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Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically., (© 2024. The Author(s).)

Core temperature stability is the result of a dynamically regulated balance of heat loss and gain, which is not reflected by a simple thermometer reading. One way in which these changes manifest is in perceived thermal comfort, 'feeling too cold' or 'feeling too hot', which can activate stress pathways. Unfortunately, there is surprisingly little preclinical research that tracks changes in perceived thermal comfort in response to either disease progression or various treatments. Without measuring this endpoint, there may be missed opportunities to evaluate disease and therapy outcomes in murine models of human disease. Here, we discuss the possibility that changes in thermal comfort in mice could be a useful and physiologically relevant measure of energy trade-offs required under various physiological or pathological conditions., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Recent studies have highlighted a key role played by the sympathetic nervous system (SNS) and adrenergic stress in mediating immune suppression associated with chronic inflammation in cancer and other diseases. The connection between chronic SNS activation, adrenergic stress and immune suppression is linked in part to the ability of catecholamines to stimulate the bone marrow release and differentiation of myeloid-derived suppressor cells (MDSC). Rodent model studies have revealed an important role for β-adrenergic receptor signalling in suppression of cancer immunity in mice subjected to chronic stresses, including thermal stress. Importantly, therapeutic blockade of beta-adrenergic responses by drugs such as propranolol can partially reverse the generation and differentiation of MDSC, and partly restore tumour immunity. Clinical trials in both humans and dogs with cancer have demonstrated that propranolol blockade can improve responses to radiation therapy, cancer vaccines and immune checkpoint inhibitors. Thus, the SNS stress response has become an important new target to relieve immune suppression in cancer and other chronic inflammatory conditions., (© 2023 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD., Competing Interests: Declaration of interests P.L.M. has received honoraria from and participated in advisory boards for Bristol Myers Squibb, Bluebird, Celgene, Janssen, Juno, Karyopharm, Magenta Therapeutics, Oncopeptides and Takeda. B.R.B serves on advisory boards for Magenta Therapeutics and BlueRock Therapeutics; receives research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Pharmaceuticals Corp., and Carisma Therapeutics, Inc.; and is a co-founder of Tmunity Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hudson Bay is a small arctic inland shelf sea which receives large amounts of freshwater from riverine discharges, with marine flow from the north and the Atlantic. A warming climate has resulted in an expanded open water season which will result in an increase in shipping of fuel oil and petroleum to communities and mines on the western shore, increasing the risk of hydrocarbon releases. To evaluate the status of hydrocarbons, surface sediments were collected at 34 locations in the transportation route and offshore and analysed for several types of hydrocarbons. Total hydrocarbons varied by over 25 times between sites, reaching a maximum of 1116 μg/g OC (organic carbon basis) in Hudson Strait due to low molecular weight n-alkanes from marine primary production. The gross mean for all sites was 344 μg/g OC (GSD = 173-682), roughly equivalent to other remote sites in the Canadian Arctic with no known local hydrocarbon source. n-alkanes accounted for >90 % of residues. Diagnostic ratios (e.g., Carbon Preference Index (CPI), Odd-Even Predominance (OEP)) indicated mixed sources of n-alkanes, likely due to the input from vascular plants and ombrotrophic peat in northern and western watersheds, and primary production within the Bay. The elevated proportion of high molecular weight n-alkanes at deep water sites is consistent with lotic particulate organic matter deposited in the nearshore environment and redeposited offshore. Ʃ 36 PAHs were a small fraction (1.9 %) of hydrocarbons, with a gross mean of 5.68 μg/g OC (GSD = 3.30-9.79). PCA separated deep water sediments from nearshore and community samples due to 4 alkylated naphthalenes which usually indicate a petrogenic source but probably indicates a natural source due to the lack of other petrogenic markers. Priority PAHs (i.e., Ʃ 16 PAH) varied from 31.5 % to 56.6 % of the Ʃ 36 PAH residues. The concentrations of individual PAHs were well below the Interim Sediment Quality Guidelines recommended by the Canadian Council of Ministers of the Environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Circadian rhythm disruption is implicated in the initiation and progression of many diseases, including cancer. External stimuli, such as sunlight, serve to synchronize physiological processes and cellular functions to a 24-h cycle. The immune system is controlled by circadian rhythms, and perturbation of these rhythms can potentially alter the immune response to infections and tumors. The effect of circadian rhythm disruption on the immune response to tumors remains unclear. Specifically, the effects of circadian disruption (CD) on immunosuppressive cell types within the tumor, such as myeloid-derived suppressor cells (MDSCs), are unknown. In this study, a shifting lighting schedule is used to disrupt the circadian rhythm of mice. After acclimation to lighting schedules, mice are inoculated with 4T1 or B16-F10 tumors. Tumor growth is increased in mice housed under circadian disrupting lighting conditions compared to standard lighting conditions. Analysis of immune populations within the spleen and tumor shows an increased accumulation of MDSCs within these tissues, suggesting that MDSC mediated immunosuppression plays a role in the enhanced tumor growth caused by circadian disruption. This paves the way for future studies of the effects of CD on immunosuppression in cancer., (© 2022 The Authors. Advanced Biology published by Wiley-VCH GmbH.)

Metabolic reprogramming is associated with myeloid-derived suppressor cell (MDSC) immunosuppressive function. Here, we outline the process for acquiring MDSCs from human and murine sources for subsequent analysis of fatty acid oxidation, oxidative phosphorylation, and glycolysis using the Seahorse XFe 96 Analyzer. Murine MDSCs can be isolated directly from tumor-bearing mice or derived through IL-6 and GM-CSF culture of bone marrow cells from non-tumor-bearing mice. To generate human MDSCs, peripheral blood mononuclear cells (PBMCs) can be cultured with IL-6 and GM-CSF. For complete details on the use and execution of this protocol, please refer to Mohammadpour et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background: Management of hand trauma has evolved to incorporate assessment, treatment and rehabilitation of patients in a 'one-stop' clinic on initial presentation. Our aim was to evaluate the effect of coronavirus disease 2019 (COVID-19) on the choice of treatment for hand fractures using inter-rater agreement between surgeons. Methods: All patients with hand fractures during the COVID-19 lockdown from March to May 2020 were included in the study. Two experienced hand surgeons blinded to management and outcomes independently reviewed radiographic images and relevant clinical history to provide their opinion on optimal treatment. Weighted kappa analysis was performed to determine concordance and inter-rater agreement between the two surgeons and actual management. Results: The study included 82 patients (62 men and 20 women) with a mean age of 40.3 (SD 19.7). The injuries occurred most often at home following an accident (34%) or a fall (28%). Fractures involved the metacarpals in 29 patients and the distal phalanx in 22 patients. Thirty-five patients underwent surgery, whereas 47 were managed conservatively. Overall agreement between actual management and consultant A and consultant B was moderate ( κ = 0.55, p < 0.0001 and κ = 0.63, p < 0.0001, respectively). Subgroup analysis showed a weak agreement between actual management of metacarpal fractures and consultant A and consultant B ( κ = 0.22, p = 0.29 and κ = 0.47, p = 0.02, respectively). Inter-rater agreement was substantial for management of metacarpal fractures ( κ = 0.73, p < 0.0001), but weak for distal phalanx fractures ( κ = 0.29, p = 0.03). Conclusion: Our study has shown that overall management of hand fractures remained optimised throughout the pandemic. However, a lack of concordance was observed in the management of metacarpals. Level of Evidence: Level IV (Therapeutic).

Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that β2 adrenergic receptor (β2-AR) expression on MDSCs increases with tumor growth and that the β2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that β2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that β2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan β-blocker propranolol or by using mice lacking the β2-adrenergic receptor (β2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking β-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced β-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or β-AR signaling in combination with immunotherapy., (©2021 American Association for Cancer Research.)

It is generally believed that the physiological consequences of stress could contribute to poor outcomes for patients being treated for cancer. However, despite preclinical and clinical evidence suggesting that stress promotes increased cancer-related mortality, a comprehensive understanding of the mechanisms involved in mediating these effects does not yet exist. We reviewed 47 clinical studies published between 2007 and 2020 to determine whether psychosocial stress affects clinical outcomes in cancer: 6.4% of studies showed a protective effect; 44.6% showed a harmful effect; 48.9% showed no association. These data suggest that psychosocial stress could affect cancer incidence and/or mortality, but the association is unclear. To shed light on this potentially important relationship, objective biomarkers of stress are needed to more accurately evaluate levels of stress and its downstream effects. As a potential candidate, the neuroendocrine signalling pathways initiated by stress are known to affect anti-tumour immune cells, and here we summarise how this may promote an immunosuppressive, pro-tumour microenvironment. Further research must be done to understand the relationships between stress and immunity to more accurately measure how stress affects cancer progression and outcome., Competing Interests: Declaration of interest None.

The accurate diagnosis of ulnar collateral ligament (UCL) injuries of the thumb is important in identifying patients requiring surgery. Stener lesion, the most severe form of such injuries, is debilitating and leads to chronic instability if misdiagnosed. We evaluated the diagnostic accuracy of ultrasonography (USS) in UCL injuries. A systematic review of existing literature was performed with a meta-analysis using a bivariate mixed-effects model to estimate summary sensitivity and specificity. All observational studies were assessed, with participants of any age, who sustained UCL injuries of the thumb. A hierarchical model was used to generate a hierarchical summary receiver operating characteristic (HSROC) curves. We identified 17 studies reporting a total of 593 UCL injuries. Pooled estimates for sensitivity and specificity were 0.96 (95% CI 0.89-0.99) and 0.90 (95% CI 0.81-0.94), respectively for the diagnosis of Stener lesions; 0.81 (95% CI 0.66-0.93) and 0.87 (95% CI 0.67-0.96), respectively for non-displaced complete ruptures and 0.82 (95% CI 0.66-0.92) and 0.94 (95% CI 0.85-0.98), respectively for complete ruptures without Stener lesion. The area under the curve (AUC) for Stener diagnosis using USS was 0.98, suggesting excellent diagnostic accuracy. Our meta-analysis suggests that USS is a reliable and accurate method of diagnosis for UCL injuries. Moreover, it has excellent diagnostic accuracy for Stener lesions and may be used in the diagnostic work-up of UCL injuries with magnetic resonance imaging being reserved for ambiguous cases.

Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of β2-AR-/- donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward Tregs rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor BM-derived myeloid-derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D+ effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.

Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR-/-) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-AR-mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in β2-AR-/- MDSCs. Our data reveal the potential of β2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.

While ionizing radiation is a major form of cancer therapy, radioresistance remains a therapeutic obstacle. We have previously shown that the mandated housing temperature for laboratory mice (∼22°C) induces mild, but chronic, cold stress resulting in increased circulating norepinephrine, which binds to, and triggers activation of, beta-adrenergic receptors (β-AR) on tumor and immune cells. This adrenergic signaling increases tumor cell intrinsic resistance to chemotherapy and suppression of the anti-tumor immune response. These findings led us to hypothesize that adrenergic stress signaling increases radioresistance in tumor cells in addition to suppressing T-cell-mediated anti-tumor immunity, thus suppressing the overall sensitivity of tumors to radiation. We used three strategies to test the effect of adrenergic signaling on responsiveness to radiation. For one strategy, mice implanted with CT26 murine colon adenocarcinoma were housed at either 22°C or at thermoneutrality (30°C), which reduces physiological adrenergic stress. For a second strategy, we used a β-AR antagonist ("beta blocker") to block adrenergic signaling in mice housed at 22°C. In either case, tumors were then irradiated with a single 6 Gy dose and the response was compared to mice whose adrenergic stress signaling was not reduced. For the third strategy, we used an in vitro approach in which several different tumor cell lines were treated with a β-AR agonist and irradiated, and cell survival was then assessed by clonogenic assay. Overall, we found that adrenergic stress significantly impaired the anti-tumor efficacy of radiation by inducing tumor cell resistance to radiation-induced cell killing and by suppression of anti-tumor immunity. Treatment using beta blockers is a promising strategy for increasing the anti-tumor efficacy of radiotherapy.

Stress in patients and pre-clinical research animals plays a critical role in disease progression Activation of the sympathetic nervous system (SNS) by stress results in secretion of the catecholamines epinephrine (Epi) and norepinephrine (NE) from the adrenal gland and sympathetic nerve endings. Adrenergic receptors for catecholamines are present on immune cells and their activity is affected by stress and the accompanying changes in levels of these neurotransmitters. In this short review, we discuss how this adrenergic stress impacts two categories of immune responses, infections and autoimmune diseases. Catecholamines signal primarily through the β2-adrenergic receptors present on innate and adaptive immune cells which are critical in responding to infections caused by pathogens. In general, this adrenergic input, particularly chronic stimulation, suppresses lymphocytes and allows infections to progress. On the other hand, insufficient adrenergic control of immune responses allows progression of several autoimmune diseases.

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8 + T-cell frequency and functional orientation within the tumor microenvironment is regulated by β 2 -adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β 2 -AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8 + T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8 + T-cell to CD4 + regulatory T-cell ratio (IFNγ + CD8 + :Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639-51. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Based on anecdotal and observational evidence, we hypothesized that the prevalence of cervical musculoskeletal disorder (C-MSD) would be high among plastic surgeons. A questionnaire review was undertaken to test this hypothesis. Ergonomic assessment was undertaken to assess causal factors of C-MSD., Method: An anonymous questionnaire recording demographics, physical symptoms and behavioral responses to C-MSD was distributed to UK Plastic Surgery consultants. The postural impact of wearing loupes was assessed using motion capture techniques and recording cervical muscular activity., Results: The questionnaire response rate was 81%. The prevalence of cervical spine morbidity was recorded as 32%. Employment implications included 28% of the cohort requiring sick leave. The professional impact was 7% permanently modifying their practice. There were 2 factors significant for C-MSD, the surgeons' age and the duration in hours of wearing loupes per week. Ergonomic assessment of surgeons operating in loupes demonstrated: 1. increased forward and lateral cervical flexion; 2. increased cervical muscular activity to maintain the protracted "head forward" posture; and 3. prolonged static posturing to maintain head position for visual focus. Table height adjustment and variation of loupe working distance can reduce neck flexion., Conclusions: Cervical morbidity is a prevalent problem among plastic surgeons. Long procedures, static postures and neck flexion result in the "head forward" posture. This posture exaggerates when operating with loupe magnification. Early-middle-aged consultants are more prone to cervical morbidity hence afflicted when at the top of their game. The work force is diminished for a potentially avoidable morbidity. Rather than accept this morbidity, co-operation between plastic surgeons and ergonomist may help to reduce injury.

Tissue samples from four ungulate species from the south Mackenzie Mountain region of the Northwest Territories (NT), Canada, were analysed for stable and radioactive elements and (15)N and (13)C stable isotopes. Elevated Cd concentrations in moose (Alces americanus) kidney have been observed in the region and are a health care concern for consumers of traditional foods. This study examined the factors associated with, and potential renal effects from, the accumulation of cadmium, and interactions with other elements in four sympatric ungulate species. Mean renal Cd concentration was highest in moose (48.3mg/kg ww), followed by mountain caribou (Rangifer tarandus caribou) (13.9mg/kg ww) and mountain goat (Oreamnos americanus) (5.78mg/kg ww). No local sources of Cd were evident and the elevated levels in moose are considered to be natural in origin. Conversely, total Hg concentration was significantly higher in mountain caribou kidney (0.21mg/kg ww) than in moose (0.011mg/kg ww). (134)Cs (t½=2.1 y) in mountain goat and Dall's sheep (Ovis dalli) muscle is evidence of deposition from the Fukushima reactor accident in 2011. (137)Cs (t½=30.2 y) in all four ungulates is primarily a remnant of the nuclear weapons tests of the 1960s. The levels of both nuclides are low and the risk to the animals and people consuming them is negligible. Stable isotope δ(15)N and δ(13)C signatures in muscle showed a separation between the mountain caribou, with a lichen-dominated diet, and moose, which browse shrubs and forbs. Isotope signatures for mountain goat and Dall's sheep showed generalist feeding patterns. Differences in elemental and radionuclide levels between species were attributed to relative levels of metal accumulation in the different food items in the diets of the respective species. Kidneys from each species showed minor histological changes in the proximal tubule and glomerulus, although glomerular changes were rare and all changes were rare in mountain goat kidney. Kidney function was not expected to be affected in any species. Provisional Monthly Intake recommendations from the WHO indicate that Cd in moose organs will continue to be a public health care concern. However, traditional foods continue to be an important nutritional component of northern diets, particularly in consideration of the shift towards store-bought food., (Copyright © 2016. Published by Elsevier Inc.)

Nipple reconstruction is an integral step in breast reconstruction. There are a variety of local-flap based techniques however one of the most commonly used is the C-V flap. The traditional flap forms a nipple shell composed of dermis and epidermis containing a core of subcutaneous fat. The shortcomings of this technique are that it relies on subcutaneous fat for nipple bulk and with time loses a significant part of its volume. We present a modification of the C-V flap designed for use in breasts with little subcutaneous fat in order to minimise post-operative nipple projection loss., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The establishment of the Grampians After-Hours Service has led to the development of a quality framework for nurse telephone triage. The service providers believe this framework is the basis for the service's success. While quality frameworks including critical evaluation and peer review are not new to the health industry, the development of organisational systems to improve quality in after-hours services is innovative. The framework developed is comprehensive, evidenced-based and emphasises training, protocols and documentation. It also involves a continuous and non-punitive quality review process that operates at the individual, small group, organisation and whole-system level. The framework will continue to improve and at this time provides a foundation for discussion and further application in the pursuit of quality improvement in rural after-hours health services.

An Avian BioAccumulation Model (ABAM) of persistent organic pollutant (POP) uptake and elimination in adult life-stage of birds was validated by simulation of concentrations of DDE, dieldrin, mirex, and HCB in herring gull eggs in Lake Ontario for the years 1985, 1990, and 1992. These chemicals represented a range of whole-body half-lives of 82-265 days in the gull. Dietary intake of POPs by a female gull was simulated by a dynamic bioenergetics model which included dependence on temperature, photoperiod, egg production, and feeding chicks. Concentrations in the two main prey fish of the gull in Lake Ontario were used for POP exposure. Clearance from the female was based on a two compartment toxicokinetic model. Egg concentrations were estimated from egg/whole body female concentration ratios. Simulated concentrations were compared to measured concentrations in gull eggs from 4 different colonies in the northern part of Lake Ontario. Simulations using a diet of 81% fish and 19% uncontaminated food resulted in the best fit with least variance among predicted and measured data. The mean ratio of predicted to measured concentrations in eggs was 1.0 +/- 0.27 among chemicals, years, and colonies for this exposure scenario. This result was in excellent agreement with field assessments of herring gull diet composition in Lake Ontario of 80-82% fish. The ability to perform accurate a priorisimulations for the range of test conditions employed in the validation constituted a rigorous test of the soundness of the model's structure and parameterization. With species-specific adjustments, ABAM can be regarded as a general model for lipophilic POPs bioaccumulation in birds.

This study summarizes the spatial and temporal trends of fallout (137)Cs concentrations in caribou and reindeer (Rangifer tarandus ssp.), reported in various programs in Canada, Alaska and Greenland, over a 40-y period. During the 1960s, the highest (137)Cs concentrations (2000-3000Bqkg(-1) wet weight in muscle) were found in the large caribou herds of central northern Canada, with levels about 50% lower in Alaska and Greenland. Concentrations varied by up to a factor of 6 between spring and fall. Concentrations in reindeer were comparable to those in caribou from the same regions. The highest (137)Cs concentrations (750Bqkg(-1)) in the late 1980s were found in the Caniapiscau herd of central Québec. The contribution from the Chernobyl accident in 1986 was estimated from (134)Cs measurements to be 10-40% of the total (137)Cs. Present concentrations have declined to 200-300Bqkg(-1). The effective half-life (T(eff)) of (137)Cs in Canadian caribou herds was estimated to be about 6 y. The potential impact on the health of northern residents is discussed.

Organochlorine pesticides and PCBs were analysed in blubber from beluga (Delphinapterus leucas), or white whales, collected at 15 sites in the Canadian Arctic between 1993 and 2001. The objective of the study was to define and interpret the spatial trends of major organic contaminants in northern beluga in terms of sources and transport pathways, and the biological factors influencing accumulation. When compared on a lipid weight basis, the concentrations of beta-HCH, cis-CHL and SigmaCHL, cis-nonachlor, heptachlor epoxide and p,p'-DDT were significantly higher in males than females at all five sites in the eastern Arctic where the two sexes were harvested. The differences were attributed to losses from the females during fetal development and lactation as reported in previous studies. Major compounds increased with age in males at most sites, however the lack of a significant increase with age at some sites was in part due to high organochlorine concentrations in young year classes (2-5 years), particularly at eastern sites such as Iqaluit and Pangnirtung. Lower concentrations of SigmaHCH and SigmaDDT compounds in young males in 2001 relative to 1995 at Hendrickson Island could be due to declining levels in the environment, changes in the diet, or differences in organochlorine loads transferred from the female after birth. Age-corrected least square mean concentrations in males showed significantly higher levels of many compounds, such as p,p'-DDE and SigmaCHB, at south Baffin Island sites than those in the west. Two notable exceptions were HCBz and beta-HCH which were higher in the west. Methoxyclor was detected in males at Sanikiluaq (58 ng g-1) and in both sexes at Kimmirut, but at no other sites. Principal component analysis grouped the 16 sites into five major groupings based on the similarity of normalised organochlorine pesticide and PCB levels. Sites from the western Arctic were grouped by higher proportions of HCBz, beta-HCH and gamma-HCH and higher chlorinated PCBs. Endosulfan and alpha-HCH comprised a larger proportion of total organochlorine residues in the northern Hudson Bay sites, while methoxychlor, chlordane compounds and octachlorobiphenyls were enriched at Sanikiluaq in eastern Hudson Bay. The analysis showed that the relative amounts of several key compounds are similar in the beluga stocks over large spatial areas (i.e. eastern versus western sites), however, some stocks have distinct fingerprints which can be used to differentiate them from adjacent stocks. Ratios of major HCH isomers largely corresponded with air and surface water measurements conducted during the 1990s, but low alpha-/beta- and alpha-/gamma-HCH ratios in all three western Arctic collections indicate rapid losses of the alpha-isomer from the food web, proportionately higher beta- and gamma-isomers in the Beaufort Sea, or a combination of the two processes. Chlordane residue patterns generally correspond to those from previous studies, however, interpretation of spatial trends are difficult due to the aging of the probable sources in the south, possible atmospheric input from new sources and complex transport pathways.

Protection of the environment from radionuclide releases requires knowledge of the normal background levels of radiation exposure in the exposed biotic community and an estimate of the detriment caused by additional exposure. This study modeled the background exposure and dose to the lungs of small burrowing mammals from 222Rn in artificial burrows in radon-rich soils at a site in southeastern Manitoba. E-PERM chambers used to measure 222Rn in soil showed good reproducibility of measurement, with an average coefficient of variance (CV) of about 10%. Geometric mean (GM) 222Rn concentrations at nine randomly selected sites ranged from 5,490 Bq/m3 (GSD = 1.57, n = 7) to 41,000 Bq/m3 (GSD = 1.02, n = 5). Long-term monitoring of 222Rn concentrations in artificial burrows showed large variation within and between burrows and did not show consistent variation with season, orientation of the burrow opening, or levels of 226Ra in the soil. Annual GM concentrations in individual burrows ranged from 7,480 Bq/m3 (GSD = 1.60) to 18,930 Bq/m3 (GSD = 1.81) in burrows several meters apart. A grand GM of 9,990 Bq/m3 (GSD = 1.81, n = 214) was measured over the site for the year. An exposure model was constructed for five small mammal species based on their respiration rates and the number of hours spent in the burrow, active or hibernating, exposed to soil gas 222Rn, and the time spent out of the burrow exposed to atmospheric 222Rn. A background dose of 0.9 mGy/a from atmospheric 222Rn (40 Bq/m3) was estimated for a large-bodied (80 kg), nonburrowing animal living on the soil surface. The highest exposures (mJ/a) in burrowing mammals occurred in those species with the highest respiration rates. Hibernation accounted for a small fraction of total annual exposure (<5%) because of very low respiration rates during this period. Absorbed dose to lung (mGy/a) was highest in the pocket gopher and decreased in the larger animals because of larger lung mass. Using mean 222Rn concentrations from the field studies and an equilibrium factor (F) of 0.5, doses to lung ranged from 90 mGy/a in the badger to 700 mGy/a in the pocket gopher. These doses closely correspond to those estimated from published dose conversion factors (DCFs) of 1.4 mGy per mJ . h/m3 for whole lung. For the ground squirrel, the DCF approach gives an estimated dose of 300 mGy/a versus 270 using the respiratory flow rate method. Based on these results, doses exceeding 500 mGy/a may be common in mammals and birds (i.e. the burrowing owl) living in radon-rich soils. Published risk coefficients for small mammals suggest that about 17 cancers would occur in 1,000 animals at these exposure rates. Although the potential effects from these exposures were not examined in this study, the study raises questions about how the animals may respond physiologically to this largely natural stress.

There has been long-standing concern with exposure to radioactivity through the consumption of caribou, particularly in indigenous populations in the western Northwest Territories, Canada, who are traditionally high consumers. We conducted a dietary survey in this region in 1994 to estimate population exposure levels. Dietary information was collected from 1012 individuals in sixteen communities (1012 days of 24-hour dietary recalls, 1012 food frequency questionnaires) and radionuclide levels in caribou flesh, liver and kidneys were measured. Monte Carlo statistical methods were employed to integrate these data sets and estimate the distribution of radiation exposure for people in five regions (Gwich'in, Sahtú, Dogrib, Deh-Cho, South Slave). The exposure levels were highest in the South Slave region and in older males (40+ years), and lowest in the Gwich'in region and in younger females (20-40 years). Median exposure level ranged from 0.95 to 5.31 mSv per year (mean of medians = 2.96 mSv/y). In each group the 95th percentile of exposure was 2-3 times greater than the median. These exposure levels are comparable to exposure levels in Alaskan Eskimos and Marshall Island residents, and are much higher than European or American urban populations. Caribou meat is a very nutritious food. We conclude that, although there is some radiation exposure from consuming caribou, the associated health risks are low and are outweighed by the physical, social and cultural benefits derived from hunting and eating caribou.

Gamma-emitting radionuclides and 210Po, an alpha-emitting product of the 238U decay chain, were analysed in tissues from 16 caribou (Rangifer tarandus) collections in the Canadian North between 1992 and 1994. The study was conducted to determine the regional variability of anthropogenic and natural radionuclides in Canadian caribou, and to estimate the background radiation dose to caribou tissues. 137Cs, 40K, 210Pb and 210Po were consistently found in most herds. Mean muscle 137Cs varied from below detection limits on Banks Island to 231 Bq kg-1 wet weight (ww) in the Beverly herd in the central Arctic. Comparison of 1992-94 levels with published values from the 1960s and 1980s showed that 137Cs in caribou is declining with an effective half-life (Teff) of 9.9 years. The highest mean bone and liver 210Pb activities were observed on south Baffin Island, which included one bone sample with 3800 Bq kg-1 ww of 210Pb and 3070 Bq kg-1 ww of 210Po. The distribution of 137Cs and 210Pb between herds was attributed to higher atmospheric deposition rates between 60 and 65 degrees N, and changes in plant community structure and lichen species composition. The highest mean absorbed dose (30 mGy year-1) was observed in 1993 in the liver of caribou from Lake Harbour. This dose translated into a weighted absorbed dose of 300 mGy year-1, assuming a radiation weighting factor (wR) of 10 to account for the increased biological efficiency of alpha particles for deterministic effects. The Lake Harbour site also had the highest individual weighted absorbed dose in bone (810 mGy year-1) and liver (530 mGy year-1) in the study. There was no significant relationship between bone 210Pb activity and age for individual or pooled herds, indicating that the estimated doses are probably present throughout the lifetime of the caribou. Because some herds number several hundred thousand individuals, collective doses may also be very high. As yet, there have been no reports of observable effects due to these relatively high exposures and many of the herds continue to thrive and increase in size.

Alpha particle energy spectra were measured at femoral endosteal surfaces of Canadian Arctic caribou (Rangifer tarandus) to assess the profile of concentration with depth of 210Po supported by 210Pb. Femur samples from five caribou all showed a pronounced superficial concentration of 210Po, in a layer 1.9 - 6.4 microns thick. Within this layer 210Po was concentrated 1.5 - 10 times with respect to diffuse volume-distributed 210Po. This result is consistent with an earlier study of 210Po at human cranial bone surfaces, which showed 210Po to be concentrated about four times in a surface layer <3 microns thick. However, the present results have higher precision than the human bone data due to the much greater concentration of 210Pb and 210Po in caribou bone. The validity of using 210Po as a marker of 210Pb, and the in vivo 210Po/210Pb ratio are discussed. As a result of the measured endosteal superficial concentration of 210Po in caribou, the alpha particle dose was calculated to be enhanced by a factor of 1.06 - 1.96 (mean 1.48) for bone lining cells, and of 1.08 - 2.39 (mean 1.69) for soft tissue above the bone surface, assuming equilibrium between 210Pb and 210Po. It is suggested that an additional longer-lived compartment for bone surface lead could be incorporated into bio-kinetic models for lead.

Nocardia erythropolis (ATCC 4277) was grown in a 28-liter fermentor on mineral salts medium and 4% hydrocarbon. Extraction of the neutral lipids with pentane removed approximately 90% of the surface activity of the culture medium. The residual surface activity of the culture medium was attributed to the polar lipid fraction which was not extracted with pentane. Analysis of the pentane extracts with thin-layer chromatography showed the presence of four major compounds. A fatty alcohol reached a maximum concentration in the early log phase of growth and then decreased to the end of the fermentation. A monoglyceride, an ester, and a fatty acid appeared during the log phase of growth and continued to increase until the end of the fermentation. The fatty acids isolated from the culture grown on hexadecane had a carbon skeleton with the same length as the substrate, with 70% of the component as the saturated acid and 30% as a monounsaturated homolog. When isolated from a kerosene culture, the fatty acids consisted of a number of homologs from C(18) to C(20), including branched-chain and unsaturated acids, reflecting the distribution of the branched-chain isomers in the substrate.

The lipopeptide, surfactin, is produced by Bacillus subtilis. A study has been made on large-scale production of this surfactant. A good yield was obtained from a glucose substrate fermentation by continuously removing the product by foam fractionation. The surfactin could be easily recovered from the collapsed foam by acid precipitation. The yield was also improved by the addition of either iron or manganese salts. Hydrocarbon addition to the medium, which normally increases biosurfactant production, completely inhibited surfactin production by B. subtilis.