Micronutrients: dietary intake v. supplement use

Whilst clinical deficiency of micronutrients is uncommon in the developed world, a suboptimal intake of certain micronutrients has been linked with an increased risk of chronic diseases such as CVD and cancer. Attention has therefore focused on increasing micronutrient status in order to theoretically reduce chronic disease risk. Increasing micronutrient status can involve a number of approaches: increasing dietary intake of micronutrient-rich foods; food fortification; use of supplements. Observational cohort studies have demonstrated an association between high intakes of micronutrients such as vitamin E, vitamin C, folic acid and beta-carotene, and lower risk of CHD, stroke and cancer at various sites. However, randomised intervention trials of micronutrient supplements have, to date, largely failed to show an improvement in clinical end points. The discordance between data from cohort studies and the results so far available from clinical trials remains to be explained. One reason may be that the complex mixture of micronutrients found, for example, in a diet high in fruit and vegetables may be more effective than large doses of a small number of micronutrients, and therefore that intervention studies that use single micronutrient supplements are unlikely to produce a lowering of disease risk. Studies concentrating on whole foods (e.g. fruit and vegetables) or diet pattern (e.g. Mediterranean diet pattern) may be more effective in demonstrating an effect on clinical end points. The present review will consider the clinical trial evidence for a beneficial effect of micronutrient supplements on health, and review the alternative approaches to the study of dietary intake of micronutrients.

INFLUENCE OF ULTRASOUND ON THE PERCUTANEOUS-ABSORPTION OF NICOTINATE ESTERS

The influence of ultrasound on the percutaneous absorption of three nicotinate esters was investigated in 10 healthy volunteers in a double-blind placebo controlled crossover clinical trial. Using a specially designed experimental protocol, the effect of continuous output ultrasound (at frequency 3.0 MHz and intensity 1.0 W/cm2 for 5 min) on the percutaneous absorption of methyl, ethyl, and hexyl nicotinates, from gel bases, was investigated. A placebo control, involving massage with each of the gels, without ultrasound for 5 min, was also incorporated. The pharmacodynamic parameter of vasodilation caused by the nicotinates was used to monitor the percutaneous absorption of the drugs. Laser Doppler velocimetry, a noninvasive optical technique, was used to measure vasodilation of the cutaneous vessels within the treatment site. Ultrasound treatment led to enhanced vasodilator response to the nicotinates, therefore indicating an enhancement of their percutaneous absorption. These agents may prove to be useful compounds in examination of the mechanism of action of phonophoresis.

PHONOPHORESIS OF METHYL NICOTINATE - A PRELIMINARY-STUDY TO ELUCIDATE THE MECHANISM OF ACTION

The skin penetration enhancement effect of ultrasound (phonophoresis) on methyl nicotinate was investigated in 10 healthy volunteers in a double-blind, placebo-controlled, crossover clinical trial. Each treatment consisted of the application of ultrasound massage (3.0 MHz, 1.0 W/cm2 continuous output) or placebo massage (0 MHz) for 5 min to the forearms of the volunteers, followed by a standardized application of methyl nicotinate at intervals of 15 sec, 1 min, and 2 min postmassage. Percutaneous absorption of methyl nicotinate was monitored using laser Doppler velocimetry. Ultrasound treatment applied prior to methyl nicotinate led to enhanced percutaneous absorption of the drug, for example, ultrasound treatment data versus control data at 2 min showed significant increases (P

Pharmaceutical care of patients with congestive heart failure: Interventions and outcomes

We evaluated a structured pharmaceutical care program for elderly patients (> 65 yrs) with congestive heart failure (CHF) based on objective measures of disease control, quality of life, and use of health care facilities in a randomized, controlled, longitudinal, prospective clinical trial. The 42 patients in group A received education from a pharmacist on the disease and its treatment, and lifestyle changes that could help control symptoms. Patients also were encouraged to monitor their symptoms and comply with prescribed drug therapy. If necessary, dosage regimens were simplified in liaison with hospital physicians. The 41 control patients (group B) received standard care. The following outcome measures were assessed in all patients at baseline (before the start of the trial) and at 3, 6, 9, and 12 months: 2-minute walk test, blood pressure, body weight, pulse, forced vital capacity, quality of life [disease-specific (Minnesota Living with Heart Failure questionnaire) and generic (SF-36)], knowledge of symptoms and drugs, compliance with therapy, and use of health care facilities (hospital admissions, visits to emergency room, emergency calls). Patients in group A showed improved compliance with drug therapy, which in turn improved their exercise capacity compared with those in group B; education on management of symptoms, lifestyle changes, and dietary recommendations were also of benefit. Group A patients significantly improved knowledge of their drug therapy over the 12-month study and had fewer hospital admissions compared with group B patients. They also had improved outcomes compared with group B, despite the small samples. An extension of this trial to other sites with pooling of results would provide additional evidence of the value of this structured program in elderly patients with CHF.

Carotenoids and co-antioxidants in age-related maculopathy:design and methods

Age-related macular degeneration (AMD), is the leading cause of blind registration in the Western World among individuals 65 years or older. Early AMD, a clinical state without overt functional loss, is said to be present clinically when yellowish deposits known as drusen and/or alterations of fundus pigmentation are seen in the macular retina. Although the etiopathogenesis of AMD remains uncertain, there is a growing body of evidence in support of the view that cumulative oxidative damage plays a causal role. Appropriate dietary antioxidant supplementation is likely to be beneficial in maintaining visual function in patients with AMD, and preventing or delaying the progression of early AMD to late AMD. The Carotenoids in Age-Related Maculopathy (CARMA) Study is a randomized and double-masked clinical trial of antioxidant supplementation versus placebo in 433 participants with either early AMD features of sufficient severity in at least one eye or any level of AMD in one eye with late AMD (neovascular AMD or central geographic atrophy) in the fellow eye. The aim of the CARMA Study is to investigate whether lutein and zeaxanthin, in combination with co-antioxidants (vitamin C, E, and zinc), has a beneficial effect on visual function and/or prevention of progression from early to late stages of disease. The primary outcome is improved or preserved distance visual acuity at 12 months. Secondary outcomes include improved or preserved interferometric acuity, contrast sensitivity, shape discrimination ability, and change in AMD severity as monitored by fundus photography. This article outlines the CARMA Study design and methodology, including its rationale.

AMD and micronutrient antioxidants

Age-related maculopathy (ARM) is a common clinical entity. The late-stage manifestations of ARM, which are known as age-related macular degeneration (AMD), have devastating consequences for vision. Various risk factors have been identified in the development of the condition, which are consistent with the premise that oxidative stress plays an important role in its pathogenesis. Thus, the possibility that antioxidant balance can be manipulated through diet or supplementation has created much interest. Associations between diet and nutrition and the clinical features of ARM have been described. Scrutiny of the literature shows consistency in the report of notable reductions in serum micronutrients in wet AMD, however, the evidence for causation is still circumstantial. In this comprehensive review of the clinical literature, we have assessed the evidence for a link between diet and nutrition as risk factors for the development of ARM and AMD. All published case control, population-based, and interventional studies on ARM were examined. Although initial support appeared to be moderate and somewhat contradictory, the evidence that lifetime oxidative stress plays an important role in the development of ARM is now compelling. The positive outcomes in the Age-Related Eye Diseases Study, a major controlled clinical trial, have given hope that modulation of the antioxidant balance through supplementation can help prevent progression of ARM to AMD.

Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects

Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 mu g folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid-fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 mu g folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 mu g/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 mu g/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.

The Utility of Fractional Exhaled Nitric Oxide Suppression in the Identification of Nonadherence in Difficult Asthma

Rationale: Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain. Objectives: Identify a test for nonadherence using fractional exhaled nitric oxide (FENO) suppression after directly observed inhaled corticosteroid (DOICS) treatment. Methods: Difficult asthma patients with an elevated FENO (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 µg) and a test for nonadherence based on changes in FENO was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview. Measurements and Main Results: After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in FENO to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a FENO test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68-1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab. Conclusions: FENO suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 01219036). Copyright © 2012 by the American Thoracic Society.

Comparison of serum and whole-blood specimens for the detection of Candida DNA in critically ill, non-neutropenic patients

In contrast to the multitude of studies on fungal PCR assay methods, little work has been reported evaluating Candida PCR performance when using whole blood compared with serum in candidaemic patients. Here, a comparison of the performance of whole-blood and serum specimens using a set of real-time PCR Candida species assays is described. Specimens were collected prospectively from non-neutropenic adults who were recruited to a diagnostic clinical trial, the primary purpose of which was to verify the performance of the assays using serum; in all, 104 participants also had whole-blood specimens submitted for analysis in addition to the serum specimen. Of these participants, 10 had laboratory-confirmed candidaemia and 94 were categorized as being 'unlikely' to have invasive Candida infection. PCR results from the whole-blood specimens are presented here and compared with the results from serum specimens in this subgroup among whom both specimen types were obtained contemporaneously. All participants with candidaemia were PCR-positive from serum samples; however, only seven were PCR-positive from whole blood. All specimens from patients in the 'unlikely' category were PCR-negative in both types of specimen. Moreover, DNA extraction from serum required 1 h; extraction from whole blood required approximately 3 h. These data tentatively suggest that, overall, serum is an appropriate specimen for Candida PCR for detection of candidaemia in non-neutropenic adults.

High-volume haemofiltration for sepsis.

Background: Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU.

Objectives: This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites.

Selection criteria: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units.

Data collection and analysis: Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists.

Main results: We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias.

Authors' conclusions: There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi-centred and have clinically relevant outcome measures. Financial implications should also be assessed.

Pneumonia and lower respiratory infections in nursing home residents:Predictors of hospitalization and mortality

OBJECTIVES: To compare predictors of hospitalization and death in nursing home residents with pneumonia and other lower respiratory infections (LRIs). DESIGN: A nested cohort study. SETTING: Nine nursing homes in southern Ontario. PARTICIPANTS: Three hundred fifty-three nursing home residents with LRIs (enrolled in the control arm of a clinical trial). MEASUREMENTS: Comorbidities, vaccination status, age, health-related quality of life, functional status, and vital statistics were evaluated as potential predictors of hospitalization and mortality at 30 days. RESULTS: Moderate to high disease severity score on a practical severity scale was a strong independent predictor of hospitalization (odds ratio (OR)=7.12, P

Encouraging lifestyle behaviour change in mild cognitive impairment patients:development of appropriate educational material

Objectives: A healthy lifestyle may help maintain cognitive function and reduce the risk of developing dementia. This study employed a focus group approach in order to gain insight into opinions of mild cognitive impairment (MCI) patients, caregivers (CG) and health professionals (HP) regarding lifestyle and its relationship with cognition. The qualitative data were used to design, develop and pilot test educational material (EM) to help encourage lifestyle behaviour change. Method: Data gathering phase: structured interviews were conducted with HP (n = 10), and focus groups with MCI patients (n = 24) and CG (n = 12). EM was developed and pilot tested with a new group of MCI patients (n = 21) and CG (n = 6). Results: HP alluded to the lack of clinical trial evidence for a lifestyle and MCI risk link. Although they felt that lifestyle modifications should be recommended to MCI patients, they appeared hesitant in communicating this information and discussions were often patient-driven. MCI patients lacked awareness of the lifestyle cognition link. Participants preferred EM to be concise, eye-catching and in written format, with personal delivery of information favoured. Most pilot testers approved of the EM but were heterogeneous in terms of lifestyle, willingness to change and support needed to change. Conclusion: MCI patients need to be made more aware of the importance of lifestyle for cognition. EM such as those developed here, which are specifically tailored for this population would be valuable for HP who, currently, appear reticent in initiating lifestyle-related discussions. Following further evaluation, the EM could be used in health promotion activities targeting MCI patients.

Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss

PURPOSE: To describe fundus autofluorescence (AF) patterns and their change over time in patients with age-related macular degeneration (AMD) and high risk of visual loss participating in the drusen laser study (DLS). DESIGN: Randomized clinical trial. METHODS: The study population consisted of 29 patients (35 eyes) participating in the DLS, which is a prospective, randomized, controlled clinical trial of prophylactic laser therapy in patients with AMD and high risk of neovascular complications. The intervention consisted of 16 eyes having prophylactic laser and 19 receiving no treatment. The main outcome measures were changes in the distribution of drusen and AF. Patients were reviewed for a median follow-up or 24 months (range 12-36 months). RESULTS: At baseline, four patterns of fundus AF were recognized: focal increased AF (n = 18), reticular AF (n = 3), combined focal and reticular AF (n = 2), and homogeneous AF (n = 12). At last follow-up, fundus AF remained unchanged in 15 untreated (78%) and in seven treated (43%) eyes. In only one untreated eye, focal areas of increased AF returned to background levels and were no longer detectable at last follow-up, compared with six treated eyes. This difference was statistically significant (P = .03). Only large foveal soft drusen (drusenoid pigment epithelium detachments) consistently corresponded with focal changes in AF, whereas no obvious correspondence was found between small soft drusen located elsewhere and changes in AF. CONCLUSION: The lack of obvious correspondence between the distribution of drusen and of AF found in this study appears to indicate that drusen and AF represent independent measures of aging in the posterior pole. © 2002 Elsevier Science Inc. All rights reserved.

Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy

Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis [1,2], EGFR targeted therapies have achieved limited clinical efficacy [3]. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction [4,5]. A directed RNAi screen revealed that glioblastoma cells overexpressing EGFRvIII [6], an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII overexpression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyperactivation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

Oral prednisone in guarded filtration procedures supplemented with antimetabolites

BACKGROUND AND OBJECTIVE: To evaluate whether a three-day course of oral prednisone perioperatively improves the surgical outcome of guarded filtering procedures supplemented with antifibrosis agents. DESIGN, MATERIALS AND METHODS: A prospective, randomized, double-masked, placebo-controlled, clinical trial was designed. Adult patients with non-inflammatory glaucoma undergoing a guarded filtration procedure supplemented with antimetabolite were enrolled. Patients received a three-day course of prednisone (50 mg BID) or placebo perioperatively. The main outcome measures were intraocular pressure (IOP) and number of antiglaucoma medications. Surgical success was defined before data collection according to two different criteria: 'success- I': IOP level = 15 mmHg with no more than one anti-glaucoma medication, and 'success-II': IOP reduction of at least 20% of baseline level with no more than one antiglaucoma medication. RESULTS: Thirty-five subjects were enrolled. Seventeen patients were treated with prednisone and eighteen with placebo. Mean follow-up was 9.2 months ± 6.2 months. The probability of success-I at 9 months was 63.0% in the study group and 65.6% in the control groups (p>0.05). The probability of success-II at 9 months was 60.2% in the study group and 55.0% in the control groups, (p>0.05). The difference in frequency of postoperative complications between groups was not statistically significant. The most common complication was choroidal detachment (n=2) in the prednisone-treated group and bleb leak (n=2) in the control group. CONCLUSION: The perioperative use of oral prednisone did not alter the surgical outcome of filtering procedures associated with antifibrosis agents in this population of glaucoma patients.