Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside

BACKGROUND: Insulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can also induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Whether low doses of AICAR can augment physiologic insulin action is unknown. In the present study we used the euglycemic hyperinsulinemic clamp to assess whether insulin action is augmented by low dose AICAR. METHODS: Anesthetized rats were studied during saline infusion or euglycemic insulin (3 mU/kg/min) clamp for 2 h in the absence or presence of AICAR for the last hour (5 mg bolus followed by 3.75 mg/kg/min). Muscle glucose uptake (R\u27g) was determined radioisotopically with (14)C-2-deoxyglucose and muscle microvascular perfusion by contrast-enhanced ultrasound with microbubbles. RESULTS: AICAR did not affect blood glucose, or lower leg R\u27g, although it significantly (p < 0.05) increased blood lactate levels and augmented muscle microvascular blood volume via a nitric oxide synthase dependent pathway. Insulin increased femoral blood flow, whole body glucose infusion rate (GIR), R\u27g, hindleg glucose uptake, and microvascular blood volume. Addition of AICAR during insulin infusion increased lactate production, further increased R\u27g in Type IIA (fast twitch oxidative) and IIB (fast twitch glycolytic) fiber containing muscles, and hindleg glucose uptake, but decreased R\u27g in the Type I (slow twitch oxidative) fiber muscle. AICAR also decreased GIR due to inhibition of insulin-mediated suppression of hepatic glucose output. AICAR augmented insulin-mediated microvascular perfusion. CONCLUSIONS: AICAR, at levels that have no direct effect on muscle glucose uptake, augments insulin-mediated microvascular blood flow and glucose uptake in white fiber type muscles. Agents targeted to endothelial AMPK activation are promising insulin sensitizers, however, the decrease in GIR and the propensity to increase blood lactate cautions against AICAR as an acute insulin sensitizer

Epidermal grafting for wound healing: a review on the harvesting systems, the ultrastructure of the graft and the mechanism of wound healing

Epidermal grafting for wound healing involves the transfer of the epidermis from a healthy location to cover a wound. The structural difference of the epidermal graft in comparison to the split-thickness skin graft and full-thickness skin graft contributes to the mechanism of effect. While skin grafting is an epidermal transfer, little is known about the precise mechanism of wound healing by epidermal graft. This paper aims to explore the evolution of the epidermal graft harvesting system over the last five decades, the structural advantages of epidermal graft for wound healing and the current hypotheses on the mechanism of wound healing by epidermal graft. Three mechanisms are proposed: keratinocyte activation, growth factor secretion and reepithelialisation from the wound edge. We evaluate and explain how these processes work and integrate to promote wound healing based on the current in vivo and in vitro evidence. We also review the ongoing clinical trials evaluating the efficacy of epidermal graft for wound healing. The epidermal graft is a promising alternative to the more invasive conventional surgical techniques as it is simple, less expensive and reduces the surgical burden for patients in need of wound coverage

Public awareness of cancer in Britain: a population-based survey of adults

*_Objective:_* To assess public awareness of cancer warning signs, anticipated delay, and perceived barriers to seeking medical advice in the British population. 
Methods: We carried out a population-based survey using face-to-face, computer-assisted interviews to administer the Cancer Awareness Measure (CAM), a newly-developed, validated measure of cancer awareness. The sample included 2216 adults (970 male and 1246 female) recruited as part of the Office for National Statistics Opinions Survey using stratified probability sampling.

*_Results:_* Awareness of cancer warning signs was low when open-ended (recall) questions were used and higher with closed (recognition) questions; but on either measure, awareness was lower in those who were male, younger, and from lower socioeconomic status (SES) groups or ethnic minorities. The most commonly endorsed barriers to help-seeking were difficulty making an appointment, worry about wasting the doctor’s time and worry about what would be found. Emotional barriers were more prominent in lower SES groups and practical barriers (e.g. too busy) more prominent in higher SES groups. Anticipated delay was lower in ethnic minority and lower SES groups. In multivariate analysis, higher symptom awareness was associated with lower anticipated delay, and more barriers with greater anticipated delay.

*_Conclusions:_* A combination of public education about symptoms and empowerment to seek medical advice, as well as support at primary care level, could enhance early presentation and improve cancer outcomes

Women's knowledge and beliefs regarding breast cancer

Approximately 20–30% of women delay for 12 weeks or more from self-discovery of a breast symptom to presentation to a health care provider, and such delay intervals are associated with poorer survival. Understanding the factors that influence patient delay is important for the development of an effective, targeted health intervention programme to shorten patient delay. The aim of the study was to elicit knowledge and beliefs about breast cancer among a sample of the general female population, and examine age and socio-economic variations in responses. Participants were randomly selected through the Postal Address File, and data were collected through the Office of National Statistics. Geographically distributed throughout the UK, 996 women participated in a short structured interview to elicit their knowledge of breast cancer risk, breast cancer symptoms, and their perceptions of the management and outcomes associated with breast cancer. Women had limited knowledge of their relative risk of developing breast cancer, of associated risk factors and of the diversity of potential breast cancer-related symptoms. Older women were particularly poor at identifying symptoms of breast cancer, risk factors associated with breast cancer and their personal risk of developing the disease. Poorer knowledge of symptoms and risks among older women may help to explain the strong association between older age and delay in help-seeking. If these findings are confirmed they suggest that any intervention programme should target older women in particular, given that advancing age is a risk factor for both developing breast cancer and for subsequent delayed presentation

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978

Risk factors for delay in symptomatic presentation of leukaemia, lymphoma and myeloma

Background: UK policy aims to improve cancer outcomes by promoting early diagnosis, which for many haematological malignancies is particularly challenging as the pathways leading to diagnosis can be difficult and prolonged. Methods: A survey about symptoms was sent to patients in England with acute leukaemia, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), myeloma and non-Hodgkin lymphoma (NHL). Symptoms and barriers to first help seeking were examined for each subtype, along with the relative risk of waiting >3 months’ time from symptom onset to first presentation to a doctor, controlling for age, sex and deprivation. Results: Of the 785 respondents, 654 (83.3%) reported symptoms; most commonly for NHL (95%) and least commonly for CLL (67.9%). Some symptoms were frequent across diseases while others were more disease-specific. Overall, 16% of patients (n=114) waited >3 months before presentation; most often in CML (24%) and least in acute leukaemia (9%). Significant risk factors for >3 months to presentation were: night sweats (particularly CLL and NHL), thirst, abdominal pain/discomfort, looking pale (particularly acute leukaemias), and extreme fatigue/tiredness (particularly CML and NHL); and not realising symptom(s) were serious. Conclusions: These findings demonstrate important differences by subtype, which should be considered in strategies promoting early presentation. Not realising the seriousness of some symptoms indicates a worrying lack of public awareness

Recognition of cancer warning signs and anticipated time to help-seeking in a population sample of adults in the UK

Background: Not recognising a symptom as suspicious is a common reason given by cancer patients for delayed help-seeking; but inevitably this is retrospective. We therefore investigated associations between recognition of warning signs for breast, colorectal and lung cancer and anticipated time to help-seeking for symptoms of each cancer. Methods: Computer-assisted telephone interviews were conducted with a population-representative sample (N=6965) of UK adults age greater than or equal to50 years, using the Awareness and Beliefs about Cancer scale. Anticipated time to help-seeking for persistent cough, rectal bleeding and breast changes was categorised as >2 vs less than or equal to2 weeks. Recognition of persistent cough, unexplained bleeding and unexplained lump as cancer warning signs was assessed (yes/no). Associations between recognition and help-seeking were examined for each symptom controlling for demographics and perceived ease of health-care access. Results: For each symptom, the odds of waiting for >2 weeks were significantly increased in those who did not recognise the related warning sign: breast changes: OR=2.45, 95% CI 1.47–4.08; rectal bleeding: OR=1.77, 1.36–2.30; persistent cough: OR=1.30, 1.17–1.46, independent of demographics and health-care access. Conclusion: Recognition of warning signs was associated with anticipating faster help-seeking for potential symptoms of cancer. Strategies to improve recognition are likely to facilitate earlier diagnosis