Background risk of breast cancer and the association between physical activity and mammographic density

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Cathepsin D SNP associated with increased risk of variant Creutzfeldt-Jakob disease

<p>Abstract</p> <p>Background</p> <p>Variant Creutzfeldt-Jakob disease (vCJD) originally resulted from the consumption of foodstuffs contaminated by bovine spongiform encephalopathy (BSE) material, with 163 confirmed cases in the UK to date. Many thousands are likely to have been exposed to dietary infection and so it is important (for surveillance, epidemic modelling, public health and understanding pathogenesis) to identify genetic factors that may affect individual susceptibility to infection. This study looked at a polymorphism in the cathepsin D gene (refSNP ID: rs17571) previously examined in Alzheimer's disease (AD).</p> <p>Methods</p> <p>Blood samples taken from 110 vCJD patients were tested for the C-T base change, and genotype data were compared with published frequencies for a control population using multiple logistic regression.</p> <p>Results</p> <p>There was a significant excess of the cathepsin D polymorphism TT genotype in the vCJD cohort compared to controls. The TT genotype was found to have a 9.75 fold increase in risk of vCJD compared to the CT genotype and a 10.92 fold increase compared to the CC genotype.</p> <p>Conclusion</p> <p>This mutation event has been observed to alter the protease activity of the cathepsin D protein and has been linked to an increase in amyloid beta plaque formation in AD. vCJD neuropathology is characterised by the presence of amyloid plaques, formed from the prion protein, and therefore alterations in the amyloid processing activity of cathepsin D may affect the neuropathogenesis of this disease.</p

Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth?

Several studies have found positive associations between birth weight and breast cancer risk at premenopausal ages. The mechanisms underlying this association are not known, but it is possible that it may be mediated through childhood growth. We examined data from a British cohort of 2176 women born in 1946 and for whom there were prospective measurements of birth weight and of body size throughout life. In all, 59 breast cancer cases occurred during follow-up, 21 of whom were known to be premenopausal. Women who weighed at least 4 kg at birth were five times (relative risk (RR)=5.03; 95% confidence interval=1.13, 22.5) more likely to develop premenopausal breast cancer than those who weighed less than 3 kg (P-value for linear trend=0.03). This corresponded to an RR of 2.31 (0.95, 5.64) per 1 kg increase in birth weight. Birth weight was also a predictor of postnatal growth, that is, women who were heavy at birth remained taller and heavier throughout their childhood and young adulthood. However, the effect of birth weight on premenopausal breast cancer risk was only reduced slightly after simultaneous adjustment for height and body mass index (BMI) at age 2 years and height and BMI velocities throughout childhood and adolescence (adjusted RR=1.94 (0.74, 5.14) per 1 kg increase in birth weight). The pathways through which birth weight is associated with premenopausal breast cancer risk seem to be largely independent of those underlying the relation of postnatal growth to risk

Caracterización de pacientes con mielopatía espondilótica cervical intervenidos por disectomía anterior

Introduction: cervical spondylotic myelopathy is a common disease, which accounts for a quarter of all upper-limb paresthesia. Anterior graft discectomy is one of the most widely used surgical techniques in the world to treat this disease.Objective: to characterize patients with cervical spondylotic myelopathy who underwent surgery using the anterior discectomy with graft technique.Methods: a retrospective, descriptive, longitudinal study was conducted in 35 patients with cervical spondylotic myelopathy who underwent surgery using the anterior graft discectomy technique at “Lucia Iñiguez Landín” Clinical Surgical Teaching Hospital from January 2017 to December 2019. The variables studied were: age, sex, race, personal pathological history, signs and symptoms (before the surgery), cervical level affected, sequelae and complications.Results: male patients predominated (59,9 %), with ages between 45 and 60 years (45,71 %) and with personal pathological history of obesity (40 %). The prevailing clinical manifestations before surgery were hyperreflexia (65,71 %) and paresthesia (62,85 %). The most affected cervical segment was C5-C7 (91,42 %). The main complications were generalized hyperreflexia (17,14 %) and pain (8,57 %).Conclusions: patients with cervical spondylotic myelopathy surgically treated by the anterior discectomy with graft technique were mostly male, in ages after the fourth decade of life. Patients presented hyperreflexia before the surgery, and could develop generalized hyperreflexia as a complication.Introducción: la mielopatía espondilótica cervical es una enfermedad frecuente, que representa la cuarta parte de las parestesias en miembros superiores.  La disectomía anterior con injerto es una de las técnicas quirúrgicas más utilizadas en el mundo para tratar esta enfermedad.Objetivo: Caracterizar los pacientes con mielopatía espondilótica cervical intervenidos quirúrgicamente por la técnica disectomía anterior con injerto.Método: Se realizó un estudio observacional, descriptivo, longitudinal retrospectivo en 35 pacientes con mielopatía espondilótica cervical intervenidos quirúrgicamente por la técnica de disectomía anterior con injerto en el Hospital Clínico Quirúrgico Docente “Lucia Iñiguez Landín” en el período de enero del 2017 a diciembre del 2019. Las variables estudiadas fueron: edad, sexo, color de piel, antecedentes patológicos personales, signos y síntomas (antes de la operación), nivel cervical afectado, secuelas y complicaciones.Resultados: Se encontró predominio de pacientes masculinos (59,9 %), con edades entre 45 y 60 años (45,71 %) y con antecedentes patológicos personales de obesidad (40 %). Las manifestaciones clínicas que predominaron antes de la intervención quirúrgica fueron la hiperreflexia (65,71 %) y la parestesia (62,85 %). El segmento cervical más afectado fue C5-C7 (91,42 %). Las principales complicaciones fueron la hiperreflexia generalizada (17,14 %) y el dolor (8,57).Conclusiones: los pacientes con mielopatía espondilótica cervical intervenidos quirúrgicamente por la técnica disectomía anterior con injerto fueron de sexo masculino en su mayoría, con edades pasadas de la cuarta década de vida. Los pacientes presentaron hiperreflexia antes de la operación, pudiendo desarrollar hiperreflexia generalizada como complicación

Acute interaction between hydrocortisone and insulin alters the plasma metabolome in humans

With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) +/-hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Adjusting for BMI in analyses of volumetric mammographic density and breast cancer risk

Abstract Background Fully automated assessment of mammographic density (MD), a biomarker of breast cancer risk, is being increasingly performed in screening settings. However, data on body mass index (BMI), a confounder of the MD–risk association, are not routinely collected at screening. We investigated whether the amount of fat in the breast, as captured by the amount of mammographic non-dense tissue seen on the mammographic image, can be used as a proxy for BMI when data on the latter are unavailable. Methods Data from a UK case control study (numbers of cases/controls: 414/685) and a Norwegian cohort study (numbers of cases/non-cases: 657/61059), both with volumetric MD measurements (dense volume (DV), non-dense volume (NDV) and percent density (%MD)) from screening-age women, were analysed. BMI (self-reported) and NDV were taken as measures of adiposity. Correlations between BMI and NDV, %MD and DV were examined after log-transformation and adjustment for age, menopausal status and parity. Logistic regression models were fitted to the UK study, and Cox regression models to the Norwegian study, to assess associations between MD and breast cancer risk, expressed as odds/hazard ratios per adjusted standard deviation (OPERA). Adjustments were first made for standard risk factors except BMI (minimally adjusted models) and then also for BMI or NDV. OPERA pooled relative risks (RRs) were estimated by fixed-effect models, and between-study heterogeneity was assessed by the I 2 statistics. Results BMI was positively correlated with NDV (adjusted r = 0.74 in the UK study and r = 0.72 in the Norwegian study) and with DV (r = 0.33 and r = 0.25, respectively). Both %MD and DV were positively associated with breast cancer risk in minimally adjusted models (pooled OPERA RR (95% confidence interval): 1.34 (1.25, 1.43) and 1.46 (1.36, 1.56), respectively; I 2 = 0%, P >0.48 for both). Further adjustment for BMI or NDV strengthened the %MD–risk association (1.51 (1.41, 1.61); I 2 = 0%, P = 0.33 and 1.51 (1.41, 1.61); I 2 = 0%, P = 0.32, respectively). Adjusting for BMI or NDV marginally affected the magnitude of the DV–risk association (1.44 (1.34, 1.54); I 2 = 0%, P = 0.87 and 1.49 (1.40, 1.60); I 2 = 0%, P = 0.36, respectively). Conclusions When volumetric MD–breast cancer risk associations are investigated, NDV can be used as a measure of adiposity when BMI data are unavailable

Male synthetic sling versus artificial urinary sphincter trial for men with urodynamic stress incontinence after prostate surgery (MASTER): Study protocol for a randomised controlled trial

© 2018 The Author(s). Background: Stress urinary incontinence (SUI) is a frequent adverse effect for men undergoing prostate surgery. A large proportion (around 8% after radical prostatectomy and 2% after transurethral resection of prostate (TURP)) are left with severe disabling incontinence which adversely effects their quality of life and many are reliant on containment measures such as pads (27% and 6% respectively). Surgery is currently the only option for active management of the problem. The overwhelming majority of surgeries for persistent bothersome SUI involve artificial urinary sphincter (AUS) insertion. However, this is expensive, and necessitates manipulation of a pump to enable voiding. More recently, an alternative to AUS has been developed - a synthetic sling for men which elevates the urethra, thus treating SUI. This is thought, by some, to be less invasive, more acceptable and less expensive than AUS but clear evidence for this is lacking. The MASTER trial aims to determine whether the male synthetic sling is non-inferior to implantation of the AUS for men who have SUI after prostate surgery (for cancer or benign disease), judged primarily on clinical effectiveness but also considering relative harms and cost-effectiveness. Methods/design: Men with urodynamic stress incontinence (USI) after prostate surgery, for whom surgery is judged appropriate, are the target population. We aim to recruit men from secondary care urological centres in the UK NHS who carry out surgery for post-prostatectomy incontinence. Outcomes will be assessed by participant-completed questionnaires and 3-day urinary bladder diaries at baseline, 6, 12 and 24 months. The 24-h urinary pad test will be used at baseline as an objective assessment of urine loss. Clinical data will be completed at the time of surgery to provide details of the operative procedures, complications and resource use in hospital. At 12 months, men will also have a clinical review to evaluate the results of surgery (including another 24-h pad test) and to identify problems or need for further treatment. Discussion: A robust examination of the comparative effectiveness of the male synthetic sling will provide high-quality evidence to determine whether or not it should be adopted widely in the NHS

A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease

Background: Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene.Methods: We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.Results: We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).Conclusions: Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD

Business process management and supply chain collaboration: a critical comparison

The link between a firm and supply chain (SC) members has been recognised as one of the key issues for ensuring business success and achieving competitive advantage. Indeed, working across organisational boundaries is required to accomplish effective responses to customers’ needs. Our preliminary research confirmed that there are positive relationships between business process management (BPM), supply chain collaboration (SCC), collaborative advantage and organisational performance. This study is a step further and uses a multiple case design to illuminate the results and gain a greater understanding from extensive discussions about these relationships. By means of semi-structured interviews, the three main issues were identified as: (1) the link between BPM and organisational performance; (2) the link between BPM and SCC; and (3) the contextual factors and benefits achieved from working collaboratively with SC partners. The different scenarios of the link between BPM and SCC were developed in a taxonomy, and the case studies were used to illustrate the experience of intra- and inter-organisational practices in the developing economy of Thailand. The case studies’ results explain in depth that both BPM and SCC are important for improving organisational performance and competitiveness. BPM not only improves organisational performance directly, but also assists with collaborative activities that in turn help to improve internal capabilities. Additionally, the comparisons in issues relating to firm size, industry type, relationship closeness and relationship length were also included in this study