Time to Diagnosis and Treatment with Palliative Radiotherapy among Inuit Patients with Cancer from the Arctic Territory of Nunavut, Canada.

AIMS: The cancer burden among Circumpolar Inuit is high. Palliative radiotherapy is a mainstay treatment for controlling symptoms of advanced cancers, but Inuit are required to travel far distances to access this service. Access to palliative radiotherapy and time away from home communities have not been explored among this population. We sought to describe the time intervals from symptom onset to the start of palliative radiotherapy among Canadian Inuit patients treated at The Ottawa Hospital (TOH). MATERIALS AND METHODS: A retrospective review of Inuit patients from Nunavut treated with radiotherapy between 2005 and 2014 at TOH. RESULTS: Of a total of 152 radiotherapy patients, 88 (58%) were treated palliatively. Of these, 61 (70%) had stage IV disease at diagnosis and 63 (72%) had lung cancer. The median time from referral for specialist care to the patient's first flight to Ottawa was 4 days (range 0-97). The median length of treatment was 7 days (range 0-27), but patients spent a median of 64.5 days (range 14-633) in Ottawa. The median survival from the date of pathological diagnosis was 5.2 months. CONCLUSIONS: Most Inuit radiotherapy patients at TOH were treated palliatively. Patients were brought from Nunavut relatively quickly for specialist care, which is encouraging. However, patients spent over 2 months away from home, in the context of a median survival of less than 6 months. Opportunities for improvement include both provider and system-level changes, which may be applicable to other Circumpolar Inuit regions across Europe and North America.

An integrated knowledge translation approach to develop a shared decision-making strategy for use by Inuit in cancer care: a qualitative study.

Background: In relation to the general Canadian population, Inuit face increased cancer risks and barriers to health services use. In shared decision-making (sdm), health care providers and patients make health care decisions together. Enhanced participation in cancer care decisions is a need for Inuit. Integrated knowledge translation (kt) supports the development of research evidence that is likely to be patient-centred and applied in practice. Objective: Using an integrated kt approach, we set out to promote the use of sdm by Inuit in cancer care. Methods: An integrated kt study involving researchers with a Steering Committee of cancer care system partners who support Inuit in cancer care ("the team") consisted of 2 theory-driven phases:■ using consensus-building methods to tailor a previously developed sdm strategy and developing training in the sdm strategy; and■ training community support workers (csws) in the sdm strategy and testing the sdm strategy with community members. Results: The team developed a sdm strategy that included a workshop and a booklet with 6 questions for use by csws with patients. The sdm strategy (training and booklet) was finalized based on feedback from 5 urban-based Inuit csws who were recruited and trained in using the strategy. Trained csws were matched with 8 community members, and use of the sdm strategy was assessed during interviews, reported as 6 themes. Participants found the sdm strategy to be useful and feasible for use. Conclusions: An integrated kt approach of structured research processes with partners developed a sdm strategy for use by Inuit in cancer care. Further work is needed to test the sdm strategy.

Changes in the vesicular zinc pattern following traumatic brain injury.

The present study aims at evaluating the significance of zinc ions on the development of brain damage in a model of traumatic brain injury (TBI). The zinc ion specific autometallographic technique, the ZnSe(AMG) method, using silver enhancement of in vivo-captured zinc ions bound in zinc-selenium nanocrystals was applied to follow changes in the vesicular zinc pattern. Balb/c mice, ZnT3 knockout (ZnT3-Ko) mice, a mouse genetically knocked out for the protein ZnT3 responsible for sequestering zinc into synaptic vesicles, and littermates from the genetically un-manipulated mother type mice, wild type (Wt), were used. The Wt and the Balb/c mice exhibited instantaneously a boost in the zinc staining adjacent to the lesion involving all six neocortical layers. Ultra-structural analyses revealed that the in vivo created ZnSe nanocrystals were still confined to the vesicles of the zinc-enriched (ZEN) neurons in the neuropil. No differences between the Balb/c and Wt mice were seen at any time points. In the ZnT3-Ko mice the ZEN terminals stayed void of AMG grains, but a number of neuronal somata around the lesion became loaded with ZnSe nanocrystals. These silver-enhanced ZnSe nanocrystals were confined to the cytoplasm of the somata and their proximal dendrites. No such soma staining was seen in the Wt or Balb/c mice. We speculate that vesicular zinc may not contribute to neuronal damage following TBI.

Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency.

The ZnT3 zinc transporter is uniquely expressed in cortical glutamatergic synapses where it organizes zinc release into the synaptic cleft and mediates beta-amyloid deposition in transgenic mice. We studied the association of zinc in plaques in relation to cytoarchitectural zinc localization in the APP/PS1 transgenic mouse model of Alzheimer's disease. The effects of low dietary zinc for 3 months upon brain pathology were also studied. We determined that synaptic zinc distribution within cortical layers is paralleled by amyloid burden, which is heaviest for both in layers 2-3 and 5. ZnT3 immunoreactivity is prominent in dystrophic neurites within amyloid plaques. Low dietary zinc caused a significant 25% increase in total plaque volume in Alzheimer's mice using stereological measures. The level of oxidized proteins in brain tissue did not changed in animals on a zinc-deficient diet compared with controls. No obvious changes were observed in the autometallographic pattern of zinc-enriched terminals in the neocortex or in the expression levels of zinc transporters, zinc importers or metallothioneins. A small decrease in plasma zinc induced by the low-zinc diet was consistent with the subclinical zinc deficiency that is common in older human populations. While the mechanism remains uncertain, our findings indicate that subclinical zinc deficiency may be a risk factor for Alzheimer's pathology.

Autometallographic tracing of quantum dots.

A short clarifying view of how semiconductor quantum dots (QDs) can be made visible in tissue sections by autometallographic (AMG) silver enhancement and how the introduction of AMG enhanceable gold nanoparticles into isolated cells can be used to follow the fate of these marked cells in organisms and cell cultures. As the AMG approach for visualizing quantum dots is extremely sensitive, QDs less than one nanometer can be made visible at both LM and EM levels.

Zinc ions in the endocrine and exocrine pancreas of zinc deficient rats.

OBJECTIVE: Zinc deficiency is a problem world-wide. Zinc and insulin are intimately related, and a reduced zinc intake may affect glucose metabolism. The present study investigates how subclinical zinc deficiency in rats affects glucose metabolism and zinc distribution in the pancreas. METHODS: Glucose metabolism was evaluated by blood-glucose, serum insulin, homeostasis model assessment (HOMA), and intraperitoneal glucose tolerance tests. Immersion zinc-sulphide autometallography (iZnSAMG) was used to describe zinc ion distribution. RESULTS: After 4 weeks on a zinc deficient diet (<10 ppm), the zinc deficient rats had a slightly impaired glucose metabolism characterized by significantly increased blood-glucose levels. No differences in serum insulin, insulin resistance, beta-cell function were observed. The zinc deficient rats had significantly decreased serum zinc without any clinical signs of zinc deficiency. Zinc ion staining intensity of the islets of Langerhans was unaffected by the zinc deficiency. In contrast, the acinar cells in the exocrine pancreas appeared depleted of iZnSAMG grains in the zinc deficient rats when compared with their controls. Though statistically non-significant, a reduction in total zinc of the pancreas was found. CONCLUSIONS: The present findings suggest that the endocrine pancreas is able to compensate for the subclinical zinc deficiency as it maintains an adequate zinc ion level in the secretory vesicles for insulin storage. The exocrine pancreas lacks this ability; it exhibits decreased levels of zinc ion staining as a consequence of 4 weeks of reduced zinc intake.

Immersion autometallographic tracing of zinc ions in Alzheimer beta-amyloid plaques.

An easy to perform autometallographic technique (AMG) for capturing zinc ions in Alzheimer plaques is presented. The possibility of visualizing loosely bound or free zinc ions in tissue by immersion autometallography (iZnS(AMG)) is a relatively recent development. The iZnS(AMG) staining is caused by zinc-sulphur nanocrystals created in 1-2 mm thick brain slices that are immersed in a 0.1% sodium sulphide, 3% glutaraldehyde phosphate buffered solution, the NeoTimm Solution (NTS), for 3 days. When the zinc-sulphur nanocrystals are subsequently silver-enhanced by autometallography, the plaques are readily identified as spheres of dark interlacing strands of different sizes, embedded in the pattern of zinc-enriched terminals. The zinc specificity of the iZnS(AMG) technique was tested by immersion of brain slides in the chelator DEDTC prior to the NTS immersion. The iZnS(AMG) detection of zinc ions is easily standardized and can be used in the quantification of plaques with stereological methods. This technique is the first to detect zinc in plaques in the cerebellum of transgenic PS1/APP mice and the first to detect zinc ions in plaques and dystrophic neurites at electron microscopical levels.

FDA labeling system for drugs in pregnancy.

OBJECTIVE: To review the current Food and Drug Administration (FDA) pregnancy labeling system, examine the new FDA-proposed pregnancy labeling system for form and content, and provide comments on its suitability for implementation. DATA SOURCES: Data were obtained from the FDA's Web site (www.fda.gov), PubMed, Federal Register, LexisNexis, Physician's Desk Reference (PDR), Drugdex, and Current Contents. STUDY SELECTION: Research and articles involving drugs and pregnancy, drugs and lactation, and the subcommittee meeting of the FDA were included. DATA EXTRACTION: Prospective, case-control studies from pregnancy registries. DATA SYNTHESIS: Currently, only 40% of drugs in the PDR have pregnancy categories listed. The medical profession has resorted to other means to assess pregnancy risk, such as retrospective chart review, case reports, and consultation with experts such as regional drug information centers. CONCLUSIONS: The proposed pregnancy labeling system strives for more clinical usefulness by reliance on human data derived from pregnancy registries. The clinical usefulness of the new labeling remains to be seen.

Effect of common over-the-counter medications on blood alcohol levels.

OBJECTIVE: To assess the clinical and legal significance of the potential pharmacokinetic interaction between common over-the-counter (OTC) medications and alcohol that may result in increased blood alcohol levels (BALs). DATA SOURCES: A MEDLINE search (1966-February 2000) of English-language articles was performed using the terms aspirin, acetaminophen, histamine (H2)-receptor antagonist, ethanol, and blood alcohol level and then supplemented by a bibliographic review of relevant articles. STUDY SELECTION AND DATA EXTRACTION: Two H2-receptor antagonist studies using methodologies representative of other published trials and a meta-analysis of 24 H2-receptor antagonist trials were chosen for detailed review. All identified studies examining aspirin and acetaminophen were addressed. DATA SYNTHESIS: More than 30 studies have examined the potential interaction between OTC drugs and blood alcohol. Because this issue has important medical and legal implications for patients, prescribing physicians, and pharmaceutical manufacturers, a critical analysis of the literature addressing this potential interaction is presented. CONCLUSIONS: Numerous factors arguing against a clinically significant interaction were identified. First, data from the relevant studies cannot be extrapolated to the general population because of the multitude of variables that determine an individual's BAL. Also, a publication bias for small studies (< or = 10 subjects) finding a statistically significant increase in peak BAL was observed. In addition, study results supporting an increase in BAL were often irreproducible when these trials were repeated under similar conditions. Finally, although some studies detected statistically significant increases in peak BAL, these changes were often clinically irrelevant.

GHB: an important pharmacologic and clinical update.

Gamma-hydroxybutyrate (GHB) intoxication is a significant cause of morbidity and mortality in patients taking the drug for recreational purposes. Due to the recent increase in emergency room visits, hospital admissions, and deaths, it has become necessary to re-examine the pharmacology, pharmacokinetics, pharmacodynamics, clinical manifestations, and potential adverse effects associated with GHB use. We present an important pharmacologic and clinical update on GHB.

Discontinuation rates of Helicobacter pylori treatment regimens: a meta-analysis.

We conducted a meta-analysis to determine what factors in treatment regimens for Helicobacter pylori are associated with increased discontinuation rates. Studies were selected from the 1990-1996 MEDLINE data base, and references in published articles and reviews were obtained. Each article was uniformally abstracted for factors that could potentially affect dropout rates. Drug regimens with high numbers of doses per day had highest dropout rates (p=0.0001). The total dropout rate was lowest for regimens containing a proton pump inhibitor (OR = 0.75, CI 0.57, 0.98). The rate was high in regimens containing a bismuth compound due to side effects (OR = 2.79, CI 1.78, 4.36). The main finding was that drug regimens for eradication of H. pylori that have a high number of doses per day result in higher discontinuation rates than regimens with fewer doses per day.

Optimal management of amiodarone therapy: efficacy and side effects.

OBJECTIVES: To review management and dosing guidelines for amiodarone therapy, and discuss the drug's adverse event profile. METHODS: Review of relevant studies and reports. RESULTS: Amiodarone is a highly effective antiarrhythmic drug, but is associated with adverse effects involving several organs. Amiodarone-induced arrhythmia is rare, with frequency of 0.3% in one study. Pulmonary toxicity is the most serious noncardiac side effect (2-17% of patients). Hypersensitivity pneumonitis can appear early in the course of therapy. Interstitial pneumonitis is a more common but insidious pulmonary reaction characterized by cough, low-grade fever, and dyspnea that occurs after months or years of therapy. Clinically important hypothyroidism and hyperthyroidism occur in 2-10% of patients. Optic neuritis or neuropathy in which patients experience decreased or blurred vision may progress to permanent blindness. Abnormalities in liver function tests, especially elevated aminotransferase and alkaline phosphatase levels, are seen in 4-25% of patients. Neurologic side effects were reported in 20-40% of patients, at times associated with tremor, ataxia, peripheral neuropathy, malaise or fatigue, sleep disturbances, dizziness, and headaches. Several types of dermatologic reactions have been reported, including allergic rash, photosensitivity, and blue-gray skin discoloration. The best strategy for early detection of pulmonary toxicity is vigilant clinical follow-up with monitoring of cardiac status and liver and thyroid function, and prescription of the lowest effective dosage. After an initial loading dose, 200 mg/day in many patients maintains arrhythmia control and minimizes the frequency of side effects. CONCLUSION: Amiodarone is a safe and efficacious antiarrhythmic agent when lower dosages are given to patients who are closely monitored and subject to careful follow-up.

Physicians' perceptions and knowledge of drug costs: results of a survey.

The objective of this survey was to determine physicians' opinions of the importance of drug costs, sources of drug cost information used, preferences for mechanisms to lower drug costs, and to assess knowledge of the relative cost of common drugs. A questionnaire containing opinion statements and five categories of drugs to be ranked from least to most expensive was sent to 598 physicians at our tertiary-care, university-affiliated teaching hospital. In all, 398 (66.6%) surveys were completed. Survey results indicate that physicians are interested in lowering the cost of drug therapy, and that they are knowledgeable of relative drug costs but would like more cost information to make more informed prescribing decisions. Most believe that a readily available drug cost index is the most beneficial mechanism to decrease drug expenditures.

Use of nifedipine in the hypertensive diseases of pregnancy.

OBJECTIVE: To review the available data about the use of nifedipine to treat hypertension in pregnancy. DATA SOURCES: All English language cases and studies published after 1984 and indexed in MEDLINE, Excerpta Medica, and BIOSIS PREVIEWS under the headings nifedipine, hypertension in pregnancy, uteroplacental blood flow, maternal/fetal hemodynamics, preeclampsia, and pregnancy outcome. MAIN OUTCOME MEASURES: The primary outcome indicators included the safety and antihypertensive efficacy of nifedipine in pregnancy; the effects of nifedipine on maternal/fetal hemodynamics; and the effect, if any, of nifedipine on perinatal outcome. CONCLUSIONS: Tradiational drug therapy choices for hypertension in pregnancy continue to be hydralazine for acute reduction of blood pressure and methyldopa for the management of chronic hypertension. Current data indicate that nifedipine is an appropriate second-line antihypertensive medication in pregnancy, but more clinical trials are needed before it can be considered an appropriate choice for initial therapy. As do other antihypertensive agents, nifedipine provides maternal benefit by lowering blood pressure and reducing the risk of cerebral hemorrhage and end-organ damage. However, perinatal benefit of nifedipine remains to be established.

Efficacy of nutritional supplements used by athletes.

Findings on the efficacy of nutritional supplements used by athletes are reviewed. Many athletes have turned away from anabolic steroids and toward nutritional supplements in the hope of gaining a competitive edge without threatening their health. Athletes may require slightly more protein than sedentary people do to maintain positive nitrogen balance, but it is dubious whether extra dietary protein will help someone to achieve athletic goals. Purified amino acids have become a popular if expensive form of protein supplementation; there is no scientific evidence, however, to support their use. Excessive protein supplementation can lead to dehydration, gout, liver and kidney damage, calcium loss, and gastrointestinal effects. Supplementation with vitamins and minerals in excess of recommended daily allowances appears to have no effect on muscle mass or athletic performance. Other substances touted as having ergogenic properties are carnitine, cobamamide, growth hormone releasers, octacosanol, and ginseng; again, there is no reliable scientific evidence to support claims that products containing these compounds have ergogenic potential, and heavy supplementation may lead to adverse effects. Nutritional supplements are promoted through unsubstantiated claims by magazine advertisements, health food stores, coaches, and other sources. The FDA considers nutritional supplements to be foodstuffs, not drugs, and therefore has not required that they be proved safe and effective. Dosage guidelines are inadequate, and quality control is poor. The FDA has begun to revise regulations governing labeling and health claims for these products. There is little if any evidence that nutritional supplements have ergogenic effects in athletes consuming a balanced diet, and some products have the potential for harm.

Drug-food interaction counseling programs in teaching hospitals.

The results of a survey to characterize drug-food interaction counseling programs in teaching hospitals and solicit opinions on these programs from pharmacists and dietitians are reported. A questionnaire was mailed to the pharmacy director and the director of dietary services at teaching hospitals nationwide. The questionnaire contained 33 questions relating to hospital characteristics, drug-food interaction counseling programs, and the standard calling for such programs issued by the Joint Commission on Accreditation of Healthcare Organizations. Of 792 questionnaires mailed, 425 were returned (response rate, 53.7). A majority of the pharmacists and dietitians (51.2%) did not consider their drug-food interaction counseling program to be formal; some had no program. The pharmacy department was involved more in program development than in the daily operation of such programs. The most frequent methods of identifying patients for counseling were using lists of patients' drugs and using physicians' orders. A mean of only five drugs were targeted per program. Slightly over half the respondents rated the Joint Commission standard less effective than other standards in its ability to improve patient care. A majority of teaching hospitals did not have formal drug-food interaction counseling programs. Pharmacists and dietitians did not view these programs as greatly beneficial and did not believe that the Joint Commission has clearly delineated the requirements for meeting its standard.