Efficacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

The aim of the study was to evaluate the efficacy and safety of vildagliptin added to metformin in patients with type 2 diabetes mellitus. A multicentre, double-blind, randomized, placebo-controlled, 24-week study in patients inadequately controlled with metformin (HbA(1c) 7.5-11%) was designed. Patients were randomized to vildagliptin (Galvus) 100 mg given in the morning (AM), vildagliptin 100 mg given in the evening (PM), or placebo. The primary objective was to demonstrate that HbA(1c) reduction with once-daily vildagliptin 100 mg AM dosing is superior to placebo. Change from baseline to study endpoint in adjusted mean (SE) HbA(1c) improved significantly with vildagliptin AM dosing (-0.66 [0.11] versus 0.17% [0.11] with placebo; p <0.001). Subgroup analyses revealed that HbA(1c) reduction from baseline was greatest in those patients who had the highest baseline HbA(1c) levels. According to a predefined set of response criteria, the percentage of responder patients was significantly greater in the vildagliptin AM dosing group than in the placebo group for all responder definitions. Further analysis also revealed comparable efficacy between AM and PM dosing. Body weight remained generally stable in the combined vildagliptin group (+0.06 kg) and decreased with placebo (-0.69 kg); the incidence of adverse events was similar with vildagliptin AM dosing and placebo (30.4 and 34.4%, respectively). Vildagliptin 100 mg given as a morning dose is an effective and well-tolerated treatment option in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy, and is equally efficacious when given as either a morning or evening dose.

QTL modulating ear size and erectness in pigs.

Ear size and erectness are important conformation measurements in pigs. An F(2) population established by crossing European Large White (small, erect ears) with Chinese Meishan (large, flop ears) was used to study the genetic influence of the two ear traits for the first time. A linkage map incorporating 152 markers on 18 autosomal chromosomes was utilised in a genome scan for QTL. Significant QTL were found on SSC1, 5, 7, 9 and 12 for the two traits. The QTL on SSC5 and SSC7 had major effects and were significant at the genome-wide level (P < 0.01). The QTL on SSC1 for ear erectness also had a major effect and was genome-wide significant (P < 0.01). The 95% confidence interval (CI) of the ear size QTL on SSC5 spanned only 4 cM. The QTL on SSC7 for the two ear traits each had a CI of <20 cM, and their positions overlapped with those of the major QTL affecting subcutaneous fat depths on the same chromosome. This study provides insights on the complex genetic influences underlying pig ear traits and will facilitate positional candidate gene analysis to identify causative DNA variants.

Serum urea concentration as a predictor of dietary lysine requirement in selected lines of pigs.

Serum urea concentrations were measured in Large White pigs from lines divergently selected for components of efficient lean growth rate and performance tested over three 14-d test periods starting at 30, 50, and 75 kg. Two methods of performance testing were used. Phase-fed pigs were fed to appetite isoenergetic diets differing in total lysine:energy ratio (0.58, 0.69, 0.81, 0.91, 1.01, 1.12, and 1.23 g/MJ of digestible energy), whereas diet-choice pigs were offered a choice of the 0.69 and 1.12 lysine:energy diets. Between test periods, all animals were fed one diet: 0.91 g of lysine/MJ of digestible energy. The study consisted of 230 boars and gilts with 150 pigs performance tested on phase-feeding and 80 pigs on diet-choice. The line selected for high lean food conversion had lower urea concentrations on each diet than the line selected for high lean growth rate, despite similar predicted lysine balances. Efficiency of lean growth rather than the rate of lean growth may be a better selection strategy in the context of nitrogen excretion. Urea concentrations at the end of each test period were correlated with lysine intake (0.33, 0.48 and 0.65; standard error, 0.08) and predicted lysine balance (0.39,0.44, and 0.64), but were uncorrelated with predicted lysine for protein deposition (0.01, 0.08, and 0.08) and maintenance. Urea concentration at the end of a test period was not a useful predictor of protein deposition, even after accounting for pretest variation in urea concentration and food intake during test. The expected response pattern of serum urea concentration to diets differing in total lysine:energy would be nonlinear, with the point of inflection occurring at the required dietary total lysine:energy for each genotype. However, there was no evidence of such an inflection point such that the prediction of lysine requirement from urea concentration was not possible for the selection lines in the study.

Serum neuropeptide Y (NPY) and leptin concentrations in pigs selected for components of efficient lean growth.

Responses in log transformed serum neuropeptide Y (NPY) concentration and leptin concentration after six generations of divergent selection on components of efficient lean growth in pigs were measured. From an animal breeding perspective, serum NPY and/or leptin concentrations could be used as physiological predictors of genetic merit if there were significant responses to selection. At 90 kg liveweight, log transformed serum NPY concentrations were increased with divergent selection for low food conversion ratio (LFC) (6.31 versus 5.72, SED 0.09 log(pmol/L)) or for high lean growth rate (LGA) (5.80 versus 5.37 log(pmol/L)) but not with selection on daily food intake (DFI) (6.26 versus 6.14 log(pmol/L)). Selection for high DFI was associated with increased serum leptin concentration (3.06 versus 2.45, SED 0.21 ng/mL human equivalent (HE)) as was selection for low LFC (3.04 versus 2.46 ng/mL HE). Correlations between leptin and predicted lipid weight increased with stage of test (0.13, 0.34 and 0.43, SE 0.08 at 30, 50 and 75 kg). The high correlations between successive serum NPY concentrations (0.80, SE 0.11) suggest that changes in body composition with time would not be reflected in serum NPY concentrations. Serum NPY and, to a lesser extent, serum leptin concentrations were insensitive to dietary differences in total lysine: energy and indicated that studies using a genetic resource population of animals may be more powerful than nutritional studies using isoenergetic diets differing in lysine content to examine aspects of function of serum concentrations of NPY and leptin in pigs.

Serum leptin concentration in pigs selected for high or low daily food intake.

Selection for high or low daily food intake (DFI) in Large White pigs resulted in higher serum leptin concentration, fat deposition and food intake in the high DFI line. The response in serum leptin concentration indicated that the higher fat deposition of the high DFI line was not due to insufficient leptin production, as in the Lepob/Lepob mouse. Serum leptin was more highly correlated with fat deposition than with food intake indicating that the response in serum leptin was primarily due to increased fat deposition rather than to higher energy intake per se. The low correlations between serum leptin measured at 30 kg and performance test traits indicate that serum leptin would not be efficient for selection of animals prior to performance test. However, the consistent positive correlations between serum leptin and a measure of fat deposition suggest that serum leptin could usefully be incorporated in selection criteria for genetic improvement of carcass lean content in pigs.

Boar taint in pigs selected for components of efficient lean growth rate.

Genetic and nutritional effects on the boar taint traits of androstenone, skatole and indole and the eating quality traits associated with boar taint were examined by testing animals from four selection lines and a control line on isoenergetic diets, which differed in ileal digestible lysine: digestible energy (0.40, 0.76 and 1.12 g lysine/MJ DE). The selected lines resulted from seven generations of selection for high daily food intake, lean food conversion ratio (LFC) and lean growth rate on ad libitum (LGA) or restricted (LGS) feeding regimes in a Large White population. During performance test, from 30 to 90 kg, boars were fed on either ad libitum or restricted (0.75 g/g ad libitum daily food intake) feeding regimes. A sensory panel assessed heated fat samples for androstenone odour, skatole odour and abnormal odour. There were no significant differences between the selection and control lines or diets for log transformed fat content of androstenone, skatole, indole. The significant diet with feeding regime interaction for log transformed fat content of skatole and indole were essentially due to significantly higher log transformed fat contents with ad libitum feeding of the high lysine diet compared to restricted feeding (skatole: -1.94 vs -3.06, s.e.d. 0.43; indole: -3.44 vs -4.22, s.e.d. 0.28), as differences between feeding regimes on diets A and C were not significantly different from zero. There were no significant differences between selection and control lines for sensory panel score for abnormal odour or androstenone odour, but the LFC and LGA selection lines had a significantly higher skatole odour score than the LGS selection line. Neither diet nor feeding regime had any significant effect on sensory panel assessment of odour. Log transformed fat content of androstenone and skatole were significantly correlated with sensory panel score for skatole odour (0.37 and 0.46, s.e. 0.12), but not with sensory panel score for androstenone odour (0.06 and 0.09), such that they would not be useful predictors of androstenone odour.

Genotype with nutrition interaction on fatty acid composition of intramuscular fat and the relationship with flavour of pig meat.

The effects of genotype, diet and the genotype with diet interaction on fatty acid composition of neutral lipid and phospholipid of intramuscular fat in pigs were examined. Pigs from four selection lines and a control line were fed isoenergetic diets, which differed in ileal digestible lysine:digestible energy (A: 0.40, C: 0.76 and E: 1.12 g lysine/MJ DE). The selected lines resulted from seven generations of selection for high daily food intake (DFI), lean food conversion ratio (LFC) and lean growth rate on ad-libitum (LGA) or restricted feeding regimes in a Large White population. During performance test, from 30 to 90 kg, pigs were fed on either ad-libitum or restricted (0.75 g/g ad-libitum daily food intake) feeding regimes. A trained sensory panel assessed intensities of pork flavour and abnormal flavour and the hedonic characteristics of flavour liking and overall acceptability. The proportion of neutral lipid in the LGA line was lower (0.64 v 0.75, s.e.d. 0.03) while the polyunsaturated:saturated (P:S) ratio of the LFC line (0.53 v 0.41, s.e.d. 0.05) was higher than the control line and other selection lines. The DFI line had a higher phospholipid n-6:n-3 ratio than other selection lines (14 v 11, s.e.d. 1.0). Diets C and E resulted in lower neutral lipid:phospholipid ratio (0.7 v 0.8, s.e.d. 0.01), n-6:n-3 ratios for both neutral lipid (5 v 13, s.e.d. 0.8) and phospholipids (7 v 20, s.e.d. 0.6) and a higher P:S ratio (0.5 v 0.3, s.e.d. 0.03) for neutral lipid than diet A. Neutral lipid fatty acids C18:2 n-6, C18:3 n-3, C20:3 n-6, C20:4 n-6, C20:5 n-3, C22:5 n-3 and C22:6 n-3 were negatively correlated with pork flavour (-0.30, s.e.d. 0.10), flavour liking (-0.33) and overall acceptability (-0.30). In contrast, the fatty acids C16:1, C18:1 ω9 and C18:1 ω11 were positively correlated with pork flavour (0.36), flavour liking (0.39) and overall acceptability (0.40). However, correlations for fatty acids in the phospholipid class were positive for C18:2 n-6, C20:4 n-6 and C22:4 n-6 with pork flavour (0.33), flavour liking (0.23) and overall acceptability (0.23). The proportion of neutral lipid had non-significant correlations with flavour traits; pork flavour (0.01), abnormal flavour (0.08), flavour liking (-0.03) and overall acceptability (0.03). The selection lines responded in a similar manner to the different diets, such that there was little evidence for genotype with nutrition interactions for fatty acid concentrations of neutral lipids and phospholipids. Selection for high lean growth will reduce intramuscular fat, but the increased relative amount of phospholipid and concentration of polyunsaturated fatty acids are unlikely to reduce eating quality. Nutritional effects on intramuscular fat characteristics were greater than genetic effects, such that nutritional approaches to feeding pigs will provide effective methods of reducing the n-6:n-3 fatty acid ratio of human dietary fat from pigmeat and improving human health.

Sensitivity of pig genotypes to short-term manipulation of plasma fatty acids by feeding linseed.

The sensitivity of pigs selected for high daily food intake (DFI), low lean food conversion (LFC) and high lean growth rate (LGS) to dietary change of plasma fatty acids was assessed. The difference between the two diets was effectively a substitution of palmitic (C16:0), oleic (C18:1 n-9) and linoleic (C18:2 n-6) with linolenic (C18:3 n-3) fatty acids. Fatty acid compositions of plasma free fatty acids, neutral lipids and phospholipids were measured in 90 kg animals fed a base or high linolenic (C18:3 n-3) fatty acid diet, based on whole linseed, for four days. There were 24 animals from each selection line and 24 animals from an unselected control line, with boars and gilts represented equally in each line. Half of the selection line animals were fed the base diet and half were fed the high C18:3 diet, but all control animals were fed the base diet. Prior to slaughter, animals were fasted for 18 h. The fatty acids primarily affected by dietary change were C18:3 n-3 and its products, C20:5 n-3 (EPA) and C22:6 n-3 (DHA). The sensitivity of a selection line to dietary change was parameterised by the relative shift in fatty acid composition through changing from the base diet to the high C18:3 diet. In neutral lipids, the sensitivities of C18:3 n-3 in the DFI and LFC lines were similar but greater than in the LGS line (3.0 v. 1.8, S.E.D. 0.15), while, for phospholipid and free fatty acids, the sensitivity of the DFI line was greater than in the LFC and LGS lines (2.3 v. 1.8 and 2.0 v. 1.4, respectively). For C20:5 n-3 and C22:6 n-3, the DFI and LFC lines were more sensitive to dietary change than the LGS line (total lipid : 2.3 v. 1.9 and 1.5 v. 1.2). In general, the DFI line was most sensitive to dietary change and the LGS line was the least sensitive. The difference in sensitivities of the lipid classes to the high C18:3 diet between the selection lines could result from differences in body fat content and may explain the general lack of genotype with nutrition interactions in post-1990 genotypes in comparison with fatter circa-1970 genotypes.

Action research in the care of patients with sexual anxieties.

Collaborative working in the Balint model of psychosexual seminar training can be used as a rigorous approach to ongoing action research. In this article, the author describes how nurses can develop awareness using this approach to patients' sexual problems.

Resinless section electron microscopy reveals the yeast cytoskeleton.

The cytoskeleton of Saccharomyces cerevisiae is essentially invisible using conventional microscopy techniques. A similar problem was solved for the mammalian cell cytoskeleton using resinless section electron microscopy, a technique applied here to yeast. In the resinless image, soluble proteins are no longer cloaked by embedding medium and must be removed by selective detergent extraction. In yeast, this requires breaching the cell wall by digesting with Zymolyase sufficiently to allow detergent extraction of the plasma membrane lipids. Gel electropherograms show that the extracted or "soluble" proteins are distinct from the retained or "structural" proteins that presumably comprise the cytoskeleton. These putative cytoskeleton proteins include the major portions of a 43-kDa protein, which is presumably actin, and of proteins in a band appearing at 55 kDa, as well as numerous less abundant, nonactin proteins. Resinless section electron micrographs show a dense, three-dimensional web of anastomosing, polymorphic filaments bounded by the remnant cell wall. Although the filament network is very heterogenous, there appear to be two principal classes of filament diameters-5 nm and 15-20 nm-which may correspond to actin and intermediate filaments, respectively. A large oval region of lower filament density probably corresponds to the vacuole, and an electron dense spheroidal body, 300-500 nm in diameter, is likely the nucleus. The techniques detailed in this report afford new approaches to the study of yeast cytoarchitecture.

Retrograde lymphatic metastasis of an ileal carcinoid.

BACKGROUND: Carcinoid tumors are uncommon tumors, derived from Kulchitsky cells, which generally follow a slow, orderly metastatic spread. They are often associated with second primary malignant neoplasms either synchronously or metachronously. CASE REPORT: A 62 year old white female with a history of severe dysplasia of the vulva and carcinoid of the distal ileum presented with a presumed vulvar malignancy by biopsy from a referring hospital. She did not have symptoms of the carcinoid syndrome. Wide vulvar excision revealed chronic inflammation without residual tumor. Bilateral superficial and deep inguinal lymphadenectomy revealed metastatic carcinoid. CONCLUSION: The inguinal lymph nodes should be considered a site of distant metastasis for carcinoid tumors of the distal ileum.

Psychotherapy training in an isolated setting.

This paper describes the setting up of a training programme in psychodynamic psychotherapy in Perth, 'the most isolated city in the world'. Previous attempts to do so have petered out after a short period of time. It had certainly never been possible to develop a training programme. Initially a study group of interested health professionals was formed in 1984 which met to study certain texts at fortnightly meetings and participated in workshops conducted by the supervisors who visited from Sydney, 3,400 km away. At the end of that year the study group was changed into the Association for Psychodynamic Psychotherapy of Western Australia. The foundation members were also the first training group. The training programme consisted of fortnightly meetings concerned with intragroup issues, administrative matters and with the didactic programme: this consisted of seminars being conducted as part of a training programme in Sydney which were recorded on videotape and flown to Perth. As the 3-year training progressed we also added additional topics of our own. On the alternative fortnight the members split into small groups for peer supervision of audiotape recordings of sessions with the patient being supervised. In addition there were supervision workshops conducted by the visiting supervisors from Sydney. The paper also discusses the logistical problems of conducting such a training as well as transference and countertransference issues that arose within the group of trainees as well as with the supervisors who were so far away.

Feulgen-deoxyribonucleic acid analysis of rabbit aortic smooth muscle cells using scanning- integrating microdensitometry.

A procedure entailing the use of the Feulgen reaction is described for precise quantification of nuclear DNA levels in smooth muscle cells (SMC) of paraffin-processed microtome sections of the rabbit aorta. It was established that maximal, stable, and reproducible Feulgen-DNA (F-DNA) staining of SMC nuclei is achieved using 3.5 N HCl hydrolysis of 30-50 min prior to staining of aortic sections in Schiff reagent for 60 min at 22 degrees C. Scanning-integrating microdensitometry of Feulgen-stained SMC revealed that the tunica media is comprised of a relatively homogeneous population of cells with between 0.3 and 1% of the SMC nuclei yielding 3C or 4C (tetraploid) F-DNA levels, depending on location within the aortic wall. The nuclear chromatin in inner medial SMC was found to be in a more dispersed state than that of outer SMC (using nuclear area and nuclear susceptibility to acid hydrolysis as indices of chromatin dispersion). A linear correspondence was evidenced between nuclear area and nuclear F-DNA stainability throughout the tunica media. The observation that the lumenal portion of the tunica media contains a greater abundance of SMC with large, vesicular nuclei is interpreted as reflecting a greater metabolic reactivity of this compartment relative to that of SMC bordering the tunica adventitia.