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While aspects of cellular fatty acid uptake have been studied as early as 50 years ago, recent developments in this rapidly evolving field have yielded new functional insights on the individual mechanistic steps in this process. The extremely low aqueous solubility of long chain fatty acids (LCFA) together with the very high affinity of serum albumin and cytoplasmic fatty acid binding proteins for LCFA have challenged the limits of technology in resolving the individual steps of this process. To date no single mechanism alone accounts for regulation of cellular LCFA uptake. Key regulatory points in cellular uptake of LCFA include: the aqueous solubility of the LCFA; the driving force(s) for LCFA entry into the cell membrane; the relative roles of diffusional and protein mediated LCFA translocation across the plasma membrane; cytoplasmic LCFA binding protein-mediated uptake and/or intracellular diffusion; the activity of LCFA-CoA synthetase; and cytoplasmic protein mediated targeting of LCFA or LCFA-CoAs toward specific metabolic pathways. The emerging picture is that the cell has multiple, overlapping mechanisms that assure adequate uptake and directed intracellular movement of LCFA required for maintenance of physiological functions. The upcoming challenge is to take advantage of new advances in this field to elucidate the differential interactions between these pathways in intact cells and in tissues.—McArthur, M. J., B. P. Atshaves, A. Frolov, W. D. Foxworth, A. B. Kier, and F. Schroeder. Cellular uptake and intracellular trafficking of long chain fatty acids. J. Lipid Res. 1999. 40: 1371–1383.

Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.

In aquifers 160 to 260m deep that used for public water-supply in an area ~150km 2 around the town of Cremona, in the Po Plain of Northern Italy, concentrations of arsenic (As) are increasing with time in some wells. The increase is due to drawdown of As-polluted groundwater (As ≤144μg/L) from overlying aquifers at depths 65 to 150m deep in response to large-scale abstraction for public supply. The increase in As threatens drinking-water quality locally, and by inference does so across the entire Po Plain, where natural As-pollution of groundwater (As >10μg/L) is a basin-wide problem. Using new and legacy data for Cl/Br, δ 18 O/δ 2 H and other hydrochemical parameters with groundwater from 32 wells, 9 surface waters, a sewage outfall and rainwater, we show that the deep aquifer (160-260m below ground level), which is tapped widely for public water-supply, is partly recharged by seepage from overlying aquifers (65-150m below ground level). Groundwater quality in deep aquifers appears free of anthropogenic influences and typically <10μg/L of As. In contrast, shallow groundwater and surface water in some, not all, areas are affected by anthropogenic contamination and natural As-pollution (As >10μg/L). Outfalls from sewage-treatment plants and black water from septic tanks firstly affect surface waters, which then locally infiltrate shallow aquifers under high channel-stages. Wastewater permeating shallow aquifers carries with it NO 3 and SO 4 which suppress reduction of iron oxyhydroxides in the aquifer sediments and so suppress the natural release of As to groundwater., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Hip fracture care has evolved, largely due to standardisation of practice, measurement of outcomes and the introduction of the Best Practice Tariff, leading to the sustained improvements documented by the National Hip Fracture Database (NHFD). The treatment of distal femoral fractures in this population has not had the same emphasis. This study defines the epidemiology, current practice and outcomes of distal femoral fractures in four English centres., Patients and Methods: 105 patients aged 50 years or greater with a distal femoral fracture, presenting to four UK major trauma centres between October 2010 and September 2011 were identified. Data was collected using an adapted NHFD data collection tool via retrospective case note and radiograph review. Local ethics approval was obtained., Results: Mean age was 77 years (range 50-99), with 86% female. 95% of injuries were sustained from a low energy mechanism, and 72% were classified as either 33-A1 or 33-C1. The mean Parker mobility score and Barthel Independence Index were 5.37 (0-9) and 75.5 (0-100) respectively. Operative management was performed in 84%, and 86% had their surgery within 36 h. Three quarters were fixed with a peri-articuar locking plate. There was no consensus on post operative rehabilitation, but no excess of complications in the centres where weight bearing as tolerated was the standard. 45% were seen by an orthogeriatrician during their admission. Mean length of stay was 29 days. Mortality at 30 days, 6 months, and 1 year was 7%, 16% and 18% respectively., Discussion: This study demonstrates that the distal femoral and hip fracture populations are similar, and highlights the current disparity in their management. The metrics and standards of care currently applied to hip fractures should be applied to the treatment of distal femoral fractures. Optimal operative treatment and rehabilitation remains unclear, and is in need of further research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Intraepidermal nerve fiber density (IENFD) is a sensitive measure of small fiber injury, and holds promise as a clinical trial endpoint measure. A total of 48 punch biopsies were obtained from 22 patients. Tissue was sectioned and stained with PGP9.5. The relative intertrial variability (RIV) of IENFD measurements for each section and punch made by two different observers was determined (interobserver variability). Intraobserver variability (same observer measuring twice) was determined for 50% of the sections and punches. Sections from 12 punch biopsies were also stained at a second laboratory. The effect of the number of sections counted and processing site on reproducibility was investigated. A total of 223 sections were analyzed. The mean IENFD was 6.7 fibers/mm. Mean (+/-standard deviation) interobserver variability was 9.6%+/-9.4 for each biopsy site and 10.2%+/-11.9 for individual sections. Mean intraobserver variability was 9.6%+/-8.9 for biopsies, and 8.8%+/-9.0 for sections. There was no significant difference in IENFD for tissue stained at different laboratories. Intraclass correlation coefficients were greater than 0.98 for each comparison. There was no relationship between absolute IENFD and reproducibility. Reproducibility was highest when four sections were counted. IENFD measurement is highly reproducible. At least four sections should be analyzed. Reliability does not vary with severity of disease. These findings suggest IENFD may be a useful endpoint measure in future neuropathy treatment trials.

The spatial distributional pattern of neurons, in the superior frontal gyrus of 32 subjects who died of acquired immune deficiency syndrome, was examined. The patients were classified as nondemented, mildly demented, and severely demented, and some were treated with the anti-retroviral drug zidovudine. Spatial statistical techniques were employed to investigate the degree of clustering in the individual cases and various groups. We found that the cluster pattern of large and small neurons differed significantly with increasing severity of dementia but was not influenced by the duration of zidovudine treatment. We conclude that this is a sensitive technique for clinicopathological correlations and that the differences may result from loss of specific neuronal populations, which could determine the degree of dementia.