Dysphagia induces silent aspiration, which is a known risk factor for aspiration pneumonia in the elderly. Dysphagia is associated with impaired substance P secretion. Because nicergoline was recently reported to enhance substance P secretion, it may improve dysphagia by upregulating substance P; however, roles for nicergoline in this process have not been demonstrated. We therefore compared the effects of nicergoline on serum substance P and dysphagia with the effects of imidapril, an angiotensin-converting enzyme (ACE) inhibitor whose efficacy in improving dysphagia and preventing pneumonia has been previously demonstrated.We randomly assigned 60 elderly patients with both dysphagia and a previous history of pneumonia to receive either imidapril (5 mg/d; n = 30) or nicergoline (15 mg/d; n = 30) for 6 months. Primary outcomes were the effects of these drugs on the substance P level and dysphagia 4 weeks after the start of treatment. Secondary outcome was the effect of these drugs on pneumonia recurrence during the 6 months of treatment.Significant elevations of serum substance P were obtained by both medications after 4 weeks of treatment. Patients whose dysphagia was improved showed significantly increased serum levels of substance P. There was no statistically significant difference in the overall proportion of patients who showed improvements in dysphagia and pneumonia recurrence with imidapril or nicergoline treatment. Nicergoline, but not imidapril, seemed to be more effective at improving dysphagia and elevating serum substance P in patients with dementia.In conclusion, nicergoline has a comparable effect to ACE inhibitors for improving dysphagia. Nicergoline might be a novel regimen for the treatment of dysphagia in the elderly who are not treatable with ACE inhibitors.

This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG-IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta-1a (63, 125, or 188 µg) with intramuscular unmodified IFN beta-1a 30 µg and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2',5'-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 µg (6 million international units [MIU]) of PEG-IFN beta-1a than with 30 µg (6 MIU) intramuscular unmodified IFN beta-1a. Increases in neopterin and 2',5'-OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG-IFN beta-1a than with unmodified IFN beta-1a. PEG-IFN beta-1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu-like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG-IFN beta-1a as a potentially effective treatment for patients with relapsing multiple sclerosis.

Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.

The purpose of the study was to determine if the effect of llama OIF on LH secretion is mediated by stimulation of the hypothalamus or pituitary gland.

This study characterized gene expression in peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage fluid (BALF) cells from control- or mannan oligosaccharide (MOS)-fed pigs with or without porcine reproductive and respiratory syndrome virus (PRRSV) at d 7 postinfection (PI). Weaned pigs (3 wk old) fed 0 or 0.2% MOS (Bio-Mos) diets were intranasally inoculated with PRRSV or a sterile medium at 5 wk of age. Total RNA (3 pigs/treatment) was extracted from cells. Double-stranded cDNA was amplified, labeled, and further hybridized to the Affymetrix GeneChip Porcine Genome Array consisting of 23,937 probe sets representing 20,201 genes. Microarray data were analyzed in R using packages from the Bioconductor project. Differential gene expression was tested by fitting a mixed linear model equivalent to a 2 × 2 factorial ANOVA using the limma package. Dietary MOS and PRRSV changed the expression of thousands of probe sets in PBMC and BALF cells (P < 0.05). The MOS × PRRSV interaction altered the expression of more nonimmune probe sets in PBMC (977 up, 1,128 down) than in BALF cells (117 up, 78 down). The MOS × PRRSV interaction (P < 0.05) for immune probe sets in PBMC affected genes encoding key inflammatory mediators. In uninfected pigs, gene expression of IL-1α, IL-6, myeloid differentiation factor 88, Toll-like receptor (TLR) 4, major histocompatibility complex (MHC) II, and dead box polypeptide 58 increased in PBMC of MOS-fed pigs (P < 0.05). This suggests that MOS enhances disease resistance in pigs and supports the fact that MOS induced a rapid increase in leukocytes at d 3 and 7 PI. Within infected pigs, however, MOS reduced the expression of IL-1β, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, MIP-1β, monocyte chemotactic protein (MCP)-1, and TLR4 genes in PBMC (P < 0.05). This finding may explain why fever was ameliorated in infected pigs fed MOS by d 7 PI. The expression of IL-1β, IL-6, MIP-1β, MCP-1, and TLR4 genes was confirmed by quantitative real-time reverse-transcription PCR. In BALF cells of infected pigs, MOS reduced the gene expression of TLR4, MHCII, and molecules associated with the complement system, but increased the gene expression of MHCI. In short, MOS regulated the expression of nonimmune and immune genes in pig leukocytes, perhaps providing benefits by enhancing the immune responses of the pigs to an infection, while preventing overstimulation of the immune system.

Although the effects of insulin on glucose homeostasis are well recognized in surgical patients, its effect on perioperative protein metabolism has received little attention. The purpose of this study was to examine the effect of high-dose insulin therapy on the plasma concentrations of amino acids (AAs) in patients undergoing coronary artery bypass grafting surgery. We studied 20 nondiabetic patients scheduled for elective coronary artery bypass grafting surgery. Patients were randomly allocated to receive either standard metabolic care (target glycemia 6.0-10.0 mmol/L, control group, n = 10) or high-dose insulin therapy (insulin group, n = 10). Insulin was administered at 5 mU·kg(-1)·min(-1) beginning at skin incision. Simultaneously, 20% dextrose was infused at a variable rate adjusted to maintain glycemia between 4.0 and 6.0 mmol/L. Plasma AAs, glucose, cortisol, and insulin were measured immediately before surgery and at sternal closure. Differences in mean values were assessed by Student t test. Plasma concentrations of all AAs decreased in the insulin group, with 15 of 22 AAs, including all branched-chain AAs, being significantly lower at sternal closure when compared with the control group. At the end of surgery, plasma glucose concentration was significantly lower in the insulin group (4.2 ± 0.6 vs 7.3 ± 1.0 mmol/L, P = .0001), whereas plasma cortisol levels did not show any difference between groups. High-dose insulin therapy resulted in a significant reduction in plasma AAs, particularly branched-chain AAs, during cardiac surgery.

To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of mavrilimumab, a human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, in subjects with rheumatoid arthritis (RA).

The aim was to determine the oestrogens receptor alpha (ERα) mRNA and the binding capacity of oestrogens (ER) and progesterone receptor (PR) in the cervix of anoestrous ewes treated with gonadotrophin-releasing hormone (GnRH) with or without progesterone (P) priming, at the expected time of induced ovulation and early luteal phase. In Experiment 1, ewes were treated with P for 10 days (n=4), with nine micro-doses of GnRH followed by a GnRH bolus injection (n=4), or with P plus GnRH treatments (n=3), and tissues were harvested either without treatment (n=4), when P was removed, or 24h after the GnRH bolus injection. In Experiment 2, ewes were treated with the same GnRH or P plus GnRH treatments and tissues were harvested on Day 1 (n=12) or Day 5 (n=10) after the GnRH bolus injection. In the cranial cervix, the P treatment decreased and the GnRH treatment (after P treatment) increased the ERα mRNA, ER and PR concentrations (P<0.002). The ERα mRNA and ER concentrations were greater on Day 1, than on Day 5 in P plus GnRH treated ewes (P<0.0005). In the caudal cervix, lesser ERα mRNA, ER and PR concentrations than cranial cervix were found (P<0.0001). In conclusion, the ERα transcriptional activity and ER and PR binding capacity were strongly influenced by P and/or GnRH treatments in the cranial cervix, while the steroid receptors binding capacity remained unchanged in the caudal cervix of anoestrous ewes at the expected time of induced ovulation and early luteal phase.

PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.

Bacteriocins with antimicrobial activity are considered as potential alternatives to antibiotics. The aim of this study was to investigate the effect of albusin B (bacteriocin) of Ruminococcus albus 7 expressed by yeast on the growth performance of broiler chickens. Ninety 1-day-old healthy broiler chickens were randomly divided into three groups: control, albusin B (2.5 g kg(-1)) and nosiheptide (2.5 mg kg(-1), antibiotic control). Growth performance and intestinal functions were measured at 5 weeks of age.

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.

Oxytocin has known stress-reducing and attachment-enhancing effects. We thus hypothesized that oxytocin would attenuate emotional and hormonal responses to stress in borderline personality disorder (BPD). Fourteen BPD and 13 healthy control (HC) adults received 40 IU intranasal oxytocin or placebo in double-blind randomized order followed by the Trier Social Stress Test. Subjective dysphoria (Profile of Mood Changes) and plasma cortisol levels were measured. Childhood trauma history, attachment style, and self-esteem were also rated. A significant "Group × Drug × Time" interaction effect for dysphoria (p=.04) reflected a proportionately greater attenuation of stress-induced dysphoria in the BPD group after oxytocin administration. Additionally, a marginally significant "Group × Drug" interaction effect for cortisol (p=.10) reflected a tendency toward greater attenuation of the stress-induced cortisol surge in the BPD group after oxytocin administration. In the combined sample, the oxytocin-placebo difference in the emotional stress reactivity was significantly predicted by childhood trauma alone (p=.037) and combined with self-esteem (p=.030), whereas the oxytocin-placebo difference in cortisol stress reactivity was predicted only by insecure attachment (p=.013). Results suggest that oxytocin may have a beneficial impact on emotional regulation in BPD, which merits further investigation and could have important treatment implications.

Altered levels of cytokines and chemokines may play a role in cancer- and cancer treatment-related cognitive difficulties. In many neurodegenerative diseases, abnormal concentrations of cytokines and chemokines affect neuronal integrity leading to cognitive impairments, but the role of cytokines in chemotherapy-related cognitive difficulties in cancer patients is not well understood. Patients receiving doxorubicin-based (with cyclophosphamide, or cyclophosphamide plus fluorouracil; AC/CAF) chemotherapy or cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy report experiencing cognitive difficulties; because these regimens work by different modes of action, it is possible that they differentially affect cytokine levels.

Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers.

Animal studies in vivo indicate that leptin treatment in extremely leptin-sensitive ob/ob mice reduces body weight exclusively by reducing fat mass and that it increases muscle mass by downregulating myostatin expression. Data from human trials are limited. Therefore, we aimed at characterizing the effects of leptin administration on fat mass, lean body mass, and circulating regulators of muscle growth in hypoleptinemic and presumably leptin-sensitive human subjects. In an open-label, single-arm trial, seven lean, strenuously exercising, amenorrheic women with low leptin concentrations (≤5 ng/ml) were given recombinant methionyl human leptin (metreleptin; 0.08 mg·kg(-1)·day(-1)) for 10 wk. In a separate randomized, double-blind, placebo-controlled trial, seven women were given metreleptin (initial dose: 0.08 mg·kg(-1)·day(-1) for 3 mo, increased thereafter to 0.12 mg·kg(-1)·day(-1) if menstruation did not occur), and six were given placebo for 9 mo. Metreleptin significantly reduced total body fat by an average of 18.6% after 10 wk (P < 0.001) in the single-arm trial and by 19.5% after 9 mo (placebo subtracted; P for interaction = 0.025, P for metreleptin = 0.004) in the placebo-controlled trial. There were no significant changes in lean body mass (P ≥ 0.33) or in serum concentrations of myostatin (P ≥ 0.35), follistatin (P ≥ 0.30), and activin A (P ≥ 0.20) whether in the 10-wk trial or the 9-mo trial. We conclude that metreleptin administration in lean hypoleptinemic women reduces fat mass exclusively and does not affect lean body mass or the myostatin-follistatin-activin axis.

Psychological stress prompts activity of the hypothalamic-pituitary-adrenal (HPA) axis resulting in increased release of cortisol. Long-term HPA aberrations have been observed for stress-related affective disorders but research into acute effects of cortisol on affect-regulation has only recently begun. Previous studies reported that exogenous cortisol acutely attenuated automatic attentional processing of task-irrelevant threatening information. This has been taken to suggest that cortisol may have acute anxiolytic properties, possibly through facilitating inhibition of threatening information. However, the role of cortisol in attentional inhibition of non-threatening arousing stimuli remained unclear. Therefore acute effects of 40 mg cortisol on performance of a masked and unmasked emotional Stroop task (EST) were assessed. Results for only the unmasked task demonstrated EST interference (interpreted as increased automatic attention) for erotic stimuli which was abolished by cortisol administration. This implies that effects of cortisol may not be restricted to attenuation of specifically anxiogenic information processing, as previously suggested.

The neuropeptide oxytocin has been shown to improve many aspects of social cognitive functioning, including facial emotion recognition, and to promote social approach behaviour. In the present study, we investigated the modulatory effects of oxytocin on the recognition of briefly presented facial expressions. In order to diversify the degree of visual awareness for the facial stimuli, presentation duration was systematically varied. Fifty-six participants were administered intranasal oxytocin or a placebo in a double-blind, randomized, between-subjects design. Participants viewed angry and happy target faces or neutral distractors for 18, 35, or 53 ms subsequently masked by neutral faces. Participants had to indicate the presence or absence of the briefly presented target face. Discrimination indices (d') showed that oxytocin generally enhanced detection accuracy of emotional stimuli. This effect was more pronounced for the recognition of happy faces. We provide evidence that a single dose of intranasally administered oxytocin enhances detection of briefly presented emotional stimuli. The possible role of stimulus valence and recognition difficulty is discussed.

An experiment was conducted to determine the effect of dietary phytic acid (PA) and phytase supplementation on small intestinal histomorphology and Na-dependent glucose transporter 1 (SGLT1) gene expression in piglets. Twenty-four piglets with an average initial BW of 7.60 ± 0.73 kg were randomly assigned to 3 experimental diets, to give 8 piglets per diet. The diets were a casein-cornstarch-based diet that was supplemented with 0 or 2% PA, or 2% PA (as Na phytate) plus an Escherichia coli-derived phytase at 500 phytase units/kg. The basal diet was formulated to meet the 1998 NRC energy, digestible AA, mineral, and vitamin requirements for piglets. After 10 d of feeding, the piglets were killed to determine small intestinal histomorphology and small intestinal SGLT1 gene expression. Phytic acid supplementation did not affect (P > 0.1) villus height (VH) and the VH-to-crypt depth (CD) ratio, but did decrease (P < 0.05) CD in the jejunum. Phytase supplementation did not affect (P > 0.1) VH, CD, and the VH-to-CD ratio. Phytic acid supplementation reduced SGLT1 gene expression in the duodenum, jejunum, and ileum by 1.1-, 5.4-, and 2.4-fold, respectively. Phytase supplementation increased SGLT1 gene expression in the jejunum by 2.6-fold, but reduced SGLT1 gene expression in the duodenum and ileum by 2.0- and 4.0-fold, respectively. In conclusion, PA reduced CD in the jejunum and SGLT1 gene expression in the duodenum, jejunum, and ileum, whereas phytase supplementation increased the expression of SGLT1 in the jejunum. The reduced SGLT1 gene expression by PA implies that PA reduces nutrient utilization in pigs partly through reduced expression of SGLT1, which is involved in glucose and Na absorption. The increased expression of SGLT1 in the jejunum by phytase supplementation implies that phytase alleviated the negative effects of PA partly through increased expression of SGLT1.

The uncertainty surrounding dietary requirements for selenium (Se) is partly due to limitations in biomarkers of Se status that are related to health outcomes. In this study we determined the effect of different doses and forms of Se on gene expression of selenoprotein S (SEPS1), selenoprotein W (SEPW1) and selenoprotein R (SEPR), and responses to an immune function challenge, influenza vaccine, were measured in order to identify functional markers of Se status.

This study aimed to investigate the effect of betamethasone treatment on the endocervical concentration of IL-1β, IL-4, IL-6, and TNF-α in preterm labor patients.