The MRC trial of assessment and management of older people in the community: objectives, design and interventions [ISRCTN23494848].

BACKGROUND: The benefit of regular multidimensional assessment of older people remains controversial. The majority of trials have been too small to produce adequate evidence to inform policy. Despite the lack of a firm evidence base, UK primary care practitioners (general practitioners) are required to offer an annual health check to patients aged 75 years and over. DESIGN: Cluster-randomised factorial trial in primary care comparing a package of assessments (i) universal versus targeted assessment and (ii) management by the primary care team (PC) or a multidisciplinary geriatric assessment team (GM). The unit of randomization is the general practice. METHODS: Older people aged 75 and over eligible for the over 75s health check and excluding those in nursing homes or terminally ill were invited to participate. All participants receive a brief assessment covering all areas of the over 75s check. In the universal arm all participants also receive a detailed health and social assessment by a study nurse while in the targeted arm only participants with a pre-determined number and range of problems at the brief assessment go on to have the detailed assessment. The study nurse follows a standard protocol based on results and responses in the detailed assessment to make referrals to (i) the randomised management team (PC or GM) (ii) other medical services, health care workers or agencies (iii) emergency referrals to the GP. The main outcomes are mortality, hospital and institutional admissions and quality of life. 106 practices and 33,000 older people have been recruited to the trial

Spina bifida

Spina bifida is a birth defect in which the vertebral column is open, often with spinal cord involvement. The most clinically significant subtype is myelomeningocele (open spina bifida), which is a condition characterized by failure of the lumbosacral spinal neural tube to close during embryonic development. The exposed neural tissue degenerates in utero, resulting in neurological deficit that varies with the level of the lesion. Occurring in approximately 1 per 1,000 births worldwide, myelomeningocele is one of the most common congenital malformations, but its cause is largely unknown. The genetic component is estimated at 60-70%, but few causative genes have been identified to date, despite much information from mouse models. Non-genetic maternal risk factors include reduced folate intake, anticonvulsant therapy, diabetes mellitus and obesity. Primary prevention by periconceptional supplementation with folic acid has been demonstrated in clinical trials, leading to food fortification programmes in many countries. Prenatal diagnosis is achieved by ultrasonography, enabling women to seek termination of pregnancy. Individuals who survive to birth have their lesions closed surgically, with subsequent management of associated defects, including the Chiari II brain malformation, hydrocephalus, and urological and orthopaedic sequelae. Fetal surgical repair of myelomeningocele has been associated with improved early neurological outcome compared with postnatal operation. Myelomeningocele affects quality of life during childhood, adolescence and adulthood, posing a challenge for individuals, families and society as a whole. For an illustrated summary of this Primer, visit: http://go.nature.com/fK9XNa

Diurnal trends in responses of blood plasma concentrations of glucose, insulin, and C-peptide following high- and low-fat meals and their relation to fat metabolism in healthy middle-aged volunteers

An experiment was conducted in twelve healthy middle-aged volunteers, six of each sex, with a mean BMI of 27 kg/m(2) to detect differences between morning and afternoon in postprandial blood glucose, insulin and C-peptide concentrations. These responses were measured following the consumption of isoenergetic meals that were high or low in fat content, at breakfast and at lunch. Over 4d each subject received the high-carbohydrate (L, 5.5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a moderately high-fat lunch (NM), in three Latin squares. Each evening a standard meal was given. Plasma glucose, insulin and C-peptide responses were greater following L than M meals and within both MM and LL treatments insulin and C-peptide responses were greater following breakfast than following lunch. The incremental C-peptide response to a fatty lunch following a fast at breakfast time (MM) was similar to that to a fatty breakfast, but the incremental insulin response for the same comparison was marginally lower at lunch (P=0.06). The relationship of C-peptide and insulin concentrations was assessed. Plasma glucose response to a fatty lunch was increased by a fatty breakfast. The relationships of these metabolic events with fat metabolism are discussed

Effects of high- and low-fat meals on the diurnal response of plasma lipid metabolite concentrations in healthy middle-aged volunteers

Three experiments were conducted in healthy middle-aged volunteers (six males and six females in Expt 1, six males and two females in Expt 2 and twelve males in Expt 3) with a mean BMI of 27 kg/m(2) to determine whether there is a difference between morning and afternoon dietary fat clearance and utilization, and to determine in what way the fat and starch contents of the meal influence postprandial blood lipid metabolites over 4.5 h. Over 4 days in Expt 1 each subject received isoenergetic, high-carbohydrate (L, 5.5 g mixed fat/meal) and moderately high-fat (M, 33 g mixed fat/meal) breakfasts and lunches, in three combinations (LL, MM, LM), or they fasted at breakfast time and received a high fat lunch (MM) in a randomized and balanced arrangement. Each evening a standard meal was given. The following effects were significant (P < 0.05): plasma triacylglycerol (TAG) responses were greater following RI meals; plasma TAG concentrations were greater in the afternoon than in the morning, following two meats of the same composition, although the postprandial incremental response was less following lunch than following breakfast and peak responses were reached much earlier than after breakfast; a low-fat breakfast, or fasting at breakfast time, delayed the peak TAG response to a M lunch. The plasma concentrations of nonesterified fatty acids (NEFA) and of free glycerol were higher in the afternoon following M meals at breakfast and lunch, especially in males. This response was reduced, by the L breakfast preceding the M lunch. Two M meals in succession lowered plasma HDL-cholesterol concentration. In Expt 2 each subject received a very low-fat (VL) breakfast, followed by a lunch of the same composition. Each of these meals was followed, 110 min from the start of eating, by an infusion of Intralipid 10 % emulsion at the rate of 1 ml/kg body weight over 60 s. Clearance rates of Intralipid were faster in the afternoon than in the morning (P = 0.024). In Expt 3 twelve subjects were randomly allocated to either treatment MM or LM meal patterns, as given in Expt 1. These were given daily for a period of 17 d, during which the change in fasting plasma TAG concentration was similar in both treatments. On days 1, 16 and 17 responses were measured to the M lunch and to a glucose tolerance test (GTT), conducted 2 h 17 min after lunch. The post-lunch responses confirmed those found in Expt 1; but immediately following the glucose dose there was an abrupt increase in plasma TAG that was greater in treatment LM than in treatment MM (P = 0.025), whereas plasma NEFA concentration decreased rapidly in both treatments at that time (P = 0.00066)

Effect of breakfast fat content on glucose tolerance and risk factors of atherosclerosis and thrombosis

Twenty-four middle-aged healthy men were given a low-fat high-carbohydrate (5.5 g fat; L), or a moderately-fatty, (25.7 g fat; M) breakfast of similar energy contents for 28 d. Other meals were under less control. An oral glucose tolerance test (OGTT) was given at 09.00 hours on day 1 before treatment allocation and at 13.30 hours on day 29. There were no significant treatment differences in fasting serum values, either on day 1 or at the termination of treatments on day 29. The following was observed on day 29: (1) the M breakfast led to higher OGTT C-peptide responses and higher areas under the curves (AUC) of OGTT serum glucose and insulin responses compared with the OGTT responses to the L breakfast (P < 0.05); (2) treatment M failed to prevent OGTT glycosuria, eliminated with treatment L; (3) serum non-esterified fatty acid (NEFA) AUC was 59% lower with treatment L than with treatment M, between 09.00 and 13.20 hours (P < 0.0001), and lower with treatment L than with treatment M during the OGTT (P = 0.005); (4) serum triacylglycerol (TAG) concentrations were similar for both treatments, especially during the morning, but their origins were different during the afternoon OGTT when the Svedberg flotation unit 20-400 lipid fraction was higher with treatment L than with treatment M (P = 0.016); plasma apolipoprotein B-48 level with treatment M was not significantly greater than that with treatment L (P = 0.086); (5) plasma tissue plasminogen-activator activity increased after breakfast with treatment L (P = 0.0008), but not. with treatment M (P = 0.80). Waist:hip circumference was positively correlated with serum insulin and glucose AUC and with fasting LDL-cholesterol, Waist:hip circumference and serum TAG and insulin AUC were correlated with factors of thrombus formation; and the OGTT NEFA and glucose AUC were correlated. A small difference in fat intake at breakfast has a large influence on circulating diurnal NEFA concentration, which it is concluded influences adversely glucose tolerance up to 6 h later

New Fathers' Perinatal Depression and Anxiety-Treatment Options: An Integrative Review.

More than 10% of fathers experience depression and anxiety during the perinatal period, but paternal perinatal depression (PPND) and anxiety have received less attention than maternal perinatal mental health problems. Few mainstream treatment options are available for men with PPND and anxiety. The aim of this literature review was to summarize the current understanding of PPND and the treatment programs specifically designed for fathers with perinatal depression. Eight electronic databases were searched using a predefined strategy, and reference lists were also hand searched. PPND and anxiety were identified to have a negative impact on family relationships, as well as the health of mothers and children. Evidence suggests a lack of support and tailored treatment options for men having trouble adjusting to the transition to fatherhood. Of the limited options available, cognitive behavioral therapy, group work, and blended delivery programs, including e-support approaches appear to be most effective in helping fathers with perinatal depression and anxiety. The review findings have important implications for the understanding of PPND and anxiety. Future research is needed to address the adoption of father-inclusive and father-specific models of care to encourage fathers' help-seeking behavior. Inclusion of male-specific requirements into support and treatment options can improve the ability of services to engage new fathers. Psychotherapeutic intervention could assist to address the cognitive differences and dissonance for men adjusting to the role of father, including male identity and role expectations

Quantifying hypoxia with diffuse reflectance spectroscopy for advanced prognostication and real-time response monitoring in rectal cancer: an in vivo feasibility study

Tumour hypoxia is a critical factor in treatment failure and resistance, and its accurate measurement with diffuse reflectance spectroscopy (DRS) could be used for prognostic and response monitoring purposes. In this in vivo characterisation study, we sequentially measured oxygenation trends over the entire course of tumour growth in mice using a multi-depth, fibre-optic DRS probe. Results demonstrated a clear downtrend in oxygenation over time. This progression was not always linear, with significant heterogeneity over time and between mice. Our findings will be further validated against gold standards prior to investigating whether hypoxia can be used to predict radiotherapy responses

TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription

TRIM5α is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that assembles on incoming retroviral capsids and induces their premature dissociation. It inhibits reverse transcription of the viral genome and can also synthesize unanchored polyubiquitin (polyUb) chains to stimulate innate immune responses. Here, we show that TRIM5α employs the E2 Ub-conjugating enzyme Ube2W to anchor the Lys63-linked polyUb chains in a process of TRIM5α auto-ubiquitination. Chain anchoring is initiated, in cells and in vitro, through Ube2W-catalyzed monoubiquitination of TRIM5α. This modification serves as a substrate for the elongation of anchored Lys63-linked polyUb chains, catalyzed by the heterodimeric E2 enzyme Ube2N/Ube2V2. Ube2W targets multiple TRIM5α internal lysines with Ub especially lysines 45 and 50, rather than modifying the N-terminal amino group, which is instead αN-acetylated in cells. E2 depletion or Ub mutation inhibits TRIM5α ubiquitination in cells and restores restricted viral reverse transcription, but not infection. Our data indicate that the stepwise formation of anchored Lys63-linked polyUb is a critical early step in the TRIM5α restriction mechanism and identify the E2 Ub-conjugating cofactors involved

Zoning of mucosal phenotype, dysplasia, and telomerase activity measured by telomerase repeat assay protocol in Barrett's esophagus

Glandular dysplasia in Barrett's esophagus may regress spontaneously but can also progress to cancer. The human telomerase RNA template and the human telomerase reverse transcriptase enzyme which do not, of themselves, correlate strongly with telomerase activity, are too often overexpressed in Barrett's dysplasia to predict individual cancer risk. This study relates telomerase activity, mucosal phenotype, and dysplasia in Barrett's esophagus. Biopsies (n = 256) from squamous esophagus, columnar-lined esophagus every 2 cm, esophago-gastric junction, gastric body, and antrum from 32 patients with long-segment Barrett's esophagus were evaluated by telomerase repeat assay protocol (TRAP). Three biopsies for histology (n = 794) were simultaneously taken at each anatomical level. These and all prior and subsequent biopsies (n = 1917) were reviewed for mucosal phenotypes and dysplasia severity. Intestinal-type Barrett's mucosa was present at all levels in Barrett's esophagus. At least one Barrett's biopsy was TRAP(+) in 22 of 32 patients. TRAP positivity of intestinal-type Barrett's mucosa increased distally, possibly as a consequence of mucosal exposure to acid or bile reflux. Native gastric mucosa was rarely TRAP(+) (1/31 corpus, 2/32 antrum), whereas native squamous mucosa usually was TRAP(+) (31/32). Dysplasia almost always involved intestinal-type Barrett's mucosa (85/87; P</p