Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer.

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

Quality of diabetes care in breast, colorectal, and prostate cancer

This is the final version. Available on open access from Springer via the DOI in this recordPURPOSE: Overlooking other medical conditions during cancer treatment and follow-up could result in excess morbidity and mortality, thereby undermining gains associated with early detection and improved treatment of cancer. We compared the quality of care for diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer to matched, diabetic non-cancer controls. METHODS: Longitudinal cohort study using primary care records from the Clinical Practice Research Datalink, United Kingdom. Patients with pre-existing diabetes were followed for up to 5 years after cancer diagnosis, or after an assigned index date (non-cancer controls). Quality of diabetes care was estimated based on Quality and Outcomes Framework indicators. Mixed effects logistic regression analyses were used to compare the unadjusted and adjusted odds of meeting quality measures between cancer patients and controls, overall and stratified by type of cancer. RESULTS: 3382 cancer patients and 11,135 controls contributed 44,507 person-years of follow-up. In adjusted analyses, cancer patients were less likely to meet five of 14 quality measures, including: total cholesterol ≤ 5 mmol/L (odds ratio [OR] = 0.82; 95% confidence interval [CI], 0.75-0.90); glycosylated hemoglobin ≤ 59 mmol/mol (adjusted OR = 0.77; 95% CI, 0.70-0.85); and albumin creatinine ratio testing (adjusted OR = 0.83; 95% CI, 0.75-0.91). However, cancer patients were as likely as their matched controls to meet quality measures for other diabetes services, including retinal screening, foot examination, and dietary review. CONCLUSIONS: Although in the short-term, cancer patients were less likely to achieve target thresholds for cholesterol and HbA1c, they continued to receive high-quality diabetes primary care throughout 5 years post diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with pre-existing diabetes because they indicate that high-quality diabetes care is maintained throughout the continuum of cancer diagnosis, treatment, and follow-up.This study was funded by the Population Research Committee, Cancer Research UK. Quality and Outcomes of Care for Chronic Conditions in Older Patients Diagnosed with Breast, Colorectal, or Prostate Cancer Compared to Non-Cancer Controls: An Observational Study Using the Clinical Practice Research Datalink (CPRD). Reference # 16609. 1 July 2013–29 February, 2016. In addition, Dr. Keating is supported by K24CA181510 from the US National Cancer Institute

The natural drug DIAVIT is protective in a type II mouse model of diabetic nephropathy

This is the author accepted manuscript. The final version is available from Public Library of Science via the DOI in this record.There is evidence to suggest that abnormal angiogenesis, inflammation, and fibrosis drive diabetic nephropathy (DN). However, there is no specific treatment to counteract these processes. We aimed to determine whether DIAVIT, a natural Vaccinium myrtillus (blueberry) and Hippophae Rhamnoides (sea buckthorn) extract, is protective in a model of type II DN. Diabetic db/db mice were administered DIAVIT in their drinking water for 14 weeks. We assessed the functional, structural, and ultra-structural phenotype of three experimental groups (lean+vehicle, db/db+vehicle, db/db+DIAVIT). We also investigated the angiogenic and fibrotic pathways involved in the mechanism of action of DIAVIT. Diabetic db/db mice developed hyperglycaemia, albuminuria, and an increased glomerular water permeability; the latter two were prevented by DIAVIT. db/db mice developed fibrotic glomeruli, endothelial insult, and glomerular ultra-structural changes, which were not present in DIAVIT-treated mice. Vascular endothelial growth factor A (VEGF-A) splicing was altered in the db/db kidney cortex, increasing the pro-angiogenic VEGF-A165 relative to the anti-angiogenic VEGF-A165b. This was partially prevented with DIAVIT treatment. Delphinidin, an anthocyanin abundant in DIAVIT, increased the VEGF-A165b expression relative to total VEGF-A165 in cultured podocytes through phosphorylation of the splice factor SRSF6. DIAVIT, in particular delphinidin, alters VEGF-A splicing in type II DN, rescuing the DN phenotype. This study highlights the therapeutic potential of natural drugs in DN through the manipulation of gene splicing and expression.British Heart FoundationDiabetes UKRichard Bright VEGF Research Trus

The effect of intervertebral cartilage on neutral posture and range of motion in the necks of sauropod dinosaurs

The necks of sauropod dinosaurs were a key factor in their evolution. The habitual posture and range of motion of these necks has been controversial, and computer-aided studies have argued for an obligatory sub-horizontal pose. However, such studies are compromised by their failure to take into account the important role of intervertebral cartilage. This cartilage takes very different forms in different animals. Mammals and crocodilians have intervertebral discs, while birds have synovial joints in their necks. The form and thickness of cartilage varies significantly even among closely related taxa. We cannot yet tell whether the neck joints of sauropods more closely resembled those of birds or mammals. Inspection of CT scans showed cartilage:bone ratios of 4.5% for Sauroposeidon and about 20% and 15% for two juvenile Apatosaurus individuals. In extant animals, this ratio varied from 2.59% for the rhea to 24% for a juvenile giraffe. It is not yet possible to disentangle ontogenetic and taxonomic signals, but mammal cartilage is generally three times as thick as that of birds. Our most detailed work, on a turkey, yielded a cartilage:bone ratio of 4.56%. Articular cartilage also added 11% to the length of the turkey's zygapophyseal facets. Simple image manipulation suggests that incorporating 4.56% of neck cartilage into an intervertebral joint of a turkey raises neutral posture by 15°. If this were also true of sauropods, the true neutral pose of the neck would be much higher than has been depicted. An additional 11% of zygapophyseal facet length translates to 11% more range of motion at each joint. More precise quantitative results must await detailed modelling. In summary, including cartilage in our models of sauropod necks shows that they were longer, more elevated and more flexible than previously recognised

Combined resistance and aerobic exercise intervention improves fitness, insulin resistance and quality of life in survivors of childhood haemopoietic stem cell transplantation with total body irradiation

Purpose: To investigate the effects of a supervised combined resistance and aerobic training programme on cardiorespiratory fitness, body composition, insulin resistance and quality of life (QoL) in survivors of childhood haematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI). Participants: HSCT/TBI survivors (n = 20; 8 females). Mean (range) for age at study and time since HSCT/TBI was 16.7 (10.9‐24.5) and 8.4 (2.3‐16.0) years, respectively. Methods: After a 6‐month run‐in, participants undertook supervised 45‐ to 60‐minute resistance and aerobic training twice weekly for 6 months, with a 6‐month follow‐up. The following assessments were made at 0, 6 (start of exercise programme), 12 (end of exercise programme) and 18 months: Body composition via dual energy X‐ray absorptiometry, homeostatic model assessment of insulin resistance (HOMA‐IR), cardiorespiratory fitness (treadmill‐based peak rate of oxygen uptake (VO2 peak) test), QoL questionnaires (36‐Item Short Form Health Survey (SF‐36) and Minneapolis‐Manchester Quality of Life Instrument (MMQL). Results: Results expressed as mean (standard deviation) or geometric mean (range). There were significant improvements in VO2 peak (35.7 (8.9) vs 41.7 (16.1) mL/min/kg, P = 0.05), fasted plasma insulin (16.56 (1.48‐72.8) vs 12.62 (1.04‐54.97) mIU/L, P = 0.03) and HOMA‐IR (3.65 (0.30‐17.26) vs 2.72 (0.22‐12.89), P = 0.02) after the exercise intervention. There were also significant improvements in the SF‐36 QoL general health domain (69.7 (14.3) vs 72.7 (16.0), P = 0.001) and the MMQL school domain (69.1 (25.2) vs (79.3 (21.6), P = 0.03) during the exercise intervention. No significant changes were observed in percentage body fat, fat mass or lean mass. Conclusion: The supervised 6‐month combined resistance and aerobic exercise programme significantly improved cardiorespiratory fitness, insulin resistance and QoL in childhood HSCT/TBI survivors, with no change in body composition, suggesting a metabolic training effect on muscle. These data support a role for targeted physical rehabilitation services in this group at high risk of diabetes and cardiovascular disease

A randomized controlled trial of sucrose and/or pacifier as analgesia for infants receiving venipuncture in a pediatric emergency department

<p>Abstract</p> <p>Background</p> <p>Although sucrose has been accepted as an effective analgesic agent for procedural pain in neonates, previous studies are largely in the NICU population using the procedure of heel lance. This is the first report of the effect of sucrose, pacifier or the combination thereof for the procedural pain of venipuncture in infants in the pediatric emergency department population.</p> <p>Methods</p> <p>The study design was a double (sucrose) and single blind (pacifier), placebo-controlled randomized trial – factorial design carried out in a pediatric emergency department. The study population was infants, aged 0 – 6 months. Eighty-four patients were randomly assigned to one of four groups: a) sucrose b) sucrose & pacifier c) control d) control & pacifier. Each child received 2 ml of either 44% sucrose or sterile water, by mouth. The primary outcome measure: FLACC pain scale score change from baseline. Secondary outcome measures: crying time and heart rate change from baseline.</p> <p>Results</p> <p>Sucrose did not significantly reduce the FLACC score, crying time or heart rate. However sub-group analysis revealed that sucrose had a much greater effect in the younger groups. Pacifier use reduced FLACC score (not statistically significant), crying times (statistically significant) but not heart rate. Subgroup analysis revealed a mean crying time difference of 76.52 seconds (p < 0.0171) (0–1 month) and 123.9 seconds (p < 0.0029) (1–3 month). For subgroup age > 3 months pacifier did not have any significant effect on crying time. Age adjusted regression analysis revealed that both sucrose and pacifier had significant effects on crying time. Crying time increased with both increasing age and increasing gestational age.</p> <p>Conclusion</p> <p>Pacifiers are inexpensive, effective analgesics and are easy to use in the PED for venipuncture in infants aged 0–3 months. The benefits of sucrose alone as an analgesic require further investigation in the older infant, but sucrose does appear to provide additional benefit when used with a pacifier in this age group.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN15819627</p

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.The funder provided support in the form of salaries for authors [AA, AB, MC, JT, MM, AW, EP, AG, PJC, RD, DP, ZL, BM, CW, NS, RS, PS, NC, DK, RB, ES], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Calcitonin gene-related peptide stimulates proliferation of alveolar epithelial cells

<p>Abstract</p> <p>Background</p> <p>Alveolar epithelial cells are known as progenitor cells for the restoration from the damage in the lung. Calcitonin gene-related peptide (CGRP) has been reported to play an important role in the proliferation of various types of epithelial and endothelial cells. We investigated the effects of CGRP on the proliferation of alveolar epithelial cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>A549 cells were cultured in Dulbecco Modified Eagle Medium with 5% fatal bovin serum for 24 hours, then CGRP was added <it>in vitro</it>. The proliferation of DNA synthesis was measured using 5-bromo-2-deoxyuridine, an analog of thymidine, by enzyme-linked immunosorbent assay.</p> <p>As one intracellular response to CGRP, we examined activation of p44/42- extracellular signal-regulated kinase (ERK) pathway by adding CGRP, using western blotting method.</p> <p>Recombinant adenovirus encoding nuclear-targeted-human β-CGRP (rhCGRP) was administered into Male Wister rat (n = 5, 10 weeks old) lungs by intratracheal instillation <it>in vivo</it>. 7 days after the administration of CGRP, rat lungs were harvested and histological findings and immunohistochemical staining of proliferating cell nuclear antigen (PCNA) were evaluated to examine cell proliferation.</p> <p>Results</p> <p><it>In vitro </it>study, CGRP increased the proliferation of A549 cells in a dose and time dependent manner. CGRP8-37 (inhibitor of CGRP receptor) decreased CGRP induced proliferation of DNA synthesis. Phosphorylation of ERK pathway was observed within 15 minutes and peaked in one hour. U0126 (inhibitor of ERK pathway) decreased CGRP induced proliferation of DNA synthesis.<it>In vivo </it>study, histological examination of the lung indicated proliferation of alveolar epithelial cells in the rhCGRP-treated group and the nuclei of alveolar epithelial cells were positive for PCNA immunostaining.</p> <p>Conclusion</p> <p>In this study, we conclude that CGRP stimulates proliferation of human alveolar epithelial cells <it>in vivo </it>and <it>in vitro</it>.</p