Evaluating the Rumen Degradation of Novel Protected Gelatin Capsules Containing Fish Oil Fed to Lactating Dairy Cows.

The objective of this study was to assess the effects of feeding gelatin capsules containing fish oil, treated with alcoholic solutions of flavoring agents followed by drying, on lactation performance, rumen fatty acids content and milk enrichment of fatty acids. In Trial 1, four multiparous ruminally fistulated Holstein cows were randomly assigned to one of four dietary treatments sequences in a 4 × 4 Latin square design. Treatments consisted of (1) Control with no capsules, (2) Control plus 200 untreated capsules per cow/day, mixed with the TMR, (3) Control plus 200 treated capsules per cow/day placed directly into the rumen, (4) Control plus 200 treated capsules per cow/day, mixed with the TMR. In Trial 2, three fistulated Holstein and three fistulated Jersey multiparous cows were randomly assigned to three dietary treatments sequences in a replicated 3 × 3 Latin square design. Treatments consisted of (1) Control with no capsules fed to the cows, (2) Control plus 180 untreated capsules per cow/day, (3) Control plus 180 treated capsules per cow/day. Compared to control, feeding fish oil capsules significantly (Trial 1) or numerically (Trial 2) reduced milk fat concentration and yield. Furthermore, in both trials, the feeding of untreated or treated capsules had no effect on animal performance or milk composition. In both trials, compared to controls, supplementing the diet with fish oil capsules consistently increased total trans C18:1 isomers and DHA concentration in the rumen and milk fat. However, for both trials, capsule protection treatment had a minimal effect on the concentration of any of the reported rumen and milk fatty acids. When assessed under laboratory control conditions, due to water absorption, the treated capsule weight was increased by 40% while resistance to pressure decreased by 84% after 2 h of incubation in water. The results of this study suggest that due to a reduction in the capsule shell's resistance to abrasion, treated capsules marginally prevented the release of fish oil in the rumen.

Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice.

Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss.

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.

Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial.

OBJECTIVE: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses. DESIGN: Twelve non-diabetic adults with overweight and obesity received 20 g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo-controlled, cross-over design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period. RESULTS: Both IPE and inulin supplementation improved insulin resistance compared with cellulose supplementation, measured by homeostatic model assessment 2 (mean±SEM 1.23±0.17 IPE vs 1.59±0.17 cellulose, p=0.001; 1.17±0.15 inulin vs 1.59±0.17 cellulose, p=0.009), with no differences between IPE and inulin (p=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased proinflammatory interleukin-8 levels compared with cellulose, while inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridiales) compared with cellulose, with small differences at the species level observed between IPE and cellulose. CONCLUSION: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.

Equivalent Hypertrophy and Strength Gains in ß-Hydroxy-ß-Methylbutyrate- or Leucine-supplemented Men.

Ingestion of proteins with high leucine content during resistance training (RT) can augment hypertrophy. Some data suggest that a leucine metabolite, ß-hydroxy, ß-methylbutyrate (HMB), is substantially more anabolically efficacious than leucine. PURPOSE: We aimed to test whether supplementation with HMB versus leucine, added to whey protein, would result in differential muscle hypertrophy and strength gains in young men performing RT. METHODS: Twenty-six resistance-trained men (23 ± 2 yr) performed 12 wk of RT with three phases. Phase 1: 8 wk of periodized RT (three training sessions per week). Phase 2: 2 wk overreaching period (five sessions per week). Phase 3: 2 wk taper (three sessions per week). Participants were randomly assigned to twice daily ingestion of: whey protein (25 g) plus HMB (1.5 g) (whey+HMB; n = 13) or whey protein (25 g) plus leucine (1.5 g) (whey+leu; n = 13). Skeletal muscle biopsies were performed before and after RT. Measures of fat- and bone-free mass, vastus lateralis (VL) muscle thickness and muscle cross-sectional area (CSA) (both by ultrasound), muscle fiber CSA, and 1-repetition maximum (1-RM) strength tests were determined. RESULTS: We observed increases in fat- and bone-free mass, VL muscle thickness, muscle CSA and fiber type CSA and 1-RM strength with no differences between groups at any phase. We observed no differences between groups or time-group interactions in hormone concentrations at any phase of the RT program. CONCLUSIONS: ß-Hydroxy-ß-methylbutyrate added to whey did not result in greater increases in any measure of muscle mass, strength, or hormonal concentration compared to leucine added to whey. Our results show that HMB is no more effective in stimulating RT-induced hypertrophy and strength gains than leucine.

Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.

BACKGROUND: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus. METHODS: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization. RESULTS: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events. CONCLUSIONS: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

Prepartum fatty acid supplementation in sheep. II. Supplementation of eicosapentaenoic acid and docosahexaenoic acid during late gestation alters the fatty acid profile of plasma, colostrum, milk and adipose tissue, and increases lipogenic gene expression of adipose tissue.

The objectives of this study were as follows: 1) to establish whether feeding a source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to ewes during late gestation changes the fatty acid profile of colostrum, milk, ewe adipose tissue, and plasma and subsequently lamb plasma and red blood cells (RBC), and 2) to investigate the effects of EPA and DHA on mRNA expression in ewe adipose tissue. Eighty-four gestating ewes (28 pens, three per pen) were blocked by lambing day and assigned to a diet with an addition of fat at 0.39% of the DM during the last 50 d of gestation using Ca salts of a palm fatty acid distillate (PFAD) high in palmitic and oleic acids or EPA + DHA. Blood samples were taken from ewes on days 20, 1 (parturition), and 30 and from lambs on days 1 and 30 for plasma fatty acid analysis. Fatty analysis of lamb RBC was performed on day 1. Colostrum samples were taken at lambing and milk samples on day 30 for fatty acid analysis. Subcutaneous adipose tissue biopsies were taken from one ewe per pen on day 20 for fatty acid analysis and gene expression analysis of 27 genes. Treatment × day interactions (P < 0.10) were observed for several isomers of C18:1, with concentrations that were greater in plasma of EPA + DHA ewes on day 20, but were not different on day 1 or 30. Plasma concentrations of EPA tended to be greater (P = 0.07), whereas DHA was greater (P < 0.001) in EPA + DHA ewes compared with PFAD ewes. There was no difference in EPA or DHA in adipose tissue with EPA + DHA vs. PFAD supplementation (P > 0.10). Concentrations of fatty acids with 6 to 10 carbons were significantly increased (P < 0.05) in colostrum and milk of EPA + DHA ewes. There was a treatment × day interaction with EPA + DHA ewes yielding greater EPA (P = 0.03) and DHA (P = 0.04) concentrations than PFAD in colostrum, but not in milk. Treatment × day interactions (P < 0.05) were observed for several C18:1 isomers with concentrations that were greater in EPA + DHA ewe colostrum, but were not different between treatments in milk. In lamb plasma and RBC, EPA and DHA were not different between treatments (P > 0.10). The expression of fatty acid synthase and leptin was significantly increased (P < 0.05), whereas the expression of diacylglycerol acyltransferase 2 tended to be increased (P = 0.08) by supplementation of EPA + DHA vs. PFAD. These results suggest that supplementation with EPA and DHA to ewes during late gestation alters the fatty acid profile of plasma, colostrum, and milk and may increase lipogenesis.

Effect of barley supplementation on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation in obese db/db mice.

PURPOSE: Barley is a low-glycemic index grain that can help diabetic and obese patients. The effect of barley intake depends on the host and the associated gut microbiota. This study investigated the effect of barley intake on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation. METHODS: Obese db/db mice were fed diets with and without barley during 8 weeks; lean mice were used as lean controls. Fecal microbiota was evaluated using 16S marker gene sequencing in a MiSeq instrument; several markers of caecal biochemistry, obesity, and inflammation were also evaluated using standard techniques. RESULTS: Bacterial richness (i.e., Operational Taxonomic Units) and Shannon diversity indexes were similar in all obese mice (with and without barley) and higher compared to lean controls. Barley intake was associated with increased abundances of Prevotella, Lactobacillus, and the fiber-degraders S24-7 (Candidatus Homeothermaceae) compared to both lean and obese controls. The analysis of unweighted UniFrac distances showed a separate clustering of samples for each experimental group, suggesting that consumption of barley contributed to a phylogenetically unique microbiota distinct from both obese and lean controls. Caecal butyrate concentrations were similar in all obese mice, while succinic acid was lower in the barley group compared to obese controls. Barley intake was also associated with lower plasma insulin and resistin levels compared to obese controls. CONCLUSIONS: This study shows that barley intake is associated with a different fecal microbiota, caecal biochemistry, and obesity biomarkers in db/db mice that tend to be more similar to lean controls.

A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. DATA SOURCES: A systematic search of Medline, Embase, CINAHL and SportDiscus. ELIGIBILITY CRITERIA: Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). RESULTS: Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. SUMMARY/CONCLUSION: Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

Impact of ghrelin on body composition and muscle function in a long-term rodent model of critical illness.

BACKGROUND: Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery. METHODS: Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days. RESULTS: Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult. CONCLUSIONS: Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.

Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo.

Kisspeptins regulate the mammalian reproductive axis by stimulating release of gonadotrophin releasing hormone (GnRH). Different length kisspeptins (KP) are found of 54, 14, 13 or 10 amino-acids which share a common C-terminal 10-amino acid sequence. KP-54 and KP-10 have been widely used to stimulate the reproductive axis but data suggest that KP-54 and KP-10 are not equally effective at eliciting reproductive hormone secretion after peripheral delivery. To confirm this, we analysed the effect of systemic administration of KP-54 or KP-10 on luteinizing hormone (LH) secretion into the bloodstream of male mice. Plasma LH measurements 10 min or 2 hours after kisspeptin injection showed that KP-54 can sustain LH release far longer than KP-10, suggesting a differential mode of action of the two peptides. To investigate the mechanism for this, we evaluated the pharmacokinetics of the two peptides in vivo and their potential to cross the blood brain barrier (BBB). We found that KP-54 has a half-life of ~32 min in the bloodstream, while KP-10 has a half-life of ~4 min. To compensate for this difference in half-life, we repeated injections of KP-10 every 10 min over 1 hr but failed to reproduce the sustained rise in LH observed after a single KP-54 injection, suggesting that the failure of KP-10 to sustain LH release may not just be related to peptide clearance. We tested the ability of peripherally administered KP-54 and KP-10 to activate c-FOS in GnRH neurons behind the blood brain barrier (BBB) and found that only KP-54 could do this. These data are consistent with KP-54 being able to cross the BBB and suggest that KP10 may be less able to do so.

A quiet harvest: linkage between ritual, seed selection and the historical use of the finger-bladed knife as a traditional plant breeding tool in Ifugao, Philippines.

The transverse harvest knife, also commonly called the finger or finger-bladed knife, has been utilized by rice farmers in southeast Asia for many centuries. The finger knife persisted in many traditional cultures long after the introduction of the sickle, a tool which provided farmers with the means to execute a much faster harvest. Several theories in interpretative archaeology have attempted to account for this rejection of more modern technological innovations. These theories, which include community-based social organization ideas and practical reasons for the continued use of the finger knife, are presented in this paper. Here I suggest an alternate theory based on a re-interpretation of existing research and fusion of existing theories: the primary reason for the historical and continued use of the finger knife is for seed selection through a centuries old tradition of plant breeding. Though I accept the accuracy of the practical and community-based, socio-cultural reasons for the use of the finger knife put forth by other authors, I suggest that seed selection and genetic improvement was the driving factor in the use of the finger knife. Indeed, intricate planting and harvesting rituals, which both ensured and encouraged varietal conservation and improvement co-evolved with the use of the finger knife as the primary harvest tool due to its unique ability to aid the farmer in the art and science of seed selection. When combined with previous ideas, this interpretative theory, based on the connection between ethnoagronomy and material culture, may provide a more complete picture of the story around the persistence of the finger knife in traditional rice-growing cultures in southeast Asia. I focus my theory on the terrace-building Ifugao people in the mountainous Cordillera region of northcentral Philippines; however, to put the use of the finger into a wider regional context, I draw from examples of the use of the finger knife in other traditional cultures throughout the region of southeast Asia.

Cost-effective recruitment methods for a large randomised trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND).

BACKGROUND: Clinical trials require cost-effective methods for identifying, randomising, and following large numbers of people in order to generate reliable evidence. ASCEND (A Study of Cardiovascular Events iN Diabetes) is a randomised '2 × 2 factorial design' study of aspirin and omega-3 fatty acid supplements for the primary prevention of cardiovascular events in people with diabetes; this study used central disease registers and a mail-based approach to identify, randomise, and follow 15,000 people. In collaboration with UK consultants and general practitioners (GPs), researchers identified potentially eligible people with diabetes from centrally held registers (e.g. for retinopathy screening) and GP-held disease registers. Permission was obtained under section 251 of the National Health Service Act 2006 (previously section 60 of the NHS act 2001) to allow invitation letters to be generated centrally in the name of the holder of the register. In addition, with the collaboration of the National Institutes for Health Research (NIHR) Diabetes and Primary Care Research Networks (DRN and PCRN), general practices sent pre-assembled invitation packs to people with a diagnosis of diabetes. Invitation packs included a cover letter, screening questionnaire (with consent form), information leaflet, and a Freepost envelope. Eligible patients entered a 2-month, pre-randomisation, run-in phase on placebo tablets and were only randomised if they completed a randomisation form and remained willing and eligible at the end of the run-in. Follow-up is ongoing, using mail-based approaches that are being supplemented by central registry data. RESULTS: Information on approximately 600,000 people listed on 58 centrally held diabetes registers was obtained, and 300,188 potentially eligible patients were invited to join the study. In addition, 785 GP practices mailed invitations to 120,875 patients. A further 2,340 potential study participants were identified via other routes. In total, 423,403 people with diabetes were invited to take part; 26,462 entered the 2-month, pre-randomisation, run-in phase; and 15,480 were randomised. CONCLUSION: If sufficient numbers of potentially eligible patients can be identified centrally and the trial treatments do not require participants to attend clinics, the recruitment and follow-up of patients by mail is feasible and cost-effective. Wider use of these methods could allow more, large, randomised trials to be undertaken successfully and cost-effectively. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN60635500 , registered on 14 July 2005.

Quantification of rat kisspeptin using a novel radioimmunoassay.

Kisspeptin is a hypothalamic peptide hormone that plays a pivotal role in pubertal onset and reproductive function. Previous studies have examined hypothalamic kisspeptin mRNA expression, either through in situ hybridisation or real-time RT-PCR, as a means quantifying kisspeptin gene expression. However, mRNA expression levels are not always reflected in levels of the translated protein. Kisspeptin-immunoreactivity (IR) has been extensively examined using immunohistochemistry, enabling detection and localisation of kisspeptin perikaya in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). However, quantification of kisspeptin-IR remains challenging. We developed a specific rodent radioimmunoassay assay (RIA) capable of detecting and quantifying kisspeptin-IR in rodent tissues. The RIA uses kisspeptin-10 as a standard and radioactive tracer, combined with a commercially available antibody raised to the kisspeptin-10 fragment. Adult female wistar rat brain samples were sectioned at 300 µm and the ARC and AVPV punch micro-dissected. Brain punches were homogenised in extraction buffer and assayed with rodent kisspeptin-RIA. In accord with the pattern of kisspeptin mRNA expression, kisspeptin-IR was detected in both the ARC (47.1±6.2 fmol/punch, mean±SEM n = 15) and AVPV (7.6±1.3 fmol/punch, mean±SEM n = 15). Kisspeptin-IR was also detectable in rat placenta (1.26±0.15 fmol/mg). Reverse phase high pressure liquid chromatography analysis showed that hypothalamic kisspeptin-IR had the same elution profile as a synthetic rodent kisspeptin standard. A specific rodent kisspeptin-RIA will allow accurate quantification of kisspeptin peptide levels within specific tissues in rodent experimental models.

A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen-induced allergic rhinitis with or without conjunctivitis, with or without asthma.

BACKGROUND: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma. METHODS: Subjects age 18-65 with clinical history of grass pollen-induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 µg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting. RESULTS: Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS ≤3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise. CONCLUSIONS: In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure. TRIAL REGISTRATION: NCT00421655.

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults.

BACKGROUND: In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration. OBJECTIVES: This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy. METHODS: Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration. RESULTS: During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred. CONCLUSIONS: In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

The thalamus and brainstem act as key hubs in alterations of human brain network connectivity induced by mild propofol sedation.

Despite their routine use during surgical procedures, no consensus has yet been reached on the precise mechanisms by which hypnotic anesthetic agents produce their effects. Molecular, animal and human studies have suggested disruption of thalamocortical communication as a key component of anesthetic action at the brain systems level. Here, we used the anesthetic agent, propofol, to modulate consciousness and to evaluate differences in the interactions of remote neural networks during altered consciousness. We investigated the effects of propofol, at a dose that produced mild sedation without loss of consciousness, on spontaneous cerebral activity of 15 healthy volunteers using functional magnetic resonance imaging (fMRI), exploiting oscillations (<0.1 Hz) in blood oxygenation level-dependent signal across functionally connected brain regions. We considered the data as a graph, or complex network of nodes and links, and used eigenvector centrality (EC) to characterize brain network properties. The EC mapping of fMRI data in healthy humans under propofol mild sedation demonstrated a decrease of centrality of the thalamus versus an increase of centrality within the pons of the brainstem, highlighting the important role of these two structures in regulating consciousness. Specifically, the decrease of thalamus centrality results from its disconnection from a widespread set of cortical and subcortical regions, while the increase of brainstem centrality may be a consequence of its increased influence, in the mildly sedated state, over a few highly central cortical regions key to the default mode network such as the posterior and anterior cingulate cortices.

Nutritional sensing and its utility in treating obesity.

Obesity remains a major worldwide health problem, with current medical treatments being poorly effective. Nutrient sensing allows organs such as the GI tract and the brain to recognize and respond to fuel substrates such as carbohydrates, protein and fats. Specialized neural and hormonal pathways exist to facilitate and regulate these chemosensory mechanisms. Manipulation of factors involved in either central or peripheral chemosensory pathways may provide possible targets for the manipulation of appetite. However, further research is required to assess the utility of this approach to developing novel anti-obesity agents.