Renal failure parathyroidectomy - Is pre-operative imaging worthwhile?

BACKGROUND: Tertiary hyperparathyroidism is a significant issue in renal failure patients and some require surgery to control their serum calcium. A number of imaging techniques are used to localise the position of the parathyroid glands prior to surgery. Currently, a combination of ultrasound and isotope preoperative localisation imaging is accepted as useful in parathyroid surgery for primary disease. However, the use of pre-operative imaging in parathyroid surgery in renal failure patients is uncertain. The role of pre-operative imaging of the parathyroid glands in patients with renal failure hyperparathyroidism was assessed with imaging outcomes compared to operative and pathological findings in two cohorts of patients undergoing parathyroid surgery - primary and tertiary. METHODS: All data were collected prospectively over a 10-year period (2003-2013) from the practice of a single surgeon. Patients were grouped into either primary hyperparathyroidism (49 patients) or tertiary hyperparathyroidism (41 patients). The majority, 63 of 90 (70%) patients, underwent both ultrasound (US) and isotope (MIBI) pre-operative imaging. Pre-operative imaging was correlated with operative and pathological findings. FINDINGS: Comparison of the results of the two groups using ordinal regression analysis confirmed these imaging techniques are significantly more accurate in primary than tertiary parathyroid surgery (p = 0.022). CONCLUSIONS: While accepted practice of pre-operative combined USS and MIBI imaging is essential in unilateral imaged-focused neck exploration for primary disease, these imaging techniques have a more limited use pre-operatively in renal failure parathyroidectomy.

Complex mixture toxicology: Evaluation of toxicity to freshwater aquatic receptors from biodegradation metabolites in groundwater at a crude oil release site, recent analogous results from other authors, and implications for risk management.

Aquatic toxicity posed by the complex mixture of biodegradation metabolites and related oxygen-containing organic compounds (OCOCs) in groundwater at typical petroleum release sites is of concern to regulatory agencies; several are using results from laboratory studies in older literature that are not appropriate analogs for risk management. Recent field studies from typical sites and natural groundwater should be utilized. In this study, OCOCs downgradient of the biodegrading crude oil release at the USGS Bemidji site were tested for freshwater aquatic toxicity using unaltered whole groundwater samples. This type of testing is optimal because the entire mixture of OCOCs present is tested directly and assessment is not affected by analytical limitations. Ceriodaphnia dubia and Pimephales promelas were tested for toxicity using USEPA Methods 1002 and 1000, which estimate chronic toxicity. OCOCs in representative samples up to the maximum concentration tested of 1710 ug/L Total Petroleum Hydrocarbons (TPH) (nC10 to nC40; without silica gel cleanup) did not result in effects relative to the lab control for C. dubia survival, or for P. promelas survival or growth; and did not result in effects above background for C. dubia reproduction. This is consistent with findings using the same testing methods and species on samples from 14 biodegrading fuel release sites: OCOCs did not cause increased toxicity relative to background at a maximum tested concentration of 1800 ug/L TPH (nC10 to nC28). Based on their toxicity testing using the same species and USEPA methods on groundwater from a biodegrading diesel release site, Washington Department of Ecology recently set a freshwater screening level for OCOCs at 3000 ug/L TPH ("Weathered DRO"). These studies indicate that, in the absence of dissolved hydrocarbons, OCOCs in groundwater from typical biodegrading fuel or crude oil releases are not toxic to C. dubia or P. promelas at typical concentrations.

Ocular Injury Associated With Prone Positioning in Adult Critical Care: A Systematic Review and Meta-Analysis.

PURPOSE: Prone positioning during the COVID-19 pandemic has become increasingly used as an adjunct to increase oxygenation in critical care patients. It is associated with an adverse event profile. This study sought to investigate the occurrence of ocular injuries reported in prone versus supine groups in adult critical care. DESIGN: Systematic review and meta-analysis. METHODS: A systematic review and meta-analysis were carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed, SCOPUS, and the Cochrane Library were searched. The search period was January 1, 1990, to July 1, 2020. RESULTS: Eleven randomized controlled trials were included, with 2,247 patients. Twenty-eight events were recorded in 3 trials (174 patients) and no events in the other 8 trials (2,073 patients). The rates of eye injury were 5 events in 1,158 patients (1.30%) and 13 events in 1,089 patients (1.19%) in the prone and supine groups, respectively, which were reduced to 2 of 1,158 patients (0.17%) and 2 of 1,089 patients (0.18%), respectively, when reports of eye or eyelid edema were removed. Meta-analysis demonstrated no significant differences between groups with (an OR of 1.40 (95% CI: 0.37-5.27) and without (OR: 0.78; 95% CI: 0.11-5.73) reported edema. CONCLUSIONS: This meta-analysis showed no significant difference in the rate of reported ocular injury between prone and supine critical care groups. These rates remain higher than the incidence reported during general anesthesia. There is a need for studies in critical care settings in which ocular injury is an end-point and which include extended patient follow-up.

Selection of Representative Constituents for Unknown, Variable, Complex, or Biological Origin Substance Assessment Based on Hierarchical Clustering.

Many of the newly produced and registered substances are complex mixtures or substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs). The latter often consist of a large number of constituents, some of them difficult-to-identify constituents, which complicates their (eco)toxicological assessment. In the present study, through a series of examples, different scenarios for selection of representatives via hierarchical clustering of UVCB constituents are exemplified. Hierarchical clustering allows grouping of the individual chemicals into small sets, where the constituents are similar to each other with respect to more than one criterion. To this end, various similarity criteria and approaches for selection of representatives are developed and analyzed. Two types of selection are addressed: (1) selection of the most "conservative" constituents, which could be also used to support prioritization of UVCBs for evaluation, and (2) obtaining of a small set of chemical representatives that covers the structural and metabolic diversity of the whole target UVCBs or a mixture that can then be evaluated for their environmental and (eco)toxicological properties. The first step is to generate all plausible UVCB or mixture constituents. It was found that the appropriate approach for selecting representative constituents depends on the target endpoint and physicochemical parameters affecting the endpoint of interest. Environ Toxicol Chem 2021;40:3205-3218. © 2021 SETAC.

Opposing actions of insulin and arsenite converge on PKCdelta to alter keratinocyte proliferative potential and differentiation.

When cultured human keratinocytes reach confluence, they undergo a program of changes replicating features of differentiation in vivo, including exit from the proliferative pool, increased cell size, and expression of specialized differentiation marker proteins. Previously, we showed that insulin is required for some of these steps and that arsenite, a human carcinogen in skin and other epithelia, opposes the differentiation process. In present work, we show that insulin signaling, probably through the IGF-I receptor, is required for the increase in cell size accompanying differentiation and that this is opposed by arsenite. We further examine the impact of insulin and arsenite on PKCdelta, a known key regulator of keratinocyte differentiation, and show that insulin increases the amount, tyrosine phosphorylation, and membrane localization of PKCdelta. All these effects are prevented by exposure of cells to arsenite or to inhibitors of downstream effectors of insulin (phosphotidylinositol 3-kinase and mammalian target of rapamycin). Retrovirally mediated expression of activated PKCdelta resulted in increased loss of proliferative potential after confluence and greatly increased formation of cross-linked envelopes, a marker of keratinocyte terminal differentiation. These effects were prevented by removal of insulin, but not by arsenite addition. We further demonstrate a role for src family kinases in regulation of PKCdelta. Finally, inhibiting epidermal growth factor receptor kinase activity diminished the ability of arsenite to prevent cell enlargement and to suppress insulin-dependent PKCdelta amount and tyrosine 311 phosphorylation. Thus suppression of PKCdelta signaling is a critical feature of arsenite action in preventing keratinocyte differentiation and maintaining proliferative capability.

Human and Aquatic Toxicity Potential of Petroleum Biodegradation Metabolite Mixtures in Groundwater from Fuel Release Sites.

The potential toxicity to human and aquatic receptors of petroleum fuel biodegradation metabolites (oxygen-containing organic compounds [OCOCs]) in groundwater has been investigated as part of a multi-year research program. Whole mixtures collected from locations upgradient and downgradient of multiple fuel release sites were tested using: 1) in vitro screening assays for human genotoxicity (the gamma-H2AX assay) and estrogenic effects (estrogen receptor transcriptional activation assay), and 2) chronic aquatic toxicity tests in 3 species (Ceriodaphnia dubia, Raphidocelis subcapitata, and Pimephales promelas). In vitro screening assay results demonstrated that the mixtures did not cause genotoxic or estrogenic effects. No OCOC-related aquatic toxicity was observed and when aquatic toxicity did occur, upgradient samples typically had the same response as samples downgradient of the release, indicating that background water quality was impacting the results. This information provides additional support for previous work that focused on the individual compounds and, taken together, indicates that OCOCs from petroleum degradation at fuel release sites are unlikely to cause toxicity to human or freshwater receptors at the concentrations present. Environ Toxicol Chem 2020;39:1634-1645. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Arsenite and insulin exhibit opposing effects on epidermal growth factor receptor and keratinocyte proliferative potential.

Previous work has suggested that arsenic exposure contributes to skin carcinogenesis by preserving the proliferative potential of human epidermal keratinocytes, thereby slowing the exit of putative target stem cells into the differentiation pathway. To find a molecular basis for this action, present work has explored the influence of arsenite on keratinocyte responses to epidermal growth factor (EGF). The ability of cultured keratinocytes to found colonies upon passaging several days after confluence was preserved by arsenite and EGF in an additive fashion, but neither was effective when the receptor tyrosine kinase activity was inhibited. Arsenite prevented the loss of EGF receptor protein and phosphorylation of tyrosine 1173, preserving its capability to signal. The level of nuclear beta-catenin was higher in cells treated with arsenite and EGF in parallel to elevated colony forming ability, and expression of a dominant negative beta-catenin suppressed the increase in both colony forming ability and yield of putative stem cells induced by arsenite and EGF. As judged by expression of three genes regulated by beta-catenin, this transcription factor had substantially higher activity in the arsenite/EGF-treated cells. Trivalent antimony exhibited the same effects as arsenite. A novel finding is that insulin in the medium induced the loss of EGF receptor protein, which was largely prevented by arsenite exposure.

Arsenite maintains germinative state in cultured human epidermal cells.

Arsenic is a well-known carcinogen for human skin, but its mechanism of action and proximal macromolecular targets remain to be elucidated. In the present study, low micromolar concentrations of sodium arsenite maintained the proliferative potential of epidermal keratinocytes, decreasing their exit from the germinative compartment under conditions that promote differentiation of untreated cells. This effect was observed in suspension and in post-confluent surface cultures as measured by colony-forming ability and by proportion of rapidly adhering colony-forming cells. Arsenite-treated cultures exhibited elevated levels of beta1-integrin and beta-catenin, two proteins enriched in cells with high proliferative potential. Levels of phosphorylated (inactive) glycogen synthase kinase 3beta were higher in the treated cultures, likely accounting for the increased levels of transcriptionally available beta-catenin. These findings suggest that arsenic could have co-carcinogenic and tumor co-promoting activities in the epidermis as a result of increasing the population and persistence of germinative cells targeted by tumor initiators and promoters. These findings also identify a critical signal transduction pathway meriting further exploration in pursuit of this phenomenon.

Biological activity of inorganic arsenic and antimony reflects oxidation state in cultured human keratinocytes.

Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a phosphate analogue, its potency in vivo appears to be enhanced by reduction to arsenite. To understand the relative importance of this reduction, which is critical in evaluating the responsiveness of cell culture models to the different oxidation states and thus to elucidating the mechanism of arsenic action, present work has correlated the extent of reduction with biological activity in human keratinocytes. The results show that at biologically relevant concentrations, arsenate reduction to appreciable levels required several days, helping rationalize a previous empirical observation that it was approximately one-third as potent as arsenite. The relatively low conversion rate also emphasizes a limitation of culture; arsenate was nearly as efficacious as arsenite, but the time required for it to reach maximal effect exceeded ordinary medium change intervals. In keratinocytes, an important role for purine nucleoside phosphorylase in the reduction could not be demonstrated, indicating that another pathway is dominant in this cell type. Methylation of inorganic arsenic, uptake of methylated forms, and their reduction were all very slow. These findings suggest that the reduced methylated forms have only a small contribution to skin carcinogenesis unless they are supplied through the circulation. In parallel experiments, trivalent antimony was similar to arsenite in potency and efficacy, whereas pentavalent antimony was virtually without biological effect. Conversion of antimony in the pentavalent to the trivalent oxidation state was not detectable in keratinocytes. These findings emphasize the importance of intracellular reduction of the metalloids for biological effects.