Drug consumption and futile medication prescribing in the last year of life: an observational study.

Background: the last year of life for many older people is associated with high symptom burden and frequent hospitalizations. Hospital physicians have an opportunity to prioritize essential medications and deprescribe potentially futile medications. Objective: to measure medication consumption during hospitalization in the last year of life and the prevalence of potentially inappropriate medications (PIMs) at hospital discharge. Design: retrospective chart review. Setting: acute hospital. Subjects: ≥65 years, hospitalized in the last year of life. Methods: medication consumption was determined by examining hospital Medication Administration Records. PIMs were defined using STOPPFrail deprescribing criteria. Results: the study included 410 patients. The mean age of participants was 80.8, 49.3% were female, and 63.7% were severely frail. The median number of days spent in hospital in the last year of life was 32 (interquartile range 15-59). During all hospitalizations, the mean number of individual medications consumed was 23.8 (standard deviation 10.1). One-in-six patients consumed 35 or more medications in their last year. Over 80% of patients were prescribed at least one PIM at discharge and 33% had ≥3 PIMs. Lipid-lowering medications, proton pump inhibitors, anti-psychotics and calcium supplements accounted for 59% of all PIMs. Full implementation of STOPPFrail recommendations would have resulted in one-in-four long-term medications being discontinued. Conclusion: high levels of medication consumption in the last year of life not only reflect high symptom burden experienced by patients but also continued prescribing of futile medications. Physicians assisted by the STOPPFrail tool can reduce medication burden for older people approaching end of life.

Instrument-assisted soft tissue mobilization: effects on the properties of human plantar flexors.

The effect of instrument-assisted soft tissue mobilization (ISTM) on passive properties and inflammation in human skeletal muscle has not been evaluated. Passive properties of muscle, inflammatory myokines and subjective reporting of functional ability were used to identify the effects of ISTM on the plantar flexors. 11 healthy men were measured for passive musculotendinous stiffness (MTS), passive range of motion (PROM), passive resistive torque (PASTQ) and maximum voluntary contraction peak torque (MVCPT) for plantar flexor muscles of the lower leg. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured from muscle biopsies from the gastrocnemius, and subjective measurements of functional ability were taken using the perception of functional ability questionnaire (PFAQ). MTS, PROM, PRT and MVCPT were measured in the treatment leg (TL) and control leg (CL) before, immediately after, 24 h, 48 h and 72 h following IASTM. Biopsies for IL-6 and TNF-α and PFAQ responses were collected before as well as 24 h, 48 h and 72 h after IASTM. There were no significant differences in MTS, PROM, PASTQ, MVCPT, IL-6 and TNF-α between the TL or CL. A significant decrease in the perception of function and a significant increase in pain for the TL were found following IASTM.

START (screening tool to alert doctors to the right treatment)--an evidence-based screening tool to detect prescribing omissions in elderly patients.

BACKGROUND: Inappropriate prescribing encompasses acts of commission i.e. giving drugs that are contraindicated or unsuitable, and acts of omission i.e. failure to prescribe drugs when indicated due to ignorance of evidence base or other irrational basis e.g. ageism. There are considerable published data on the prevalence of inappropriate prescribing; however, there are no recent published data on the prevalence of acts of omission. The aim of this study was to calculate the prevalence of acts of prescribing omission in a population of consecutively hospitalised elderly people. METHODS: A screening tool (screening tool to alert doctors to the right treatment acronym, START), devised from evidence-based prescribing indicators and arranged according to physiological systems was prepared and validated for identifying prescribing omissions in older adults. Data on active medical problems and prescribed medicines were collected in 600 consecutive elderly patients admitted from the community with acute illness to a teaching hospital. On identification of an omitted medication, the patient's medical records were studied to look for a valid reason for the prescribing omission. RESULTS: Using the START list, we found one or more prescribing omissions in 57.9% of patients. In order of prevalence, the most common prescribing omissions were: statins in atherosclerotic disease (26%), warfarin in chronic atrial fibrillation (9.5%), anti-platelet therapy in arterial disease (7.3%) and calcium/vitamin D supplementation in symptomatic osteoporosis (6%). CONCLUSION: Failure to prescribe appropriate medicines is a highly prevalent problem among older people presenting to hospital with acute illness. A validated screening tool (START) is one method of systematically identifying appropriate omitted medicines in clinical practice.

Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential.

Bipolar affective disorder is often poorly controlled by prescribed drugs. Cannabis use is common in patients with this disorder and anecdotal reports suggest that some patients take it to alleviate symptoms of both mania and depression. We undertook a literature review of cannabis use by patients with bipolar disorder and of the neuropharmacological properties of cannabinoids suggesting possible therapeutic effects in this condition. No systematic studies of cannabinoids in bipolar disorder were found to exist, although some patients claim that cannabis relieves symptoms of mania and/or depression. The cannabinoids Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) may exert sedative, hypnotic, anxiolytic, antidepressant, antipsychotic and anticonvulsant effects. Pure synthetic cannabinoids, such as dronabinol and nabilone and specific plant extracts containing THC, CBD, or a mixture of the two in known concentrations, are available and can be delivered sublingually. Controlled trials of these cannabinoids as adjunctive medication in bipolar disorder are now indicated.

Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3.

Potassium leak conductances were recently revealed to exist as independent molecular entities. Here, the genomic structure, cardiac localization, and biophysical properties of a murine example are considered. Kcnk3 subunits have two pore-forming P domains and unique functional attributes. At steady state, Kcnk3 channels behave like open, potassium-selective, transmembrane holes that are inhibited by physiological levels of proton. With voltage steps, Kcnk3 channels open and close in two phases, one appears to be immediate and one is time-dependent (tau = approximately 5 ms). Both proton block and gating are potassium-sensitive; this produces an anomalous increase in outward flux as external potassium levels rise because of decreased proton block. Single Kcnk3 channels open across the physiological voltage range; hence they are "leak" conductances; however, they open only briefly and rarely even after exposure to agents that activate other potassium channels.

Genomic organization and chromosomal localization of the murine 2 P domain potassium channel gene Kcnk8: conservation of gene structure in 2 P domain potassium channels.

A 2 P domain potassium channel expressed in eye, lung, and stomach, Kcnk8, has recently been identified. To initiate further biochemical and genetic studies of this channel, we assembled the murine Kcnk8 cDNA sequence, characterized the genomic structure of the Kcnk8 gene, determined its chromosomal localization, and analyzed its activity in a Xenopus laevis oocyte expression system. The composite cDNA has an open reading frame of 1029 bp and encodes a protein of 343 amino acids with a predicted molecular mass of 36 kDa. Structure analyses predict 2 P domains and four potential transmembrane helices with a potential single EF-hand motif and four potential SH3-binding motifs in the COOH-terminus. Cloning of the Kcnk8 chromosomal gene revealed that it is composed of three exons distributed over 4 kb of genomic DNA. Genome database searching revealed that one of the intron/exon boundaries identified in Kcnk8 is present in other mammalian 2 P domain potassium channels genes and many C. elegans 2P domain potassium channel genes, revealing evolutionary conservation of gene structure. Using fluorescence in situ hybridization, the murine Kcnk8 gene was mapped to chromosome 19, 2B, the locus of the murine dancer phenotype, and syntenic to 11q11-11q13, the location of the human homologue. No significant currents were generated in a Xenopus laevis oocyte expression system using the composite Kcnk8 cDNA sequence, suggesting, like many potassium channels, additional channel subunits, modulator substances, or cellular chaperones are required for channel function.

Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma.

Animal studies have suggested that omega-6 fatty acids found in vegetable oils may promote prostate cancer. Our goal was to use erythrocyte membrane and adipose tissue fatty acid composition as biomarkers to investigate whether essential fatty acids modulated prostate cancer risk. An outpatient clinic-based study of 89 cases and 38 controls was conducted in North Carolina between July 1989 and December 1991. Cases were recruited from a university-based urology outpatient clinic. Eligible cases were more than 45 years of age and had histological confirmation of a prostate cancer diagnosis within 1 year of entry into the study. Controls were histologically confirmed free of prostate cancer. Erythrocyte membranes from venous blood and adipose tissue fatty acids from s.c. fat samples were analyzed in batches using capillary gas chromatography. Unconditional logistic regression analysis was used to calculate odds ratios for the association of each fatty acid with prostate cancer while controlling for potential confounders. Linoleic acid consumption was positively associated with prostate cancer risk. The odds ratios comparing the first and fourth quartiles of linoleic acid consumption were 3.54 (95% confidence interval, 1.0-12.53) with P trend < 0.04 for erythrocyte membranes, and 2.47 (95% confidence interval, 0.66-9.26) with P trend < 0.08 for adipose tissue. These data suggest that linoleic acid consumption may increase prostate cancer risk, which is consistent with results from animal experiments. Linoleic acid is found in vegetable oils used in cooking and in cereals, snack foods, and baked goods. Our data failed to demonstrate consistently a protective effect of marine omega-3 fatty acids on prostate cancer.

Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation.

BACKGROUND: Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease. METHODS AND RESULTS: To examine the hypothesis that the allele (T) that codes for the thermolabile defect increases the risk of coronary heart disease, we studied 111 patients with clinical and objective investigational evidence of coronary heart disease and 105 control subjects. The frequencies of the thermolabile defect (T) in patients and control subjects were measured, and the prevalence of elevated plasma total homocysteine according to genotype was assessed. The frequency of the defective allele was higher in patients than in control subjects with an OR of 1.6 (95% CI, 1.1 to 2.4; P = .02). The OR in the coronary heart disease group for the homozygous TT genotype was 2.9 (95% CI, 1.2 to 7.2; P = .02); 17% of patients and 7% of control subjects had the TT genotype. Plasma total homocysteine levels were significantly associated with disease status, a relationship that matched the strength of the association between disease and homozygous inheritance of the defective enzyme. CONCLUSIONS: Homozygotes for the defective allele (T) are at increased risk of premature coronary heart disease. MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population.

Correlation between biomarkers of omega-3 fatty acid consumption and questionnaire data in African American and Caucasian United States males with and without prostatic carcinoma.

Results from animal studies suggest that omega-3 fatty acids from marine sources are protective against cancer. To determine whether adipose tissue and erythrocyte membrane fatty acid composition could serve as biomarkers of essential fatty acid consumption in subjects with prostate cancer, we compared fish consumption, which was estimated using a food frequency survey, to the omega-3 fatty acid content of adipose tissue and erythrocyte membranes. The study was conducted using 127 men who had undergone a prostate biopsy. All subjects were recruited from a university hospital urology clinic. African Americans comprised 23% of the subjects, and 70% were diagnosed with prostate cancer. We found a correlation of 0.44 with 95% confidence intervals (CIs) = 0.29-0.57 between reported fish consumption and the omega-3 fatty acid eicosapentaenoic acid composition in erythrocyte membranes and 0.38 with 95% CI = 0.21-0.53 when the dietary survey was compared to eicosapentaenoic acid in adipose tissue. The survey/biomarker correlations in cases were not significantly different from the correlations in controls. The study had 90% power to detect a 0.35 difference between correlations. These results suggest that the presence of prostate cancer does not affect the adipose tissue or erythrocyte membrane biomarkers of fatty acid consumption, and that erythrocyte membranes are as useful as biomarkers as is adipose tissue. Our findings corroborate previous studies that found that tissue biomarkers can reflect past fatty acid consumption and support the use of biomarkers in case-control studies using cancer patients.

A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects.

It is now well-established that folic acid, taken peri-conceptionally, can reduce the risk of neural tube defects (NTDs). Recent work has demonstrated that an abnormality of homocysteine metabolism is a critical factor. The gene for 5,10 methylenetetrahydrofolate reductase, an enzyme important in homocysteine metabolism, was studied in relation to NTDs. To determine the frequency of the allele for the thermolabile form of the reductase, DNA samples were collected from people with NTDs, parents of people with NTDs, and normal controls. Of 82 people with NTDs, 15 (18.3%) were homozygous for the abnormal, thermolabile allele. This was significantly higher (p = 0.01) than the rate of 6.1% in the control population (odds ratio 3.47, 95% CI 1.28-9.41). This is the first specific genetic abnormality to be identified in NTDs. It explains the association between some NTDs and elevated homocysteine, given that the reductase is important in homocysteine metabolism. It also explains how folic acid supplementation prevents some NTDs, by overcoming a partial block in the conversion of 5,10 methylenetetrahydrofolate to 5 methyltetrahydrofolate. Genetic screening could identify women who will require folic acid supplements to reduce their risk of having a child with an NTD.

Intakes of calcium, phosphorus, and protein, and physical-activity level are related to radial bone mass in young adult women.

A cross-sectional study of 38 24-28-y-old Caucasian women was undertaken to identify associations between dietary factors, physical activity (PA), and radial bone measurements during the third decade. Measurements included radial bone mineral content (BMC) and bone density (BD), nutrient intakes, and PA patterns. PA and calcium intake were positively associated by multiple linear-regression analysis whereas protein and phosphorus were negatively associated with radial bone measurements (P < 0.05). Lean body mass was positively associated with mid BMC only (P = 0.0203). No significant effect of age on BD or BMC was observed. We conclude that in this sample of 24-28-y-old women BD and BMC did not differ by age, and behaviors that had a positive impact on radial bone measurements included at least moderate PA and adequate dietary calcium intake, whereas adverse dietary practices for BD included intakes of protein and phosphorus greater than recommended amounts.

Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits.

Modified Watanabe heritable hyperlipidemic rabbits (M-WHHL) were fed either standard rabbit diet or diet supplemented with 0.5% wt/wt of the lipophilic antioxidant vitamin E (d,l-alpha-tocopherol). Animals of 10-12 weeks of age were divided into two groups matched for distribution of serum cholesterol levels at the beginning of the 12 week study period. A significant hypocholesterolemic response to vitamin E feeding was observed throughout the study. Vitamin E supplementation increased serum vitamin E levels approximately fourfold and restricted ex-vivo copper mediated oxidative modification of low density lipoprotein (LDL) as quantitated by fluorescence at 430 nm. Post mortem examination of aortic tissue revealed a significant (32%) inhibition of surface area lesion involvement in the arch region as determined by image analysis. It is concluded that administration of vitamin E to M-WHHL rabbits brings about a significant hypocholesterolemic response, confers on LDL significant protection against oxidative modification and either or both contribute to the inhibition of early aortic lesion development.

Effect of polyunsaturated fatty acids of the n-3 and n-6 series on lipid composition and eicosanoid synthesis of platelets and aorta and on immunological induction of atherosclerosis in rabbits.

The effect of dietary fish oil (rich in n-3 polyunsaturated fatty acids (PUFA], corn oil (rich in n-6 PUFA) and coconut oil (low in n-3 and n-6 PUFA) on the induction of atherosclerosis by serum sickness in rabbits was investigated over a 12-month period. Dietary fish oil led to a significant increase in the level of eicosapentaenoic acid (EPA) in all platelet phospholipid fractions and to a significant reduction in the level of platelet phosphatidylethanolamine arachidonic acid (AA). In aortic total phospholipids, rabbits given fish oil showed a significant reduction in AA and a significant increase in EPA. Rabbits given fish oil showed significantly lower collagen-induced platelet thromboxane A2 release and aortic production of 6-keto-PGF1 alpha. Serum total immune complex levels and anti-horse serum IgG levels were not influenced by diet. There was a significant reduction in total aortic atherosclerosis in fish oil-fed animals compared with coconut oil fed animals.

Rigid sigmoidoscopy: an evaluation of three parameters regarding diagnostic accuracy.

Rigid sigmoidoscopy is the method employed for examining the rectum and sigmoid colon in most general surgical clinics. Commonly, this is performed without any prior preparation of the bowel and with the patient in the left lateral (Sims') position. This study was designed to assess three factors relating to this method: preparation of the bowel; position of the patient; and the experience of the operator. The study shows that diagnostic accuracy without preparation is adequate in only 50 per cent of cases but, by employing a preliminary disposable (Fletcher's) enema, this can be improved to 80 per cent. Employing the knee-elbow position gave only slight advantage over the usual Sims' position and operator experience did not improve diagnostic accuracy once familiarity with the use of the sigmoidoscope had been achieved. The study underlines the importance of preparation as an essential prelude to sigmoidoscopy.

5-Acyl-3-substituted-benzofuran-2(3H)-ones as potential antiinflammatory agents.

A series of 5-acyl-3-substituted-benzofuran-2(3H)-ones and their respective ring-opened o-hydroxy acids were synthesized. The antiinflammatory activity was evaluated in terms of their ability to improve adjuvant induced arthritis in rats. Their effect on the production of both cyclooxygenase (CO) and lipoxygenase (LO) metabolites of arachidonic acid in guinea pig peritoneal polymorphonuclear neutrophils (PMNs) was also examined. No correlation between the antiinflammatory activity and increasing stability of the lactones could be found. The degree of activity in general shown by the benzofuranones was similar to that of their corresponding o-hydroxy acids. This, coupled with the evidence from studies on opening of the lactone ring, suggests an in vivo transformation of the former into the latter. Benzofuranones displayed a dual inhibition of CO and LO products, while a moderate reduction in CO metabolites was shown by their acids.