What factors are associated with physical activity in older people, assessed objectively by accelerometry?

OBJECTIVES: To assess physical activity (PA) levels measured objectively using accelerometers in community-dwelling older people and to examine the associations with health, disability, anthropometric measures and psychosocial factors. DESIGN: Cross-sectional survey. SETTING: Single general practice (primary care centre), United Kingdom. PARTICIPANTS: Random selection of 560 community-dwelling older people at least 65 years old, registered with the practice. 43% (238/560) participated. ASSESSMENT OF RISK FACTORS: Participants completed a questionnaire assessing health, disability, psychosocial factors and PA levels; underwent anthropometric assessment; and wore an accelerometer (Actigraph) for 7 days. MAIN OUTCOME MEASURES: Average daily accelerometer step-counts and time spent in different PA levels. Associations between step-counts and other factors were examined using linear regression. RESULTS: Average daily step-count was 6443 (95% CI 6032 to 6853). Men achieved 754 (84 to 1424) more steps daily than women. Step-count declined steadily with age. Independent predictors of average daily step-count were: age; general health; disability; diabetes; body mass index; exercise self-efficacy; and perceived exercise control. Activities associated independently with higher step-counts included number of long walks and dog-walking. Only 2.5% (6/238) of participants achieved the recommended 150 minutes weekly of at least moderate-intensity activity in > or = 10 minute bouts; 62% (147/238) achieved none. CONCLUSIONS: This is the first population-based sample of older people with objective PA and anthropometric measures. PA levels in older people are well below recommended levels, emphasising the need to increase PA in this age group, particularly in those who are overweight/obese or have diabetes. The independent effects of exercise self-efficacy and exercise control on PA levels highlight their role as potential mediators for intervention studies.

Molecular cloning of a human gastric lipase and expression of the enzyme in yeast.

The molecular cloning of a cDNA coding for human gastric lipase and its expression in yeast is described. A lipase present in human gastric aspirates was purified and its N-terminal amino-acid sequence was determined. This was found to be homologous with the N-terminal sequence of rat lingual lipase. A cDNA library was constructed from mRNA isolated from human stomach tissue and probed with cloned rat lingual lipase DNA. One clone, pGL17, consisting of approximately 1450 base-pairs, contained the entire coding sequence for a human gastric lipase. The amino-acid sequence from the isolated protein and the DNA sequence obtained from the cloned gene indicated that human gastric lipase consists of a 379 amino acid polypeptide with an unglycosylated Mr of 43,162. Human gastric lipase and rat lingual lipase amino-acid sequences were closely homologous but were unrelated to porcine pancreatic lipase apart from a 6 amino-acid sequence around the essential Ser-152 of porcine pancreatic lipase. A yeast expression plasmid containing the phosphoglycerate kinase promoter and terminator sequences together with the human gastric lipase gene was constructed. Yeast transformed with this vector synthesised the lipolytically active enzyme.

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Effect of prolonged catecholamine infusion on immunoregulatory function: implications in congestive heart failure.

OBJECTIVES: This study sought to characterize the effects of prolonged catecholamine infusion on immunoregulatory cell traffic and activation. BACKGROUND: Immunoregulation has been shown to be partially controlled by the sympathetic nervous system. Although short-term elevation of catecholamine levels is known to alter immunoregulatory cell traffic and activation, the effects of prolonged heightened sympathetic nervous system activity have not adequately been studied. We believe that the alterations in immune function seen in patients with congestive heart failure are linked to a prolonged elevation of circulating catecholamine levels. METHODS: To characterize the effects of prolonged elevation of catecholamine levels, rats received 4 weeks of constant infusion of epinephrine or norepinephrine through implanted osmotic minipumps. Peripheral and splenic leukocyte subsets, T cell proliferation and interleukin-2 receptor expression were quantified. Antibody production to the novel antigen keyhole limpet hemocyanin was assessed over the 4-week treatment period. RESULTS: Both epinephrine and norepinephrine caused significant splenic atrophy and cardiac hypertrophy; both were blocked by propranolol. Epinephrine induced lymphocytosis; both catecholamines caused an increase in natural killer cells. In the spleen, both epinephrine and norepinephrine led to a dose-dependent decrease in total T cells, suppressor/cytotoxic T cells and natural killer cells and a significant increase in B cells. Epinephrine at the low dose enhanced mitogen-induced proliferation and interleukin-2 receptor expression. Norepinephrine at the low dose appeared to diminish proliferation. Epinephrine tended to inhibit IgG antibody production, whereas norepinephrine had no effect. CONCLUSIONS: The results of our study indicate that prolonged elevation of catecholamine levels alters immune cell proliferation and differentiation. These alterations differ greatly from those induced by short-term stimulation but, for the most part, parallel those found in patients with congestive heart failure. We postulate that the shifts in immunoregulatory cell type and function seen in patients with congestive heart failure are due, in part, to longstanding increases in circulating catecholamine levels and may play an important role in the pathogenesis and progression of disease.

Promising Targets for the Treatment of Neurodegenerative Diseases.

Genetics and pathology have proven to be an effective combination to identify an evolving and deepening landscape of pathways and potential therapeutic targets in neurodegenerative diseases. Initially this landscape appeared to be populated with distinct therapeutic targets but with potentially overlapping mechanisms in each neurodegenerative disease. Our understanding has expanded to recognize that multiple pathologies are common in neurodegenerative disease, and that there is considerable overlap in pathways and targets driving neurodegenerative diseases. This potentially opens the way for future treatments to be indicated by tissue pathology and genetic basis rather than clinical phenotype. The potential to treat neurodegenerative disease by addressing underlying pathophysiology is still in the early days and challenges remain, especially the likely need to address pathologies early in disease. This will require redefinition of diagnosis and the tools to enable earlier diagnosis.

Testing drug response in the presence of genetic information: sampling issues for clinical trials.

Progress towards construction of a dense map of di-allelic markers across the human genome has generated considerable enthusiasm for pharmacogenomic applications. To date, however, nearly all of the effort on single nucleotide polymorphism (SNP) projects has been focused on marker identification and screening, not on how the SNP genotype data actually can be used in clinical trials to advance medical practice. Here, we explore how different properties of SNPs impact the size, scope and design of clinical trials using a simple trial design. We evaluate the clinical trial sampling requirements under different allele frequencies, gene action, gene effect size and number of markers in a genome screen. Power and sample size calculations suggest that allele frequency and type of gene action can have a dramatic impact on trial sample sizes, in that under some conditions the required sample sizes are too large to be applicable in a costly clinical trial setting. In other situations, however, pharmacogenomic clinical trials can yield significant sampling/cost savings over traditional trials. These properties are discussed with regard to the general usage of genetic information in clinical trial settings.

The nucleotide sequence of cDNA coding for the structural proteins of foot-and-mouth disease virus.

The complete nucleotide sequence of cDNA coding for the structural capsid polypeptides of foot-and-mouth disease virus (FMDV) (strain A(10)61) has been determined. Portions of the flanking sequence coding for the nonstructural proteins p20a and p52 are also provided. The three larger structural polypeptides VP1, VP2 and VP3 have unmodified Mrs of 23248, 24649 and 24213, respectively. The size of the smaller polypeptide, VP4, can only be estimated at 7360 because the 5'-limit of its coding region is not yet known with certainty. The sequence data for VP1 (the major immunising antigen) and the amino-terminal quarter of p52 are compared with the data of Kurz et al. (Nucl. Acids Res. 9 (1981) 1919-1931) for a different serotype (O1K). This shows that variation is much greater in the region coding for VP1 than in that coding for p52. This is reflected in the level of amino acid sequence variation predicted for the two proteins. Analysis of relative codon usage reveals a strong bias in favour of C and G over U and A in the third base position. The dinucleotide frequencies show a bias against A-U and U-A, and for A-C and C-A.

Radiotherapy for superficial skin cancer at the Queensland Radium Institute: famine in the land of plenty.

Superficial skin cancer is the most common malignancy in man, and radiotherapy has played an important curative role since the early part of the 20th century. We present an overview of the changing pattern of care for patients with superficial skin cancer at the Queensland Radium Institute (QRI), Brisbane--the skin cancer "capital" of the world. Although some 90,000 clinically-diagnosed skin cancers have been treated by radiotherapy at the QRI during the period 1944-1985, we document a dramatic decline in radiotherapy usage for superficial skin cancers over the past 10-15 years. We identify and discuss the major reasons for this changing pattern of care: (a) policy changes initiated by radiation oncologists because of unsightly radiation scars caused by the Queensland climate, (b) improvements in the availability and technical aspects of surgery and dermatology, and (c) surgical preference.

Myocardial ischemia alters immunoregulatory cell traffic and function in the rat independent of exogenous catecholamine administration.

Recent investigation has suggested there is an adrenergically-driven efflux of beta 2-receptor rich lymphocyte subsets into the circulation with altered function following either exercise or infusion of exogenous catecholamines. Myocardial ischemia, like exercise, is associated with generalized sympathoadrenal activation. To determine whether ischemia influences immunoregulatory cell traffic and function in a manner comparable to beta 2-adrenergic stimulation via isoproterenol, rats underwent thoracotomy with or without coronary ligation. Another group of rats received either isoproterenol (1 mg/kg) or vehicle (10 mM HCl) intraperitoneally. Thoracotomy, regardless of whether or not myocardial ischemia was induced, led to lymphocytosis, reflected primarily by an increase in Thelper (Th) cells and, to a lesser degree, in Tsuppressor/cytotoxic (Ts/c) and natural killer (NK) cells, with a tendency toward an increased Th/Ts/c ratio. To the contrary, isoproterenol injection resulted in a relative lymphopenia characterized by diminished B and Th cell numbers, preserved Ts/c and increased NK cell numbers leading to a significant decrease in the Th/Ts/c ratio. With respect to splenic composition, 60 but not 15 min of myocardial ischemia led to diminished Th and B cell numbers compared to sham operated controls, whereas isoproterenol appeared to stimulate an efflux of only NK cells. Both ischemia and isoproterenol enhanced basal splenocyte function; however, only ischemia significantly boosted splenocyte responsiveness to the mitogen Concanavalin A. Surgically induced myocardial ischemia leads to alterations in immunoregulatory cell migration and function which are distinct from those found with beta 2-adrenergic stimulation via isoproterenol.

Effects of E-2078, a stable dynorphin A(1-8) analog, on sedation and serum prolactin levels in rhesus monkeys.

RATIONALE: The dynorphins are endogenous opioid peptides with relative binding selectivity for kappa-receptors. It is unclear whether the dynorphins share the pharmacological profile observed with synthetic kappa-agonists in primates. OBJECTIVE: The main objective of this study was to compare the effects of s.c. E-2078, a stable dynorphin A(1-8) analog, with two synthetic kappa-opioid ligands, spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a "peripherally selective" kappa-agonist) in behavioral and neuroendocrine endpoints in rhesus monkeys. METHODS: Dose-effect curves were determined for s.c. E-2078, spiradoline and ICI204,448 in causing overt sedation and muscle relaxation (as detected in observational rating scales), in increasing latency to retrieve and consume a food pellet and in increasing serum levels of the anterior pituitary hormone, prolactin, in intact female rhesus monkeys. RESULTS: E-2078 and ICI204,448 (0.1-3.2 mg/kg) caused increases in sedation and muscle relaxation scores, but were less potent and apparently less effective than spiradoline (0.001-0.1 mg/kg) up to the highest doses presently studied. All three agonists were equieffective and approximately equipotent in increasing the latency to retrieve and consume a pellet. Furthermore, E-2078 (0.001-0.032 mg/kg) was equipotent and equieffective with spiradoline in increasing serum prolactin levels, whereas ICI204,448 was less potent, but slightly more effective than the former two agonists. The effects of E-2078 on serum prolactin levels were surmountably antagonized by quadazocine (1 mg/kg) and naltrexone (0.1 mg/kg). CONCLUSIONS: The present studies show that serum prolactin levels are a highly sensitive, quantitative endpoint to study the potency and effectiveness of systemically administered E-2078, and show that the dynorphins may be potent and effective in causing some, but not all, the effects that are observed after the administration of synthetic kappa-agonists.

System for projection of a three-dimensional, moving virtual target for studies of eye-hand coordination.

Eye-hand tracking of moving visual objects in three-dimensional (3D) space is common in the behavioral repertoire of primates. However, behavioral and/or neurophysiological studies of this function are lacking mainly because devices do not exist that allow its investigation. We describe a device by which a spot of light can be presented in the immediate extrapersonal space of a subject and can be moved in various trajectories in 3D space. The target is a real image of a circular aperture produced by a system consisting of a light source, aperture, filters, several lenses and fold mirrors, and a large concave mirror to focus the final real image. Rapid, computer-controlled movement of the image is obtained by tilting a gimbal-mounted guide mirror (for x and y motion) and by translating a lens (for motion in the z direction). A second configuration of the system allows movement of a 3D image in the 3D space. Hand motion is monitored by means of a sonic, 3D, position-measurement system.

Apparent efficacy of kappa-opioid receptor ligands on serum prolactin levels in rhesus monkeys.

These studies investigated whether serum prolactin levels could be a quantitative marker of the apparent efficacy of kappa-opioid receptor ligands in primates. The effects of s.c. bremazocine and U50,488 (trans-(+/-)-3, 4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e; agonists), nalorphine (partial agonist) and nalmefene (antagonist) on prolactin levels were studied in intact female rhesus monkeys. The above compounds, except nalmefene, increased prolactin levels, and their actions conformed to sigmoidal dose-effect curves. The rank order of the compounds' maximum effects in this neuroendocrine endpoint is similar to that in cloned kappa-receptors in vitro, and in a presently studied thermal antinociception assay in vivo. Prolactin may therefore be a quantitative marker of the apparent efficacy of kappa-opioid receptor ligands in primates.

Melanoma of the head and neck in Queensland.

The incidence of melanoma in Queensland, 40 cases per 100,000 population, is the highest in the world. In this series of 740 melanomas over a 7-year period at the Royal Brisbane Hospital, 21.75% occurred on the head and neck. Of these, 46.5% arose in Hutchinson's melanotic freckle and 54.8% were histologically superficial, that is, Clark Levels I and II or less than 0.76 mm in thickness, or both. As local recurrence and distant metastasis is infrequent in superficial melanoma, less radical surgical excision of these lesions is advocated than for thicker lesions or those exhibiting a greater depth of invasion, where aggressive excision and even regional node dissection may be required. Anatomical variations in areas such as the nose, eyelid, ear, and scalp influence patterns of spread and necessitate differences in treatment at each site.

Sequence analysis of a cDNA clone encoding the C-terminal end of human complement factor H.

Peptide sequencing of the complement system regulatory protein, factor H, permitted the synthesis of a mixed sequence oligonucleotide probe. Human liver cDNA libraries were screened and factor H-specific clones selected. No full-length clone was obtained, but the largest available clone, R2a, was found to encode the C-terminal 657 amino acids of factor H. The derived amino acid sequence consists of 10 contiguous internally homologous segments, each about 60 amino acids long. Sequences homologous to these are found in several other complement and non-complement proteins. Such sequences are likely to represent a particular type of tertiary structure subunit.

Do income questions and seeking consent to link medical records reduce survey response rates? A randomised controlled trial among older people.

Traditional measures of socioeconomic status may not be reliable for older people and income may be a useful measure for research into inequalities in health. At the same time, researchers increasingly wish to link survey findings to individual data taken from medical records. For this, consent must be sought. To examine whether questions on household income and seeking consent for medical record linkage affected response rates, a postal health survey of patients aged 65 to 74 was undertaken in an inner London practice. The overall response rate was 62.8%. In this study, the inclusion of an income question or seeking consent to access medical records did not reduce response rates to a health survey among older people.

Persistent efficacy of doramectin against experimental nematode infections in calves.

Three studies were conducted involving cattle exposed to experimental nematode infections. These studies were designed to investigate the prophylactic activity of a single subcutaneous treatment of doramectin at 200 micrograms kg-1 body weight against infections of Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus. For each study, parasite-naive calves were randomly allocated to either a treated or a matched control group. One group received doramectin and the other received doramectin and the other received either no treatment or an injection of saline at 1 ml per 50 kg body weight by the subcutaneous route. Thereafter, all calves received a daily oral challenge of infective larvae of the particular parasite species on test in each study. Challenge of each pair of treatment/control groups continued for periods of 14, 21 or 28 days. An interval of 14-21 days was then allowed to permit the parasites which had established to mature, after which all animals were slaughtered and their worm burdens determined using standard techniques. Geometric mean worm burdens were calculated from the log worm counts and used to estimate percentage efficacy. Accumulated burdens of C. oncophora in doramectin-treated cattle resulting from a daily challenge infection for 14 or 21 days were reduced by 99.2% and 90.7% respectively, in comparison with those of non-treated control animals. For D. viviparus, burdens were reduced by 100% and 99.9% after a 21 or 28 day challenge, respectively. The corresponding figures for O. ostertagi were 99.9% after a 21 day challenge and 93.7% after a 28 day challenge.

Efficacy of doramectin in the prevention of gastrointestinal nematode infections in grazing cattle.

Two studies were performed to investigate the efficacy of doramectin in the prevention of infection with Ostertagia ostertagi and Cooperia oncophora in grazing calves. In each study, 24 parasite-naive calves were randomly allotted to two equal groups and treated with either doramectin at 200 micrograms kg-1 or saline prior to mid-season turnout (Day 0) onto contaminated pasture. Faecal egg counts were carried out twice weekly from 15 to 64 days after turnout and the cumulative faecal egg count was calculated for each group of calves. In the doramectin-treated animals, eggs first appeared in the faeces 19 days and 22 days later than in controls for Studies 1 and 2, respectively. Mean cumulative faecal egg counts over the 64 days were reduced in the doramectin-treated groups by 71% and 87% for Studies 1 and 2, respectively (P < 0.01). The potential utility of injectable doramectin in the seasonal control of gastrointestinal nematode infestations in relation to these findings is discussed.

Extensive facial skin cancers.

An examination of extensive skin cancers of the face with a review of symptoms, disease progression and treatments available.

Interaction between coccidia and Nematodirus battus in lambs on pasture.

Five thousand oocysts of each of two species of coccidia, Eimeria crandallis and E ovinoidalis or 30,000 infective larvae of Nematodirus battus, given as single infections to three- to five-week-old lambs, caused only transient diarrhoea and had no effect on growth. Lambs infected first with coccidia and two weeks later with N battus suffered severe diarrhoea, weight loss and some deaths. Simultaneous administration of the coccidia and the nematodes increased the clinical severity of the syndrome and increased the numbers of nematode eggs produced.

Activity of morantel citrate against strains of benzimidazole-resistant nematodes of sheep in the United Kingdom.

The activity of morantel citrate (5.94 mg/kg base) was determined in laboratory tests against field isolates of benzimidazole-resistant nematodes. Its efficacies against adult and seven-day-old worms were 100 per cent and 100 per cent for Cooperia curticei, 95.1 per cent and 69.8 per cent for Haemonchus contortus and 100 per cent and 82 per cent for Ostertagia circumcincta. Morantel citrate was 100 per cent effective against benzimidazole-susceptible Nematodirus battus and Trichostrongylus vitrinus, and it reduced faecal egg counts by 97.9 per cent in sheep infected naturally with benzimidazole-resistant H contortus and O circumcincta.