The impact of growth promoters on muscle growth and the potential consequences for meat quality

To meet the demands of increased global meat consumption, animal production systems will have to become more efficient, or at least maintain the current efficiency utilizing feed ingredients that are not also used for human consumption. Use of growth promoters is a potential option for increasing production animal feed efficiency and increased muscle growth. The objective of this manuscript is to describe the mechanisms by which the growth promoters, beta-adrenergic agonists and growth hormone, mediate their effects, with specific consideration of the aspects which have implications for meat quality.The work described in this manuscript was supported by a BBSRC LINK Zoetis grant, number BB/J005320/1, as well as a BBSRC CASE PhD studentship awarded to David Brown and Krystal Hemmings and a PhD scholarship awarded to Molebeledi HD Mareko by the Botswana College of Agricultur

Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenic protein translation. Therefore, they strongly reduced cell proliferation and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients

Mutations and Deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascades Which Alter Therapy Response

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors

Characterisation and Regulation of Ovine Myosin Heavy Chain Isoform Expression

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Top ten research priorities for Idiopathic Intracranial Hypertension (IIH)

Idiopathic Intracranial Hypertension (IIH) is under-researched. Patient engagement and patient voice are regarded as central to both the research agenda and funding. The aim was to determine the top 10 research priorities for IIH

What are the research priorities for idiopathic intracranial hypertension? A priority setting partnership between patients and healthcare professionals.

OBJECTIVE Idiopathic intracranial hypertension (IIH) is under-researched and the aim was to determine the top 10 research priorities for this disease. DESIGN A modified nominal group technique was used to engage participants who had experience of IIH. SETTING This James Lind Alliance Priority Setting Partnership was commissioned by IIH UK, a charity. PARTICIPANTS People with IIH, carers, family and friends, and healthcare professionals participated in two rounds of surveys to identify unique research questions unanswered by current evidence. The most popular 26 uncertainties were presented to stakeholders who then agreed the top 10 topics. RESULTS The top 10 research priorities for IIH included aetiology of IIH, the pathological mechanisms of headache in IIH, new treatments in IIH, the difference between acute and gradual visual loss, the best ways to monitor visual function, biomarkers of the disease, hormonal causes of IIH, drug therapies for the treatment of headache, weight loss and its role in IIH and finally, the best intervention to treat IIH and when should surgery be performed. CONCLUSIONS This priority setting encouraged people with direct experience of IIH to collectively identify critical gaps in the existing evidence. The overarching research aspiration was to understand the aetiology and management of IIH

Circulatory Endotoxin Concentration and Cytokine Profile During Multi-Stage Ultra-Marathon Competition Conducted in a Hot Ambient Environment.

Gastrointestinal distress is a commonly reported feature of prolonged physical exertion in the heat. Indeed, exertional-heat stress has the potential to disturb the integrity of gastrointestinal mucosal structures, potentially leading to increased intestinal permeability of enteric microorganisms and associated clinical manifestations (e.g. endotoxaemia, cytokine induced pyrogenesis and heat stoke). This observational study aimed to determine changes in circulatory endotoxin concentration and cytokine responses during a 230km multi-stage ultra-marathon (MSUM) conducted over five days in hot ambient conditions (32 to 40ºC) and routed over arid undulating terrain. Body mass, tympanic temperature and venous blood samples were taken from ultra-endurance runners (UER, N=19) and control non-runners (CON, N=12) before and immediately after each stage of the MSUM. Aliquots of plasma were used to determine plasma osmolality by freezepoint osmometry, endotoxin by LAL chromogenic endpoint assay, CRP and cytokine profile by ELISA. Gastrointestinal symptoms were monitored each day along the MSUM. Data was analysed using ANOVA with post hoc Tukeys. Significance was accepted as p\u3c0.05. Stage mean body mass loss ranged between 1.0% to 2.5%. Pre- and post-stage tympanic temperature was within normal range in all UER. Overall mean pre- and post-stage plasma osmolality in UER was 277±15mOsmol/kg and 293±14mOsmol/kg, respectively. Pre- to post-stage increases (17%) in plasma endotoxin concentration were observed in 89% of UER (p=0.005). Pre- and post-stage plasma CRP concentration in UER increased by Stage 2 (5.8 and 4.6-fold, respectively; p\u3c0.001) and remained elevated throughout the MSUM. In UER, plasma concentrations of IL-6 were higher pre-Stages 2 and 3 (p=0.036), IL-1β and IL-1ra were higher pre-Stages 2 to 5 (p\u3c0.001), TNFα and IFNγ were higher pre-Stages 3 to 5 (p=0.013 and p=0.002, respectively), compared with pre-Stage 1. Pre-stage plasma concentrations of CRP, IL-6, TNFα and IL-10 were higher in UER than CON along the MSUM (p\u3c0.05). Pre- to post-stage increases in IL-6 (37%, p=0.008), IL-1β (14%, p=0.003), IL-1ra (58%, p\u3c0.001), TNFα (18%, p=0.083) and IFNγ (13%, p=0.065) were observed in UER. Incidences of gastrointestinal distress were reported by 92% of UER along competition. MSUM competition in the heat resulted in significantly increased pro-inflammatory immune responses, which may have been exacerbated by the modest rise in circulatory endotoxin concentration. It is likely that thermoregulatory management and maintenance of euhydration in the majority of UER contributed to attenuating further exacerbation of these responses. Contrary to previous literature, no associations between gastrointestinal distress and blood parameters measured were observed

The Impact of a 24-hour Continuous Running Competition Conducted in a Thermoneutral Environment on Circulatory Endotoxin Concentration and Cytokine Profile

Modest rises in circulatory endotoxin concentration and increased pro-inflammatory cytokine responses have previously been observed during exertional-heat stress. How these immune variables respond to physical exertion without heat stress but inclusion of other stressors (e.g. sleep deprivation and severe energy deficit) during ultra-marathon competition is unknown. This observational study aimed to determine circulatory endotoxin concentration and cytokine responses to a continuous 24-hours ultra-marathon competition (total distance range: 122-207km; average intensity: 7.2METs) conducted in thermoneutral ambient conditions. Body mass, tympanic temperature and venous blood samples were taken from ultra-endurance runners (UER, N=25) and control non-runners (CON, N=20) before and immediately after competition. Aliquots of plasma were used to determine plasma osmolality by freezepoint osmometry, endotoxin by LAL chromogenic endpoint assay, CRP and cytokine profile by ELISA. Total energy expenditure was determined by triaxial accelerometer; while total food and fluid intake was established through direct dietary monitoring technique and analysed on dietary analysis software. Gastrointestinal symptoms were monitored throughout the ultra-marathon. Data was analysed using ANOVA with post hoc Tukeys, and verification by non-parametric equivalents were appropriate. Significance was accepted as p\u3c0.05. Total energy expenditure and intake in UER was 13080±2587kcal and 4708±2568kcal, respectively (p\u3c0.001 vs. CON). Individual body mass loss ranged between -2.4% to 4.4%. Overall mean pre- and post-competition plasma osmolality in UER was 285±11mOsmol/kg and 287±10mOsmol/kg, respectively. Tympanic temperature was within normal range in all UER before and after competition. 24-hours of continuous competition resulted in 43% average rise (p=0.021) in plasma endotoxin concentration, which was evident in 68% of all UER (p=0.005 vs. CON). A 31.8-fold average increase in plasma CRP concentration was observed immediately after competition in UER (p\u3c0.001), with no change in CON. IL-6 (32-fold, p\u3c0.000), TNFα (34%, p=0.015), IL-10 (4.2-fold, p\u3c0.001) and IL-8 (3.2-fold, p\u3c0.001) plasma concentrations were raised following competition in UER. Pre-competition cytokine profile did not differ between UER and CON; however IL-6, TNFα, IL-1β, IL-12p70, IL-10 and IL-8 plasma concentrations were higher in UER than CON immediately after competition (p\u3c0.05). Incidences of gastrointestinal distress were reported by 65% of UER, but no associations with blood parameters measured were identified. 24-hours of ultra-marathon competition in thermoneutral ambient conditions resulted in a disturbed pro-inflammatory immune profile, which may have been exacerbated by the substantial rise in circulatory endotoxin concentration. In addition, the accompanying acute period of sleep deprivation and severe energy deficit may have also contributed to the perturbed responses observed following competition

Idiopathic intracranial hypertension: consensus guidelines on management.

The aim was to capture interdisciplinary expertise from a large group of clinicians, reflecting practice from across the UK and further, to inform subsequent development of a national consensus guidance for optimal management of idiopathic intracranial hypertension (IIH). METHODS Between September 2015 and October 2017, a specialist interest group including neurology, neurosurgery, neuroradiology, ophthalmology, nursing, primary care doctors and patient representatives met. An initial UK survey of attitudes and practice in IIH was sent to a wide group of physicians and surgeons who investigate and manage IIH regularly. A comprehensive systematic literature review was performed to assemble the foundations of the statements. An international panel along with four national professional bodies, namely the Association of British Neurologists, British Association for the Study of Headache, the Society of British Neurological Surgeons and the Royal College of Ophthalmologists critically reviewed the statements. RESULTS Over 20 questions were constructed: one based on the diagnostic principles for optimal investigation of papilloedema and 21 for the management of IIH. Three main principles were identified: (1) to treat the underlying disease; (2) to protect the vision; and (3) to minimise the headache morbidity. Statements presented provide insight to uncertainties in IIH where research opportunities exist. CONCLUSIONS In collaboration with many different specialists, professions and patient representatives, we have developed guidance statements for the investigation and management of adult IIH