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The highway maintenance sector within the United Kingdom consumes considerable amounts of natural resources and accounts for a large amount of carbon emissions. Carbon emissions reduction is now considered an integral part of tender selection criteria and project performance issue by highway clients. This requires contractors to be able to assess and reduce both direct and indirect emissions associated with highway maintenance. This presents a challenge for the sector as despite the availability of methods to assess carbon there are no routine tools to allow a lifecycle assessment (LCA) approach to carbon reduction as part of ongoing maintenance management. Thus, there is a need for a consistent, project-focused carbon assessment tool, underpinned by a robust LCA methodology that can assess emissions and emissions reduction across core highway maintenance processes. This paper describes the development and business implementation of such a tool based on the Publicly Available Specification (PAS) 2050 protocol. The protocol is an independent standard developed by the British Standards Institution (BSI) in 2008 and updated in 2011 to produce a consistent approach for lifecycle emissions assessment from goods and services. It offers an iterative process, where the scope and objectives of the assessment are defined, relevant data collected for analysis and interpreted within the scope and system boundary defined by the standard. Twelve case studies were undertaken using the tool and the results demonstrated the tool's potential to produce credible emissions information that can be integrated into highway maintenance decision-making processes. The tool identifies areas of emissions hotspots, opportunities for reduction, and then establishes a reduction hierarchy that can allow emissions reduction efforts to be prioritized in lifecycle terms. The study further presents sensitivity analyses with respect to choice of fuel, distance to site, material transport mode and distance, and design life of pavements. Although the implementation of the tool presented in this paper is specific to pavement resurfacing works, the tool can also be used to assess carbon emissions for other core highway maintenance processes, such as road marking, street lighting works and grass cutting, with the potential to evaluate full environmental impacts (e.g., Toxicity, Acidification and Ozone formation) associated with such highway maintenance processes. [ABSTRACT FROM AUTHOR]

A 6-week-old Staffordshire Bull Terrier cross was presented with a 4-week history of vomiting and small bowel diarrhoea. Abdominal ultrasound showed thickening of the distal jejunum and ileum. The dog underwent two exploratory laparotomies, during which grossly abnormal sections of intestine were resected. The patient developed septic peritonitis 48 h after the second surgery, caused by dehiscence of an intestinal anastomosis, and was euthanased. All intestinal tissue samples were examined histopathologically and a diagnosis of gastrointestinal ganglioneuromatosis was made. Intestinal ganglioneuromatosis is rare and this case represents a novel occurrence in the small intestine of a dog. [ABSTRACT FROM AUTHOR]

A correction to the article "Small intestinal ganglioneuromatosis in a dog" that was published in the 2011 issue is presented.

Background/aim: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in cancer. Buparlisib (BKM120), an oral pan-PI3K inhibitor, inhibits proliferation of human cancer in preclinical models. Studies of buparlisib in Western and Japanese adults with advanced solid tumors established a recommended dose of 100 mg/day and showed an acceptable safety profile and evidence of efficacy. This phase I dose-escalation/expansion study aimed to establish the maximum tolerated dose (MTD) of single-agent, once daily oral buparlisib in Chinese patients with advanced solid tumors., Materials and Methods: Patients (n=32; primary tumor site: lung (n=15), breast (n=10) or head and neck (n=7); ≥2 prior lines of antineoplastic therapy (n=26)) received 80 mg (n=15) or 100 mg (n=17) daily buparlisib., Results: Five patients experienced dose-limiting toxicities: grade (G)3 depression (n=1), G2 hyperglycemia (n=3) and G3 hyperglycemia (n=1). Most frequent buparlisib-related adverse events were hyperglycemia (n=18; 56%), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase (n=9; 28%), as well as anxiety (n=6; 19%); most common buparlisib-related G3/4 adverse events: hyperglycemia (n=3; 9%), ALT and AST increase (n=2; 6%), as well as gamma-glutamyltransferase increase (n=2; 6%). Best response was stable disease (SD) in 10 patients (31%)., Conclusion: The MTD of buparlisib was declared as 100 mg/day. Safety, efficacy and pharmacokinetic data from this study were similar to those previously reported in Western and Japanese populations., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞ ] and Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0-1.3 h). Buparlisib exposure (AUC∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment., (© 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Purpose: To determine the pharmacokinetics of the p110α-selective inhibitor alpelisib (BYL719) in humans, to identify metabolites in plasma and excreta, and to characterize pathways of biotransformation., Methods: Four healthy male volunteers received a single oral dose of [(14)C]-labeled alpelisib (400 mg, 2.78 MBq). Blood, urine, and feces samples were collected throughout the study. Total radioactivity was measured by liquid scintillation counting, and metabolites were quantified and identified by radiometry and mass spectrometry. Complementary in vitro experiments characterized the hydrolytic, oxidative, and conjugative enzymes involved in metabolite formation., Results: Over 50 % of [(14)C] alpelisib was absorbed, with a T(max) of 2 h and an elimination half-life from plasma of 13.7 h. Over the first 12 h, exposure to alpelisib and the primary metabolite M4 was 67.9 and 26.7 % of total drug-related material in circulation, respectively. Mass balance was achieved, with 94.5 % of administered radioactivity recovered in excreta. In total, 38.2 % of alpelisib was excreted unchanged, while 39.5 % was excreted as M4. Based on the excreta pools analyzed, excretion occurred mainly via feces (79.8 % of administered dose); 13.1 % was excreted via urine. In vitro experiments showed that spontaneous and enzymatic hydrolysis contributed to M4 formation, while CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation formed minor metabolites. Alpelisib was well tolerated, and no new safety concerns were raised during this study., Conclusions: Alpelisib was rapidly absorbed and cleared by multiple metabolic pathways; the primary metabolite M4 is pharmacologically inactive. Alpelisib has limited potential for drug-drug interactions and is therefore a promising candidate for combination therapy.

A 7-year-old, spayed female Domestic Longhair cat was evaluated for a 6-week history of coughing. Thoracic radiography revealed a pleural effusion. Thoracic ultrasound revealed a pleural effusion and a focal lung mass. The cat underwent exploratory thoracotomy and a total left pneumonectomy was performed. Histopathology and cultures revealed fungal pneumonia and pyothorax caused by Aspergillus fumigatus. Abdominal ultrasound, repeat thoracic radiography, urinalysis with culture, and retroviral screening failed to detect evidence of systemic disease. The cat's poorly regulated diabetes mellitus is suspected to be the predisposing factor allowing a fungal pulmonary infection to become established. At 18 months after surgery the cat was still disease-free. To our knowledge this is the first reported case of successful treatment of pulmonary aspergillosis in the cat., (© 2011 The Authors. Australian Veterinary Journal © 2011 Australian Veterinary Association.)

Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).

Purpose: To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients., Patients and Methods: Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats., Results: Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses., Conclusion: A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.