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1.
Role of Integrative Health on Neuropathic Pain.
Kandah, M, Wilson, C, Pilitsis, JG
Current pain and headache reports. 2023;(4):49-55
Abstract
PURPOSE OF REVIEW Patients diagnosed with neuropathic pain experience continuous or intermittent spontaneous pain throughout their lives. Pharmacological treatments often provide limited relief; therefore, a multidisciplinary approach should be utilized to manage neuropathic pain. This review examines the current literature on integrative health modalities (anti-inflammatory diets, functional movement, acupuncture, meditation, and transcutaneous therapy) for treating patients with neuropathic pain. RECENT FINDINGS The use of an anti-inflammatory diet, functional movement, acupuncture, meditation, and transcutaneous therapy in treating neuropathic pain has been investigated in prior literature with positive outcomes. However, there remains a large void in evidence-based knowledge and clinical applicability for these interventions. Overall, integrative health offers a cost-efficient and harmless way of creating a multidisciplinary approach to managing neuropathic pain. There are many complementary approaches to treating neuropathic pain as part of an integrative medicine approach. Research is needed to explore other herbs and spices not yet reported in the peer-review literature. Additionally, follow-on research is needed to understand the clinical applicability of the proposed interventions as well as the dose and timing of the interventions to predict response and duration.
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Tackling the adverse health effects of excess body fat in breast cancer: where does physical activity fit in?
Saxton, JM, Wilson, C
The Proceedings of the Nutrition Society. 2023;(1):63-68
Abstract
Weight gain is commonly observed during and after breast cancer treatment due to chemotherapy and endocrine therapies, induced menopause, changes in metabolism and food intake and decreased physical activity. Systematic reviews show that women who are overweight or obese at diagnosis, and those who gain weight, have poorer breast cancer survival outcomes than women of a healthy weight, irrespective of menopausal status. Excess body weight after breast cancer also increases the risk of type 2 diabetes mellitus and CVD. The adverse impact of excess body weight on survival outcomes is clearly shown for women with oestrogen receptor-positive (ER+) breast cancer, which accounts for 70 % of all breast cancer cases. Higher body fat is thought to increase the risk of ER+ recurrence because of increased aromatase activity. However, this could be compounded by other risk factors, including abnormal insulin and adipokine metabolism, impaired anti-tumour immunity and chronic low-grade systemic inflammation. Observational evidence linking poorer survival outcomes with excess body fat and low physical activity in women recovering from early-stage curative-intent breast cancer treatment is reviewed, before reflecting on the proposed biological mechanisms. The issues and sensitivities surrounding exercise participation amongst overweight breast cancer patients is also discussed, before providing an overview of the co-design process involved in development of an intervention (support programme) with appropriate content, structure and delivery model to address the weight management challenges faced by overweight ER+ breast cancer patients.
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Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology.
Greenway, F, Loveridge, B, Grimes, RM, Tucker, TR, Alexander, M, Hepford, SA, Fontenot, J, Nobles-James, C, Wilson, C, Starr, AM, et al
International journal of molecular sciences. 2022;(3)
Abstract
Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.
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Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review.
Vinarov, Z, Abdallah, M, Agundez, JAG, Allegaert, K, Basit, AW, Braeckmans, M, Ceulemans, J, Corsetti, M, Griffin, BT, Grimm, M, et al
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2021;:105812
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Abstract
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
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Carbenoxolone and 18β-glycyrrhetinic acid inhibit inositol 1,4,5-trisphosphate-mediated endothelial cell calcium signalling and depolarise mitochondria.
Buckley, C, Zhang, X, Wilson, C, McCarron, JG
British journal of pharmacology. 2021;(4):896-912
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Abstract
BACKGROUND AND PURPOSE Coordinated endothelial control of cardiovascular function is proposed to occur by endothelial cell communication via gap junctions and connexins. To study intercellular communication, the pharmacological agents carbenoxolone (CBX) and 18β-glycyrrhetinic acid (18βGA) are used widely as connexin inhibitors and gap junction blockers. EXPERIMENTAL APPROACH We investigated the effects of CBX and 18βGA on intercellular Ca2+ waves, evoked by inositol 1,4,5-trisphosphate (IP3 ) in the endothelium of intact mesenteric resistance arteries. KEY RESULTS Acetycholine-evoked IP3 -mediated Ca2+ release and propagated waves were inhibited by CBX (100 μM) and 18βGA (40 μM). Unexpectedly, the Ca2+ signals were inhibited uniformly in all cells, suggesting that CBX and 18βGA reduced Ca2+ release. Localised photolysis of caged IP3 (cIP3 ) was used to provide precise spatiotemporal control of site of cell activation. Local cIP3 photolysis generated reproducible Ca2+ increases and Ca2+ waves that propagated across cells distant to the photolysis site. CBX and 18βGA each blocked Ca2+ waves in a time-dependent manner by inhibiting the initiating IP3 -evoked Ca2+ release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K+ -channel blockers. Furthermore, CBX and 18βGA each rapidly and reversibly collapsed the mitochondrial membrane potential. CONCLUSION AND IMPLICATIONS CBX and 18βGA inhibit IP3 -mediated Ca2+ release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18βGA may block cell-cell communication by acting at sites that are unrelated to gap junctions.
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Health behaviour outcomes of a family based intervention for paediatric obesity in primary care: A randomized type II hybrid effectiveness-implementation trial.
Smith, JD, Berkel, C, Carroll, AJ, Fu, E, Grimm, KJ, Mauricio, AM, Rudo-Stern, J, Winslow, E, Dishion, TJ, Jordan, N, et al
Pediatric obesity. 2021;(9):e12780
Abstract
BACKGROUND Paediatric obesity is a multifaceted public health problem. Family based behavioural interventions are the recommended approach for the prevention of excess weight gain in children and adolescents, yet few have been tested under "real-world" conditions. OBJECTIVES To evaluate the effectiveness of a family based intervention, delivered in coordination with paediatric primary care, on child and family health outcomes. METHODS A sample of 240 families with racially and ethnically diverse (86% non-White) and predominantly low-income children (49% female) ages 6 to 12 years (M = 9.5 years) with body mass index (BMI) ≥85th percentile for age and gender were identified in paediatric primary care. Participants were randomized to either the Family Check-Up 4 Health (FCU4Health) program (N = 141) or usual care plus information (N = 99). FCU4Health, an assessment-driven individually tailored intervention designed to preempt excess weight gain by improving parenting skills was delivered for 6 months in clinic, at home and in the community. Child BMI and body fat were assessed using a bioelectrical impedance scale and caregiver-reported health behaviours (eg, diet, physical activity and family health routines) were obtained at baseline, 3, 6 and 12 months. RESULTS Change in child BMI and percent body fat did not differ by group assignment. Path analysis indicated significant group differences in child health behaviours at 12 months, mediated by improved family health routines at 6 months. CONCLUSION The FCU4Health, delivered in coordination with paediatric primary care, significantly impacted child and family health behaviours that are associated with the development and maintenance of paediatric obesity. BMI did not significantly differ.
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Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias.
Njegic, A, Wilson, C, Cartwright, EJ
Frontiers in physiology. 2020;:1068
Abstract
Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socio-economic burden. Calcium (Ca2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca2+ cycling and signaling play a vital role in maintaining Ca2+ homeostasis. Changes to the expression levels and function of Ca2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca2+ homeostasis in CVD. The remodeling of Ca2+-handling proteins therefore results in impaired Ca2+ cycling, Ca2+ leak from the sarcoplasmic reticulum and reduced Ca2+ clearance, all of which contributes to increased intracellular Ca2+. Currently, approved treatments for targeting Ca2+ handling dysfunction in CVD are focused on Ca2+ channel blockers. However, whilst Ca2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca2+-handling and -signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.
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What is the prevalence, and what are the clinical correlates, of insulin resistance in young people presenting for mental health care? A cross-sectional study.
Scott, EM, Carpenter, JS, Iorfino, F, Cross, SPM, Hermens, DF, Gehue, J, Wilson, C, White, D, Naismith, SL, Guastella, AJ, et al
BMJ open. 2019;(5):e025674
Abstract
OBJECTIVES To report the distribution and predictors of insulin resistance (IR) in young people presenting to primary care-based mental health services. DESIGN Cross-sectional. SETTING Headspace-linked clinics operated by the Brain and Mind Centre of the University of Sydney. PARTICIPANTS 768 young people (66% female, mean age 19.7±3.5, range 12-30 years). MAIN OUTCOME MEASURES IR was estimated using the updated homeostatic model assessment (HOMA2-IR). Height and weight were collected from direct measurement or self-report for body mass index (BMI). RESULTS For BMI, 20.6% of the cohort were overweight and 10.2% were obese. However, <1% had an abnormally high fasting blood glucose (>6.9 mmol/L). By contrast, 9.9% had a HOMA2-IR score >2.0 (suggesting development of IR) and 11.7% (n=90) had a score between 1.5 and 2. Further, there was a positive correlation between BMI and HOMA2-IR (r=0.44, p<0.001). Participants in the upper third of HOMA2-IR scores are characterised by younger age, higher BMIs and depression as a primary diagnosis. HOMA2-IR was predicted by younger age (β=0.19, p<0.001) and higher BMI (β=0.49, p<0.001), together explaining 22% of the variance (F(2,361)=52.1, p<0.001). CONCLUSIONS Emerging IR is evident in a significant subgroup of young people presenting to primary care-based mental health services. While the major modifiable risk factor is BMI, a large proportion of the variance is not accounted for by other demographic, clinical or treatment factors. Given the early emergence of IR, secondary prevention interventions may need to commence prior to the development of full-threshold or major mood or psychotic disorders.
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Pilot test of brief instructions to improve the self-management of general food cravings.
Chapman, J, Zientara, J, Wilson, C
Eating behaviors. 2018;:88-92
Abstract
OBJECTIVE To provide a preliminary investigation into the impact of brief online acceptance-based vs. control-based techniques to self-manage food cravings in women. METHOD Female participants (N = 151) were randomised to 'acceptance' or 'control' groups. Measures of general food cravings (primary outcome), and depression, anxiety and stress (secondary outcomes) were taken at baseline, two weeks and four weeks. RESULTS Linear mixed models showed a significant group × time interaction, with food cravings significantly reduced in the thought-control group compared to the acceptance group over four weeks, along with a reduction in food consumption. Levels of depression, anxiety and stress decreased over the course of the study, but did not differ by group. CONCLUSION These findings provide preliminary support for the acceptability of a minimal technique to self-manage food cravings without deleterious effects, and suggest that simple control-based techniques may be useful in non-clinical, real-world settings.
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3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.
Iveson, TJ, Kerr, RS, Saunders, MP, Cassidy, J, Hollander, NH, Tabernero, J, Haydon, A, Glimelius, B, Harkin, A, Allan, K, et al
The Lancet. Oncology. 2018;(4):562-578
Abstract
BACKGROUND 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. METHODS The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. FINDINGS 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). INTERPRETATION In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. FUNDING Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.