. and testing was performed at 1:30 a.m., 3 a.m., 4 a.m., and 6 a.m. Lane drifting was the primary outcome measure. Other measures were reaction times, self-rated fatigue, sleepiness and recovery sleep. RESULTS: Without treatment, lane drifting increased throughout the night, and objective and subjective vigilance declined. Paired comparisons showed that lane drifting was significantly worse at 6 a.m. and at 4 a.m. than at 1:30 a.m. There was a global treatment effect on lane drifting. Lane drifting at 6 a.m. was significantly decreased with C+L+ compared to C-L-. CONCLUSIONS: Bright light therapy combined with caffeine administered at 1 a.m. decreased lane drifting by healthy volunteers during simulated nighttime driving.

Circadian rhythms, melatonin and depression.

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.

Systematic review of effectiveness of different treatments for childhood retinoblastoma.

OBJECTIVES: To assess the clinical effectiveness of treatments for childhood retinoblastoma. DATA SOURCES: Electronic databases were searched from inception to April 2004. REVIEW METHODS: Studies of participants diagnosed with childhood retinoblastoma, any interventions and all clinical outcomes were eligible for inclusion. Randomised and non-randomised controlled trials and cohort studies with clear comparisons between treatment groups were included. Methodological quality was assessed. A narrative synthesis was conducted. Where possible, studies assessing common interventions were grouped together, with prospective and retrospective studies grouped separately. Emphasis was placed on prospective studies. RESULTS: Thirty-one individual studies, from 42 publications, were included in the review. Apart from one non-randomised controlled trial, only comparative studies of observational design were available for any of the treatments. Four of the included studies were prospective and the remaining 27 were retrospective. Most of the studies were of radiotherapy or chemotherapy, with few studies available on enucleation or focal treatments such as brachytherapy, photocoagulation, cryotherapy and thermotherapy. The methodological quality was generally poor, with a high risk of bias in all included studies. The main problems were in relation to how treatment was allocated and lack of consideration of potentially confounding factors, such as initial disease severity, in the study design and data analysis. The evidence base for effectiveness of treatments for childhood retinoblastoma is extremely limited. Owing to the considerable limitations of the evidence identified, it was not possible to make meaningful and robust conclusions about the relative effectiveness of different treatment approaches for childhood retinoblastoma. CONCLUSIONS: In the authors' opinion, the evidence base for the effectiveness of treatments for childhood retinoblastoma is not sufficiently robust to provide clear guidance for clinical practice. Ideally, good-quality randomised controlled trials (RCTs) assessing the effectiveness of different treatment options for childhood retinoblastoma are required. Research is required on all the treatments currently used for this condition. Where RCTs are not feasible, for ethical or practical reasons, only high-quality, prospective, non-randomised studies should be given consideration, owing to the generally higher risk of bias in retrospective studies. To reduce the risk of confounding due to allocation by clinical indication, studies should compare patients with similar disease severity rather than compare patients of mixed disease severities. Standardised outcomes should be agreed for use in studies assessing the effectiveness of treatment. These outcomes should encompass potential important adverse effects of treatment such as loss of visual acuity and cosmetic outcome, as well as beneficial effects.

How do carers of disabled children cope? The Ugandan perspective.

BACKGROUND: Community-based rehabilitation (CBR) was recommended by the World Health Organization in 1989 as the strategy for improving the quality of life of disabled people and their families, which should be built on local knowledge and practices. In Uganda, there is no documentation on how services relate to local knowledge. There is a need for increased knowledge and understanding of how family members cope with their disabled children to provide the basis for future service development. METHODS: A qualitative phenomenological design was used to develop an in-depth understanding of how Ugandan families cope with their disabled children in their own communities. Data were collected from 52 families with children with disabilities from five impairment groups, through interviews and observations in three districts of Uganda, one urban, two rural. RESULTS: There are many children with disabilities who are included, loved and cared for by their families. A lot of time and money is spent on seeking a cure. The extended family systems are breaking down and the main burden of caring for a disabled family member generally falls on one, sometimes two, female carers. Male members act as gatekeepers, controlling the key decisions concerning the child and the associated resources. CONCLUSIONS: CBR should move the focus of their services away from the disabled individual towards the whole family. It is important to provide accurate information about causes and prevention of impairments, the realities of a cure, support and respite for the female carers, and opportunities for the involvement of fathers. This methodology is a practical mechanism for collecting data that have the potential to positively influence and guide the development of CBR practice in the locality. At a conceptual level the data support the philosophy of inclusion, social integration, the importance of trust and respect, and utilizing a holistic approach. These are eminently transferable to other settings.

Exclusion of grass roots from soil organic layers by Calluna: the role of ericoid mycorrhizas.

The role of ericoid mycorrhizal colonization in competition between the dwarf shrub Calluna vulgaris and coarse grass Nardus stricta was investigated. Nardus was grown alone, or in competition with Calluna, in a layered organic/sand substrate with and without inoculation with the ericoid mycorrhizal endophyte Hymenoscyphus ericae, and with and without the addition of nitrogen. Root length and allocation between different substrate layers was assessed along with plant biomass, nutrient uptake and mycorrhizal colonization. Calluna was the superior competitor for nutrients, probably because of its ability to concentrate root growth in the upper organic layer. In the presence of Calluna both the absolute amount and proportion of Nardus root length in the organic layer were reduced, and this reduction was greatest when Calluna was mycorrhizal. The presence of ericoid mycorrhizal colonization did not reduce Nardus shoot nutrient content or concentration, suggesting that ericoid mycorrhizal suppression of Nardus growth was not due to nutrient competition: alternative mechanisms of interference are discussed.

Zinc supplementation during lactation: effects on maternal status and milk zinc concentrations.

The effects of a zinc supplement on maternal zinc status and milk zinc concentrations through > or = 7 mo of lactation were examined. Seventy-one lactating women received either a daily 15-mg zinc supplement (ZS, n = 40) or placebo (NZS, n = 31) started by 2 wk postpartum in a double-blind, randomized design. Overall mean zinc intakes were 13.0 +/- 3.4 mg/d for the NZS group and 25.7 +/- 3.9 mg/d (including supplement) for the ZS group. Plasma zinc concentrations of the ZS group were significantly higher than those of the NZS group (P = 0.05). Milk zinc concentrations declined significantly over the course of the study for all subjects but were not affected by zinc supplementation. The mean dietary zinc intake observed in the nonsupplemented group was adequate to maintain normal maternal zinc status and milk zinc concentrations through > or = 7 mo lactation. Similar controlled intervention trials in less well-nourished populations will be required to assess the impact of lower zinc intakes on milk zinc concentrations.