Struggling for normality: experiences of patients with diabetic lower extremity amputations and post-amputation wounds in primary care.

AIM: To explore the experiences of patients living with diabetic lower extremity amputation (DLEA) and its post-amputation wound in primary care. BACKGROUND: DLEA, including both minor and major amputation, is a life-altering condition that brings numerous challenges to an individual's life. Post-amputation physical wound healing is complicated and challenging because of wound dehiscence and prolonged healing times. Understanding patients' experiences after DLEA with a post-amputation wound will enable healthcare professionals to develop interventions to assist patients in physical healing and psychosocial recovery. METHODS: This study employs a qualitative design using interpretative phenomenological analysis (IPA). A purposive maximum variation sample of nine patients who had had lower extremity amputations and post-amputation wound attributed to diabetes in the previous 12 months was recruited from a primary care setting in Singapore. Semi-structured audio recorded one-to-one interviews with a duration of 45-60 min each were conducted between September 2018 and January 2019. The interviews were transcribed verbatim and analysed using IPA. FINDINGS: The essential meaning of the phenomenon 'the lived experiences for patients with DLEA and post-amputated wound' can be interpreted as 'struggling for "normality"' which encompasses four domains of sense making: physical loss disrupted normality, emotional impact aggravated the disrupted normality, social challenges further provoked the disrupted normality, and attempt to regain normality. The study highlights the complex physical and psychosocial transition facing patients after DLEA before post-amputation wound closure. In primary care, an amputation, whether minor or major, is a life-altering experience that requires physical healing, emotional recovery, and social adaptation to regain normality. Patients living with DLEA and a post-amputation wound may benefit from an interdisciplinary team care model to assist them with physical and psychosocial adjustment and resume normality

"When nothing happens, nobody is afraid!" beliefs and perceptions around self-care and health-seeking behaviours: Voices of patients living with diabetic lower extremity amputation in primary care.

Self-management and self-care are the cornerstone of diabetes care and an essential part of successfully preventing or delaying diabetes complications. Yet, despite being armed with the required information and guidance for self-management, self-care and adherence to foot self-care recommendations and compliance to medication among patients with diabetic foot ulcer and diabetic lower extremity amputations remain low and suboptimal. This study reveals in-depth account of nine such patients' beliefs and perceptions around their illness, their self-care, and their health-seeking behaviours. Patients living with diabetic lower extremity amputation displayed profound lack of knowledge of self-care of diabetes and foot and passive health-related behaviours. The overarching sense that "when nothing happens, nobody is afraid," points to a lack of motivation in taking charge of one's own health, whether this is with reference to treatment or care adherence, following recommended self-care advice, or seeking timely treatment. The Health Beliefs Model provides the theoretical framework for probing into the factors for the participants' suboptimal self-care and passive health-seeking behaviours. Two themes emerged from data analysis: profound knowledge deficit and passive health-related behaviours. The beliefs and perceptions around self-care and health-seeking behaviours for patients with lower extremity amputation are interpreted as the "ignorant self" with passive health-seeking behaviours. Patients with diabetes and diabetic foot diseases may benefit from personalized education, motivational interviewing, and family support

An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.This work was supported by NIHR Exeter Clinical Research Facility through funding for SE and ATH and general infrastructure. The authors thank Michael Day, Annet Damhuis and Richard Gilbert for technical assistance. We thank Karen Knapp for providing the data for the DEXA calculations. SE, ATH, SO are supported by Wellcome Weedon et al. Page 6 Nat Genet. Author manuscript; available in PMC 2014 February 01. Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts Trust Senior Investigator awards. DS and RKS (098498/Z/12/Z) are supported by Wellcome Trust Senior Research Fellowships in Clinical Science. MNW is supported by the Wellcome Trust as part of the WT Biomedical Informatics Hub funding. RO is supported by Diabetes UK. DS, RKS and SO are supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. KJG is supported by the Agency for Science, Technology and Research, Singapore (A*STAR). LAL and MJP are supported by grants NCI-61-6845 and 62-4860

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Use-Exposure Relationships of Pesticides for Aquatic Risk Assessment

Field-scale environmental models have been widely used in aquatic exposure assessments of pesticides. Those models usually require a large set of input parameters and separate simulations for each pesticide in evaluation. In this study, a simple use-exposure relationship is developed based on regression analysis of stochastic simulation results generated from the Pesticide Root-Zone Model (PRZM). The developed mathematical relationship estimates edge-of-field peak concentrations of pesticides from aerobic soil metabolism half-life (AERO), organic carbon-normalized soil sorption coefficient (KOC), and application rate (RATE). In a case study of California crop scenarios, the relationships explained 90–95% of the variances in the peak concentrations of dissolved pesticides as predicted by PRZM simulations for a 30-year period. KOC was identified as the governing parameter in determining the relative magnitudes of pesticide exposures in a given crop scenario. The results of model application also indicated that the effects of chemical fate processes such as partitioning and degradation on pesticide exposure were similar among crop scenarios, while the cross-scenario variations were mainly associated with the landscape characteristics, such as organic carbon contents and curve numbers. With a minimum set of input data, the use-exposure relationships proposed in this study could be used in screening procedures for potential water quality impacts from the off-site movement of pesticides

REGγ is associated with multiple oncogenic pathways in human cancers

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest a role of the proteasome activator, REGγ, in cancer progression. Since there are limited numbers of known REGγ targets, it is not known which cancers and pathways are associated with REGγ.</p> <p>Methods</p> <p>REGγ protein expressions in four different cancers were investigated by immunohistochemistry (IHC) analysis. Following NCBI Gene Expression Omnibus (GEO) database search, microarray platform validation, differential expressions of REGγ in corresponding cancers were statistically analyzed. Genes highly correlated with REGγ were defined based on Pearson's correlation coefficient. Functional links were estimated by Ingenuity Core analysis. Finally, validation was performed by RT-PCR analysis in established cancer cell lines and IHC in human colon cancer tissues</p> <p>Results</p> <p>Here, we demonstrate overexpression of REGγ in four different cancer types by micro-tissue array analysis. Using meta-analysis of publicly available microarray databases and biological studies, we verified elevated REGγ gene expression in the four types of cancers and identified genes significantly correlated with REGγ expression, including genes in p53, Myc pathways, and multiple other cancer-related pathways. The predicted correlations were largely consistent with quantitative RT-PCR analysis.</p> <p>Conclusions</p> <p>This study provides us novel insights in REGγ gene expression profiles and its link to multiple cancer-related pathways in cancers. Our results indicate potentially important pathogenic roles of REGγ in multiple cancer types and implicate REGγ as a putative cancer marker.</p

Alteration of EGFR Spatiotemporal Dynamics Suppresses Signal Transduction

The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA

Discovering hidden relationships between renal diseases and regulated genes through 3D network visualizations

Abstract Background In a recent study, two-dimensional (2D) network layouts were used to visualize and quantitatively analyze the relationship between chronic renal diseases and regulated genes. The results revealed complex relationships between disease type, gene specificity, and gene regulation type, which led to important insights about the underlying biological pathways. Here we describe an attempt to extend our understanding of these complex relationships by reanalyzing the data using three-dimensional (3D) network layouts, displayed through 2D and 3D viewing methods. Findings The 3D network layout (displayed through the 3D viewing method) revealed that genes implicated in many diseases (non-specific genes) tended to be predominantly down-regulated, whereas genes regulated in a few diseases (disease-specific genes) tended to be up-regulated. This new global relationship was quantitatively validated through comparison to 1000 random permutations of networks of the same size and distribution. Our new finding appeared to be the result of using specific features of the 3D viewing method to analyze the 3D renal network. Conclusions The global relationship between gene regulation and gene specificity is the first clue from human studies that there exist common mechanisms across several renal diseases, which suggest hypotheses for the underlying mechanisms. Furthermore, the study suggests hypotheses for why the 3D visualization helped to make salient a new regularity that was difficult to detect in 2D. Future research that tests these hypotheses should enable a more systematic understanding of when and how to use 3D network visualizations to reveal complex regularities in biological networks.http://deepblue.lib.umich.edu/bitstream/2027.42/112972/1/13104_2010_Article_700.pd

Effect of trabecular bone loss on cortical strain rate during impact in an in vitro model of avian femur

BACKGROUND: Osteoporotic hip fractures occur due to loss of cortical and trabecular bone mass and consequent degradation in whole bone strength. The direct cause of most fractures is a fall, and hence, characterizing the mechanical behavior of a whole osteopenic bone under impact is important. However, very little is known about the mechanical interactions between cortical and trabecular bone during impact, and it is specifically unclear to what extent epiphyseal trabecular bone contributes to impact resistance of whole bones. We hypothesized that trabecular bone serves as a structural support to the cortex during impact, and hence, loss of a critical mass of trabecular bone reduces internal constraining of the cortex, and, thereby, decreases the impact tolerance of the whole bone. METHODS: To test this hypothesis, we conducted cortical strain rate measurements in adult chicken's proximal femora subjected to a Charpy impact test, after removing different trabecular bone core masses to simulate different osteopenic severities. RESULTS: We found that removal of core trabecular bone decreased by ~10-fold the cortical strain rate at the side opposite to impact (p < 0.01), i.e. from 359,815 ± 1799 μm/m per second (mean ± standard error) for an intact (control) specimen down to 35,997 ± 180 μm/m per second where 67% of the total trabecular bone mass (~0.7 grams in adult chicken) were removed. After normalizing the strain rate by the initial weight of bone specimens, a sigmoid relation emerged between normalized strain rate and removed mass of trabecular bone, showing very little effect on the cortex strain rate if below 10% of the trabecular mass is removed, but most of the effect was already apparent for less than 30% trabecular bone loss. An analytical model of the experiments supported this behavior. CONCLUSION: We conclude that in our in vitro avian model, loss of over 10% of core trabecular bone substantially altered the deformation response of whole bone to impact, which supports the above hypothesis and indicates that integrity of trabecular bone is critical for resisting impact loads