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.

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.

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.

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.

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.

Tracking the Salmonella status of pigs and pork from lairage through the slaughter process in the Republic of Ireland.

Salmonella Typhimurium is the predominant serotype isolated from humans in Europe. Pork and pork products are recognized vehicles of Salmonella and are responsible for outbreaks of human salmonellosis. Pigs can become infected with Salmonella on the breeding or fattening farm and during transport, lairage, and slaughter. The aim of this study was to investigate selected points of Salmonella contamination from the time pigs entered the lairage to the time the carcass was processed in the boning hall and to determine the importance of different sources of Salmonella along the Irish pork production chain. A second objective was to evaluate whether the serological status or category of a herd influenced the levels of bacteriological contamination detected on individual carcasses and pork cuts during slaughter and dressing operations. All samples were tested for the presence and numbers of Salmonella. Enterobacteriaceae numbers were also determined. Serotype, phage type, and pulsed-field gel electrophoresis were utilized to determine similarity among Salmonella isolates. Lairage was a major source of cross-contamination with Salmonella as were the hands of evisceration operatives, conveyor belts, and equipment in the boning hall. Cross-contamination within the slaughter plant environment accounted for up to 69 % of Salmonella carcass contamination. In general, herd category reflected the bacteriological status of carcasses and pork cuts. Major findings were a strong association (P < 0.01) between Enterobacteriaceae counts and Salmonella occurrence on prechill carcasses and a significant association (P < 0.05) between Enterobacteriaceae counts and Salmonella occurrence on pork cut samples.

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.

Blind bedside insertion of small bowel feeding tubes.

BACKGROUND: The use of Naso-Jejunal (NJ) feeding is limited by difficulty in feeding tube placement. Patients have traditionally required transfer to Endoscopy or Radiology for insertion of small bowel feeding tubes, with clear resource implications. We hypothesised that the adoption of a simple bedside procedure would be effective and reduce cost. Clinical nutrition and nurse specialist personnel were trained in the 10/10/10 method of blind bedside NJ insertion. AIMS: The aims of this prospective study were to evaluate safety, efficaciousness and resource implications of bedside NJ tube insertion. METHODS: A total of 22 patients had 37 NJ tubes inserted in the study period (12 months). The majority were inserted by either a nurse specialist or clinical nutritionist. RESULTS: Out of the 37 insertions, 32 (86%) were in the correct position. Compared to Endoscopy insertion, this technique saved an estimated €8,353.60 for the duration of the study. CONCLUSION: This study demonstrates that the bedside insertion of NJ tubes by clinical nutritionists and nurse specialists is safe, efficacious and highly cost effective.

Prevalence, numbers and characteristics of Salmonella spp. on Irish retail pork.

Salmonella is a common contaminant of raw pork and represents a public health risk. Both qualitative and quantitative data on Salmonella in pork at retail are required for assessment of consumer exposure to the pathogen. Pork samples (n=500) were collected at random from butchers' shops and supermarkets in the Republic of Ireland between January and November, 2007 and examined for prevalence and numbers of Salmonella using a PCR screen followed by cultural examination of positive samples. Salmonella numbers were assessed using a three tube most probable number (MPN) technique. Any Salmonella recovered were characterised by serotype, phage type and antibiogram, and subtyped by pulsed-field gel electrophoresis (PFGE). Enterobacteriaceae were also enumerated to see if there was a correlation between the Salmonella status of the pork and hygiene levels at retail outlets. Salmonella spp. were detected on 13/500 (2.6%) pork cuts at numbers between <0.03 and 2.10 MPN/g. The mean Enterobacteriaceae counts was 3.12 log(10) CFU/g (range -0.26-6.52 log(10) CFU/g). Salmonella Typhimurium was the most common serotype and the majority of isolates were multi antibiotic resistant. PFGE analysis showed evidence of persistence of some strains, with an S. Typhimurium U310 recovered from a pork abattoir being identical (100%) to a strain found a year later in a sample from a retail outlet. There was also evidence of cross contamination of Salmonella isolates between samples. There was a direct association between Salmonella contamination of pork and Enterobacteriaceae numbers, which indicates the need for good hygiene practices at retail for control of this pathogen.

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 sainsbury centre for mental health: forensic mental health services in England and wales]. / El Centro Sainsbury de Salud Mental: Los Servicios Forenses de Salud Mental en Inglaterra y el País de Gales.

The Sainsbury Centre for Mental Health (SCMH) is a charity founded in 1985 by Gatsby Charitable Foundation. The SCMH works to improve the quality of life for people with mental health problems by influencing policy and practice in mental health and related services. Working to improve the quality of mental health care for people in prison is one of SCMH main work theme. This paper describes some epidemiological aspects of mental health situation of prisoners in England and Wales and the available forensic facilities to manage this kind of patients in prison.

The care home activity project: does introducing an occupational therapy programme reduce depression in care homes?

The primary aim of the study was to test the hypothesis that depression severity in care homes for older people would be reduced by an occupational therapy programme. This was a feasibility study for a cluster randomised controlled trial and involved four intervention and four control homes in northern England. In each intervention home a registered occupational therapist worked full-time for one year delivering an individualised programme to participants. Pre- and post-intervention data for the Geriatric Mental State-Depression Scale (primary outcome measure) were obtained for 143 participants. Secondary outcomes included dependency and quality of life. No significant intervention effects were found in any of the quantitative outcome measures, though qualitative interviews showed the intervention was valued by many participants, staff and relatives. Therapist ratings and qualitative interviews suggested that the intervention was beneficial to some participants but no distinctive characteristics were found that might enable prediction of likely benefit on initial assessment. This exploratory study provides no evidence that this intervention produced benefits in terms of depression, dependency or quality of life. Lack of prior power calculations means these are not definitive findings; but numbers were sufficient to perform the required analyses and data did not suggest effects that would have reached statistical significance with a larger sample. This study highlights issues for consideration in providing such services in care homes.

Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

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.

Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose.

BACKGROUND: Previous studies have indicated the benefits of adding long acting beta(2) agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma. The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied. METHODS: After a run in period of 7-14 days on existing medication, 663 symptomatic patients were randomised to receive budesonide Turbohaler 400 microg twice daily together with either eformoterol Turbohaler 9 micro g (delivered dose) or placebo twice daily. After 4 weeks patients whose asthma was well controlled (n=505) were re-randomised to receive budesonide 400 microg daily and either eformoterol 9 micro g or placebo twice daily for a further 6 months. RESULTS: Patients receiving eformoterol achieved asthma control 10 days sooner than those receiving budesonide alone, and improvements in lung function, symptoms, quality of life, and relief beta(2) agonist use were significantly greater with eformoterol. During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone (7.2 versus 10.5 per patient, 95% confidence interval for ratio 0.49 to 0.96, p=0.03). The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group (p=0.003). CONCLUSIONS: Adding eformoterol to a low or moderate dose of budesonide in mild asthma resulted in faster and more effective control than treatment with budesonide alone. Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone. These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma.

Development of an ELISA for bovine IL-10.

The objective of the study was to develop an assay for bovine IL-10 that could be applied to analyses of immune responses and advance understanding of a variety of diseases of cattle. Recombinant bovine IL-10 (rbo IL-10) was transiently expressed in Cos-7 cells and shown to inhibit the synthesis of IFN gamma by bovine cells stimulated with antigen in vitro. Mice were immunised with a plasmid containing a cDNA insert encoding rbo IL-10 and inoculated with rbo IL-10. A number of monoclonal antibodies (mAb) were generated that reacted with rbo IL-10 in an ELISA. Some of these mAb neutralised the ability of rbo IL-10 to inhibit IFN gamma synthesis by antigen-stimulated bovine cells. A pair of mAb was identified that together could be used to detect both recombinant and natural bovine IL-10 present in supernatant of PBMC stimulated with ConA. A luminescent detection method was applied to the ELISA making it more sensitive. Using this method native IL-10 was detected in supernatants of PBMC, diluted blood and undiluted blood from cattle immunised with Mycobacterium bovis BCG or ovalbumin and incubated in vitro with antigen indicating the applicability of the assay to a number of in vitro culture systems.