A transatlantic survey of nutrition practice in acute pancreatitis.

BACKGROUND: Many guidelines exist for the nutritional management of acute pancreatitis; however, little is known regarding current practice. We aimed to investigate feeding practices, including the use of parenteral/enteral nutrition. METHODS: The study design was a cross-sectional, descriptive survey. Electronic surveys were sent to dietitians in the UK, the Republic of Ireland and Canada. Of 253 dietitians surveyed, 204 saw patients with acute pancreatitis regularly or occasionally and were included in the analyses. RESULTS: Most dietitians (92.8%) considered early feeding to mean <48 h after presentation. Over half (54.2%) favoured early feeding in severe disease, less in obesity (42%) and more with pre-existing malnutrition (81.9%). There was a tendency to feed earlier in university hospitals (P = 0.015), especially in obesity (P = 0.011). There was a tendency towards enteral (versus parenteral) nutrition in university hospitals (P = 0.000). The majority preferred the jejunal route (64.2%), although this was lower in the UK (43.8%) than in Canada (77.8%) or Ireland (54.2%). Under one-quarter of UK dietitians (23.2%) reported the existence of a pancreatic multidisciplinary team in their institutions, although this was lower in Ireland and Canada. CONCLUSIONS: Despite guidelines, there are gaps in the nutritional management of acute pancreatitis, including a continued reliance on parenteral feeding.

The Effect of Time-Restricted Eating on Insulin Levels and Insulin Sensitivity in Patients with Polycystic Ovarian Syndrome: A Systematic Review.

Results: 2662 papers were identified with 37 selected for full-text review and one paper meeting criteria for inclusion. Ramadan fasting was the only time-restricted eating regimen trialled in this population with no strong evidence of a significant effect on insulin levels. Conclusion: As the systematic review retrieved only one study investigating time-restricted eating to reduce insulin in patients with PCOS, there is no evidence to suggest that this intervention is effective. From the narrative review, based on studies in other patient groups, time-restricted eating could improve insulin resistance in those with PCOS; however, well-designed studies are required before this intervention can be recommended.

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.

High sensitivity cytokine detection in acute coronary syndrome reveals up-regulation of interferon gamma and interleukin-10 post myocardial infarction.

Inflammation is an important element in the development and destabilization of atherosclerotic plaque. Using a high sensitivity multiplex assay, previously untested in the context of atherosclerotic disease, we determined serum concentrations of GM-CSF, IFNgamma, IL-1beta, IL-2, IL-10, IL-12p70, TNF alpha, IL-6, and IL-8 in 48 Myocardial Infarction (MI) patients, 14 Unstable Angina (UA) patients and 12 healthy controls. IFNgamma levels were significantly higher in MI compared to UA (p=0.0091) and Control groups (p=0.0014). IL-10 also showed higher expression levels between MI, UA groups and Controls (p=0.0299).This up-regulation may reflect the extent of plaque instability and/or rupture in MI patients.Our observations provide evidence that IFNgamma and IL-10 merit further investigation in atherosclerotic disease states as potential markers of disease and therapeutic targets.

Meeting complex health needs in prisons.

The vast majority of prisoners have several health needs which combine at different levels of severity. This complexity of needs often amalgamates to include mental and physical illnesses, homelessness, unemployment, and drug and alcohol addictions. 'Complexity' can serve as an umbrella term for a number of health and social justice agendas, including public health, primary and secondary care, and social care, and must be fully understood to meet the 'complex needs imperative' that exists in all prisons.

Prevalence and numbers of Salmonella spp. and Enterobacteriaceae on pork cuts in abattoirs in the Republic of Ireland.

AIMS: This study aimed to determine the numbers and types of Salmonella spp. and Enterobacteriaceae on pork cuts in the meat cutting room environment of four commercial pork abattoirs in the Republic of Ireland. METHODS AND RESULTS: Pork oysters (M. gluteus medius; n = 720) and swabs (n = 56) from equipment and surfaces were screened for Salmonella spp. using a DNA-based PCR method and confirmed by culture. Salmonella numbers were assessed using a three-tube most probable number (MPN) technique. Salmonella spp. was detected on 24/720 (3.3%) pork cuts (range of <0.03-0.36 MPN g(-1)) and in 7/56 (12.5%) environmental swabs (range of <0.03-1.10 MPN cm(-2)). There was significant variation in the prevalence of Salmonella on pork between different abattoirs and days of sampling (range of 0-31.7%). The predominant serotype was Salmonella serotype Typhimurium followed by Salmonella serotype Derby. CONCLUSIONS: Overall prevalence data conceal the key finding that there was considerable variation in the incidence of Salmonella on different days. A direct association between Salmonella contamination of pork cuts and equipment/surfaces was observed. SIGNIFICANCE AND IMPACT OF THE STUDY: Prevalence and numbers of Salmonella were low; however, results clearly demonstrate the potential for cross-contamination from equipment and meat contact surfaces in the cutting room environment.

The nutritional management of type 3c (pancreatogenic) diabetes in chronic pancreatitis.

Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic diabetes, refers to diabetes caused by disease of the exocrine pancreas. T3cDM is not commonly recognised by clinicians and frequently it is misclassified as T1DM, or more commonly, T2DM. T3cDM can be difficult to distinguish from T1DM and T2DM, and it often co-exists with the latter. The aim of this review is to describe T3cDM, along with its complications, diagnosis and management. We focus on the nutritional implications of T3cDM for those with chronic pancreatitis, and provide a practical guide to the nutritional management of this condition.

Biosynthesis of vitamin B12: the multi-enzyme synthesis of precorrin-4 and factor IV.

BACKGROUND: In order to study the biosynthesis of vitamin B12, it is necessary to produce various intermediates along the biosynthetic pathway by enzymic methods. Recently, information on the organisation of the biosynthetic pathway has permitted the selection of the set of enzymes needed to biosynthesise any specific identified intermediate. The aim of the present work was to use recombinant enzymes in reconstituted multi-enzyme systems to biosynthesise particular intermediates. RESULTS: The products of the cobG and cobJ genes from Pseudomonas denitrificans were expressed heterologously in Escherichia coli to afford good levels of activity of the corresponding enzymes, CobG and CobJ. Aerobic incubation of precorrin-3A with the CobG enzyme alone yielded precorrin-3B. When CobJ and S-adenosyl-L-methionine were included in the incubation, the product was precorrin-4. Both precorrin 3B and precorrin-4 are known precursors of vitamin B12 and their availability has allowed new mechanistic studies of enzymic transformations. CONCLUSIONS: Our results show that the expression of the CobG and CobJ enzymes has been successful, thus facilitating the biosynthesis of two precursors of vitamin B12. This lays the foundation for the structure determination of CobG and CobJ as well as future enzymic experiments focusing on later steps of vitamin B12 biosynthesis.

Gammadelta T cells present antigen to CD4+ alphabeta T cells.

Gammadelta and alphabeta TCR+ T cells share many properties and their interactions are likely to be coordinated and regulated. We provide evidence that cattle gammadelta T cells are able to present antigen to CD4+ T cells. To help elucidate their function gammadelta T cell lines were propagated for extensive characterization. Cells expressed high levels of MHC class II and production of co-stimulatory molecules as evidenced by the binding of a CTLA-4 fusion protein and synthesis of CD80 transcripts. These properties and the presence of a well-developed endosomal compartment indicated the cells might function as antigen-presenting cells. Resting CD4+ T cells from calves immunized with ovalbumin or respiratory syncytial virus-antigen proliferated in response to gammadelta T cells pulsed with antigen that appeared to be endocytosed via clathrin-coated pits or specific receptors.

Outbreak of coral-eating Crown-of-Thorns creates continuous cloud of larvae over 320 km of the Great Barrier Reef.

Coral reefs are in decline worldwide due to a combination of local and global causes. Over 40% of the recent coral loss on Australia's Great Barrier Reef (GBR) has been attributed to outbreaks of the coral-eating Crown-of-Thorns Seastar (CoTS). Testing of the hypotheses explaining these outbreaks is hampered by an inability to investigate the spatio-temporal distribution of larvae because they resemble other planktotrophic echinoderm larvae. We developed a genetic marker and tested it on 48 plankton samples collected during the 2014 spawning season in the northern GBR, and verified the method by PCR amplification of single larva. Surprisingly, most samples collected contained CoTS larvae. Larvae were detected 100 km south of current outbreaks of adult seastars, highlighting the potential for rapid expansion of the outbreak. A minimum estimate suggested that larvae numbers in the outbreak area (>10(10)) are about 4 orders of magnitude higher than adults (~10(6)) in the same area, implying that attempts to halt outbreaks by removing adults may be futile.

Esomeprazole 20 mg on-demand is more acceptable to patients than continuous lansoprazole 15 mg in the long-term maintenance of endoscopy-negative gastro-oesophageal reflux patients: the COMMAND Study.

BACKGROUND: Symptom relief, through adherence to appropriate maintenance therapy, is the sole objective of treatment for patients with endoscopy-negative gastro-oesophageal reflux disease. AIM: To compare the efficacy of 'on-demand' treatment with esomeprazole 20 mg vs. continuous treatment with lansoprazole 15 mg daily in patients with endoscopy-negative gastro-oesophageal reflux disease. METHODS: Endoscopy-negative gastro-oesophageal reflux disease patients who achieved complete resolution of heartburn after short-term (2-4 weeks) treatment with esomeprazole 20 mg (n = 774) were randomized to receive either esomeprazole 20 mg on-demand (n =311) or lansoprazole 15 mg continuous daily treatment (n = 311) for 6 months. RESULTS: Significantly more patients were willing to continue taking esomeprazole on-demand than lansoprazole continuous therapy after 6 months (93% vs. 88%; P = 0.02). This superior outcome was achieved despite patients on esomeprazole requiring medication only 38% as often as those on lansoprazole, leading to direct cost savings of more than one-third (36%). Furthermore, patients receiving esomeprazole 20 mg on-demand were more satisfied with their treatment after 1 month compared with patients taking lansoprazole 15 mg continuously. CONCLUSIONS: In patients with endoscopy-negative gastro-oesophageal reflux disease, esomeprazole 20 mg on-demand is more acceptable to patients and is an economically more effective treatment than lansoprazole 15 mg continuously.

Highly fructose selective transport promoted by boronic acids based on a pentaerythritol core.

We have designed and synthesized a highly lipophilic boronic acid (11) with a molecular shape that makes it much more effective at carrying sugars through organic membranes than a previously used steroidal boronic acid. The corresponding diboronic acid (12) was also found to transport fructose ahead of glucose with a very high selectivity (7.6:1.0). Modeling suggests that 12 is able to carry two fructose molecules at once in a complex stabilized through hydrogen bonding and ion pairing.

Use of differential normal pulse voltammetry for the measurement of locus coeruleus catecholaminergic metabolism in an acute anaesthetized rodent model of allodynia: effect of mexiletine.

Neuropathic pain can be triggered by non-painful stimuli (e.g., light touch), a sensory abnormality termed allodynia. The acute blockade of spinal glycine receptors with intrathecal strychnine induces a reversible allodynia-like state in the rat. We describe the application of in vivo differential normal pulse voltammetry with carbon fibre micro-electrodes for monitoring the catechol oxidation current (CAOC) of the locus coeruleus (LC) in the strychnine model of allodynia. In addition, we tested the effect of mexiletine, a drug useful in the management of clinical neuropathic pain in this model. Our results show that somatosensory processing in the spinal cord of urethane-anaesthetized rats is radically altered during glycine receptor blockade such that the normally innocuous stimulus of hair deflection causes the marked activation of the LC as determined using in vivo differential normal pulse voltammetry. Mexiletine suppressed the LC and cardiovascular responses of strychnine induced allodynia. Results of this study indicate that LC CAOC, an index of LC neuronal activity: (a) is a sensitive biochemical index of strychnine-allodynia; (b) is temporally correlated with the cardiovascular and motor responses evoked by hair deflection during glycine receptor blockade; and (c) can be used to quantitate allodynia in the strychnine model.

The role of excitatory amino acids in the expression of precipitated acute and chronic clonidine withdrawal: an in vivo voltammetric study in the rat locus coeruleus.

It has been previously shown that activation of excitatory amino acid (EAA) pathways contributes to hyperactivity of the locus coeruleus (LC) in antagonist precipitated opioid withdrawal. In this study, using differential normal pulse voltammetry to monitor catechol oxidation as an index of the activity of the LC, the role of EAA pathways in antagonist precipitated withdrawal after acute and chronic clonidine treatment was examined. Intracerebroventricular clonidine (10 micrograms i.c.v.) significantly reduced LC activity to 54.4 +/- 3.1% of baseline 45 minutes following the injection. Subsequent systemic injection of the selective alpha 2 receptor antagonist atipamezole (0.2 mg/kg i.v.) or yohimbine (0.5 mg/kg i.v.) resulted in a rapid reversal of the depressant effects and a significant increase in LC activity above baseline. Pretreatment with the non-selective EAA receptor antagonist gamma-D-glutamylglycine (DGG) (50 micrograms i.c.v.) attenuated the atipamezole-induced rebound response of the LC but not the reversal of clonidine action. However, both the yohimbine-induced rebound and reversal of clonidine effects were attenuated by DGG treated animals. In chronic clonidine treated animals (2, 5, 7, 10 micrograms/h i.c.v., 5 days), a challenge with atipamezole (0.2 mg/kg i.v.) produced an immediate increase in LC activity, blood pressure and heart rate. The magnitude of these responses was dependent on the dose of clonidine. The atipamezole-induced increase in LC activity and blood pressure was significantly attenuated by pretreatment with DGG (200 micrograms i.c.v.). These findings suggest that LC hyperactivity and blood pressure increases elicited during clonidine withdrawal are mediated in part by activation of EAA receptors. In this regard, the mechanisms underlying clonidine withdrawal closely resembles those underlying opioid withdrawal.

Innocuous hair deflection evokes a nociceptive-like activation of catechol oxidation in the rat locus coeruleus following intrathecal strychnine: a biochemical index of allodynia using in vivo voltammetry.

Blockade of spinal glycinergic inhibition with intrathecal (i.t.) strychnine induces a reversible allodynia-like state in both conscious and lightly-anaesthetized rats. Since the locus coeruleus (LC) is activated by noxious stimuli, we determined the effect of non-noxious hair deflection (HD) on noradrenergic neuronal activity in the LC of rats treated with i.t. strychnine. Differential normal pulse voltammetry was used to measure the catechol oxidation current (CA.OC), an index of LC activity. Rats were maintained in a light plane of anaesthesia with i.v. urethane and i.t. strychnine (40 micrograms) was injected near the L1-L2 segment. HD, applied to the caudal dermatomes affected by i.t. strychnine, evoked a significant increase (max. 141 +/- 7%, n = 5, P < 0.05) in CA.OC and mean arterial pressure as compared to baseline (no strychnine). In contrast, HD had no significant effect on CA.OC or mean arterial pressure in the saline-treated rats (n = 5). Pre-treatment with i.t. MK801 (30 micrograms) significantly blocked the increase in CA.OC and mean arterial pressure evoked by HD in strychnine-treated rats. The results of this study indicated that HD, in the presence of i.t. strychnine but not saline, can evoke noradrenergic activity in the LC of lightly anaesthetized rats. This effect on the LC is: (1) comparable to that observed with noxious stimulation without i.t. strychnine; (2) segmentally localized, corresponding to the spinal site of strychnine injection; and (3) mediated by spinal NMDA receptors, consistent with the role of excitatory amino acids in sensory transmission. These data provide the first neurochemical evidence that HD, in the presence of i.t. strychnine, is a nociceptive event, supporting the use of this preparation as an experimental model of allodynia.

Young adults' immediate and delayed reactions to simulated marital conflicts: implications for intergenerational patterns of violence in intimate relationships.

This study investigated the thoughts and feelings that young adults from violent (VPA) and nonviolent (NPA) interparental-conflict backgrounds reported while listening to simulated marital conflicts and after a delay for reflection. While listening to conflicts, VPAs were more likely than NPAs to predict negative outcomes and to place blame. No between-groups differences regarding negative outcomes emerged after a delay. VPAs also reported perpetrating and experiencing more aggressive conflict in their dating relationships. Post hoc probes revealed that the negative-outcome-prediction and blaming variables played no significant mediating role in participants' intergenerational patterns of intimate-relationship aggression; however, methodological limitations likely compromised the statistical power for examining this mediational model. Results are discussed in light of research regarding intergenerational patterns of violence within families.

Doctors' attitudes towards the detection and treatment of hypertension in older people.

Within the former northern region a questionnaire was sent to a one in two random sample of general practitioners and to consultant physicians involved in the treatment of older hypertensive patients, to determine current attitudes of doctors to the management of hypertension in older people. A total of 407 general practitioners and 125 consultant physicians (including 38 consultant geriatricians) completed the questionnaire; response rates of 58% and 73% respectively. The median (range) threshold level for intervention of an otherwise well 75-year-old patient was 180 (140-240)/100 (90-120) mm Hg for general practitioners as against current recommendations of > or = 160/90 mm Hg. Geriatricians adopted significantly lower thresholds than both general practitioners and other specialists. Target blood pressure (BP) and drug therapy were in line with British Hypertension Society recommendations. The majority of general practitioners stated that they would initiate treatment for hypertension later, be less aggressive in their treatment and accept higher levels of BP than with younger patients. Approximately half perceived compliance and lifestyle changes as problematic in older people, while approximately a third were concerned about the problems created by drug treatment and uncertainty about the practicality of treating all older hypertensive patients. A quarter expressed reluctance to initiate hypertensive treatment because of side effects and to treat isolated systolic hypertension. These stated attitudes amongst general practitioners may explain the continuing conservatism in the management of hypertension. This study found considerable variation in diagnostic threshold between doctors, which suggests that current management of hypertension in older people is likely to vary significantly.

Defining hypertension in older people from primary care case notes review.

A method of defining blood pressure (BP) status from a review of primary care patient records was developed and then validated using the case notes of a general practitioner with an interest in hypertension. Data were drawn from the records of the previous 6 years of all 65 to 80-year-old patients in the practice (n = 263). Patients were then categorised as hypertensive, normotensive or 'undetermined' by using a flowchart based on the mean of the three most recent BP measurements, antihypertensive medication and comorbidities of ischaemic heart disease, myocardial infarction, angina, oedema or cardiac failure. Mean systolic BP of > or = 160 mm Hg and/or diastolic BP of > or = 90 mm Hg were used as a threshold definition of hypertension and of BP control. Disagreement between general practitioner and the notes based definition occurred in 11% of patients (5% hypertensive, 6% normotensive). Reasons for disagreement were: controlled hypertensives with comorbidities such as angina or heart failure (4%), isolated elevated readings (3%), use of antihypertensive medication for separate indications (2%), other reasons (2%). The resulting sensitivity and specificity was 86% and 88% respectively. Including the recording of a diagnosis of hypertension in the definition increased the sensitivity to 98% with specificity unchanged at 88%. Actual sensitivity of the instrument when used in other practices is likely to lie between 88% and 98% depending on the quality of the doctor's recording of the diagnosis of hypertension. These findings suggest that data from primary care case notes can provide a ready and valid means of defining cases of hypertension for studying the management of hypertension in primary care and for research purposes.

Bovine interleukin-12 and modulation of IFNgamma production.

The effects of IL-12 on the responses of cattle peripheral blood mononuclear cells (PBMC) to bovine respiratory syncytial virus (BRSV) antigen and ovalbumin (OVA) were tested, in vitro. IL-12 did not affect the proliferative responses of PBMC to these antigens but markedly accelerated and augmented the level of IFNgamma secreted. When tested on lymphoblasts rather than resting T-cells IL-12 also enhanced proliferation. In contrast IL-4 and, to greater extent, IL-10 inhibited the response. The effect of IL-12 on IFNgamma synthesis was confirmed at the level of IFNgamma. mRNA expression using Taqman PCR. CD4 and CD8 T-cell populations produced IFNgamma, however, CD4 T-cells comprised the largest contributors to the IFNgamma production. Gamma/delta T-cells did not contribute markedly. A comparison of the species cross-reactivity showed bovine IL-12 was also active in the human system. This study shows that antigen-driven responses in cattle can be significantly influenced by exogenous cytokines and suggests the IL-12/IL-10 balance is crucial for regulation of IFNgamma.