Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

The lessons learned working in diagnostic and therapeutic radiography departments through the COVID-19 pandemic in Northern Ireland, UK. What can we do differently the next time?

INTRODUCTION: Following the emergence of the COVID-19 pandemic in January 2020, a radical restructure of NHS services occurred, prioritising the acute needs of infected patients. This included suspending routine procedures, leading to an inevitable resurgence in the future, placing increased demands on the NHS, including diagnostic and therapeutic radiographers. With radiography departments already experiencing staff shortages due to COVID-19 related illnesses and vulnerable staff shielding, there is a need to implement plans within radiography departments to ensure their sustainability in the future. METHODS: A mixed methods study was undertaken in Northern Ireland, involving distribution of a survey to diagnostic and therapeutic radiographers alongside conducting interviews with radiography department managers. RESULTS: 106 radiographers completed the survey, with 9 radiography managers and 2 band eight superintendents participating in interviews. Over 60% of participants felt that morale declined in their departments, with the majority feeling that the pandemic had a negative impact on their physical or mental health and wellbeing. Managers felt that to improve staff morale and motivation, incentives need to be offered including remuneration, flexible working and support for professional development. CONCLUSION: Whilst predicting when the next wave of a COVID-19 variant or the next pandemic will occur is impossible, preparation and planning will help manage the situation better. This requires identifying clinical areas for expansion/retraction and having access to additional staff to meet the demands on the service to ensure all patients receive care not just those acutely ill. IMPLICATIONS FOR PRACTICE: This study has identified key lessons learned from the pandemic within the radiography departments. This will enable preparation and strategic planning for future pandemics.

The impact of COVID-19 on the mental health of radiography staff and managers in Northern Ireland, UK: The radiography managers' perspective.

INTRODUCTION: Increasing evidence suggests that the COVID-19 pandemic has influenced the mental health of health professionals, including radiographers. Less is known about the effect of the pandemic on the mental health of radiography managers. Radiography managers have led their teams through the pandemic, making unpopular decisions to safeguard staff and patients. This study explores radiography managers' perceptions regarding the impact of the COVID-19 pandemic on the mental health of themselves and their staff. METHODS: Ethical approval was obtained from the NHS Research Ethics Committee (ID 287032). Eleven interviews were conducted with therapeutic and diagnostic radiography managers between March-April 2021. Written information was also included from a paediatric diagnostic radiography manager. Data was analysed independently by 2 researchers using thematic analysis. RESULTS: Three central themes emerged: 1) Factors perceived to have negatively influenced mental health, which included changing PPE guidance, restructuring of work conditions, social isolation, challenges to patient care and lack of quality vacation leave. 2) Factors perceived to have positively influenced mental health, which included witnessing staff resilience and team camaraderie. 3) Support provided for mental health. CONCLUSION: Managers felt that they had implemented appropriate strategies to support their staff throughout the first year of the pandemic and expressed feeling responsible for the wellbeing of their staff. Strong empathy was evident towards staff and their experiences. Despite the availability of mental health support services, managers felt that resources were underutilised by radiography teams. IMPLICATIONS FOR PRACTICE: Managers should be proactive in communicating their appreciation for their staff in an era where remote working can add to disconnect between staff and management. Mental health support services should be promoted and continually reviewed, to ensure that appropriate support services are maintained.

Impact of COVID-19 on service delivery in radiology and radiotherapy.

INTRODUCTION: The COVID-19 pandemic has had a profound impact on radiography services globally. The reshaping of service delivery continues to impact patient management and the experience of the radiography workforce should be evaluated to determine how effective service delivery can be maintained in the ongoing and post-pandemic world. METHODS: A mixed methods approach was adopted. Questionnaires, designed using Qualtrics (Qualtrics, Provo, UT) online survey software, were used to survey radiographers throughout Northern Ireland (NI). Semi-structured interviews were conducted with radiography service managers in the NHS and private sector in NI. All interviews were digitally recorded, transcribed and coded independently by 2 researchers. RESULTS: A total of 106 Radiographers completed the online survey i.e. 82 Diagnostic and 24 Therapeutic. Variations were reported regarding staff concern for contracting COVID-19 and passing it on. Clinical workload was reported to fluctuate during the early period of the pandemic, however, both diagnostic and therapeutic radiographers reported workloads which were higher than normal at the time of the data collection. Nine service managers participated in the interviews plus two band 8 superintendent radiographers. Staff faced many challenges whilst delivering services due to COVID-19. The two most frequently cited challenges included issues related to (i) Implementation of PPE and (ii) Changes to work practices. CONCLUSION: A pre-prepared pandemic plan should be established and stress tested for the future. The plan should be devised in consultation with both the public and private sector to determine the very best use of resources. IMPLICATIONS FOR PRACTICE: The radiography workforce has worked continuously throughout the pandemic and needs to be supported to deal with the potential increase in demand for services in the post-pandemic world.

TRUFU: Therapeutic radiographer undertaking follow up for prostate cancer patients.

INTRODUCTION: A study was proposed to examine the impact to patients and the Oncology review team, of extending the role of the Therapeutic Radiographer to undertake follow up review of prostate cancer patients who have completed a radical course of external beam radiotherapy treatment. METHOD: A total of 30 patients attending for routine radiotherapy follow up were included in an observational study. Patients were assigned for review with a Doctor or a Therapeutic Radiographer using 1:1 randomisation and a number of time points were recorded and analysed. RESULTS: Of the 44 patients screened, 30 patients were recruited. Average time from scheduled appointment time to departure from clinic was 36 min for both the doctor and Therapeutic Radiographer. The average length of Consultation was 19 min for the Therapeutic Radiographer and 10 min for the Doctor. Average length of wait for patients from scheduled appointment time to being taken for review was 17 min for the Therapeutic Radiographer and 25 min for the Doctor. Of the patients who completed questionnaires, 23/28 had no preference of reviewer, 2/28 declared a preference to be seen by a doctor, whilst 3/28 stated a preference for review with a Therapeutic Radiographer. CONCLUSION: The results of the study are encouraging and should be further investigated in an attempt of developing what would be a very rewarding aspect of the Therapeutic Radiographers role.

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes.

AIMS: Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. METHODS: We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. RESULTS: Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. CONCLUSIONS: Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

Clozapine directly increases insulin and glucagon secretion from islets: implications for impairment of glucose tolerance.

Second generation antipsychotics cause derangements in glucose metabolism that are often interpreted as insulin resistance. In previous studies we have shown that this is not classical insulin resistance but the drugs were actually inducing a hyperglycaemic state associated with elevated hepatic glucose output (HGO) and increased levels of glucagon and insulin. However, it remains unclear whether these effects are directly elicited by drug actions in the liver and pancreas, or whether they are indirectly mediated. Here we investigated if clozapine is capable of inducing insulin resistance in the liver or enhancing insulin and glucagon secretion from the pancreas. It was observed that insulin signalling was elevated in livers from animals treated with clozapine indicating there was no insulin resistance in the early steps of insulin signalling. To explore whether the defects arise at later stages of insulin action we used an isolated perfused liver system. In this model, clozapine had no direct effect on insulin's counter regulatory effect on epinephrine-induced HGO. In isolated mouse islets clozapine significantly increased glucose-stimulated insulin secretion while simultaneously blocking glucose-induced reductions in glucagon secretion. We also show that the non-peptidic glucagon receptor like peptide-1 (GLP-1) receptor agonist Boc5 was able to overcome the inhibitory effects of clozapine on glucose metabolism. Taken together these results suggest that clozapine does not have any direct effect on glucose metabolism in the liver but it simultaneously stimulates insulin and glucagon secretion, a situation that would allow for the concurrent presence of high glucose and high insulin levels in treated animals.

The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect.

The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy.

Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat.

The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels.

Both p110alpha and p110beta isoforms of phosphatidylinositol 3-OH-kinase are required for insulin signalling in the hypothalamus.

Both insulin and leptin action in the brain are considered to involve activation of phosphoinositide 3-kinase (PI3K), although the roles of different PI3K isoforms in insulin signalling in the hypothalamus are unknown. In the present study, we characterised the roles of these isoforms in hypothalamic insulin and leptin signalling and investigated the cross-talk of both hormones. To evaluate PI3K levels in the hypothalamus, PI3K was immunoprecipitated using an antibody directed against the p85 subunit, and then total PI3K activity was measured in the presence of novel isoform-selective pharmacological inhibitors of each isoform of PI3K. Subsequently, these inhibitors were administered into the lateral ventricle of male Sprague-Dawley rats, followed by vehicle, insulin, leptin or both hormones 45 min later. PI3K activity was determined by immunohistochemical detection of phosphorylated AKT (S473). In a separate study, the effects of the inhibitors on the anorexigenic action of insulin and leptin were determined. Hypothalamic insulin signalling was specifically mediated by the combined actions of the class Ia isoforms p110alpha and p110beta. Total hypothalamic PI3K activity was inhibited 65% by a p110alpha inhibitor, and 35% by a p110beta inhibitor, with a combination of inhibitors being equally effective as the broad-spectrum PI3K inhibitor wortmannin. Individual i.c.v. administration of p110alpha and p110beta inhibitors partly prevented insulin-induced phosphorylated AKT (S473) in the arcuate nucleus, whereas simultaneous application completely blocked insulin action. Unlike insulin, leptin did not induce phosphorylated AKT in the hypothalamus, as detected by immunohistochemistry, and the anorectic effects of leptin were not affected by pre-treatment with a combination of p110alpha and p110beta inhibitors. The enhanced anorectic effect of a combined i.c.v. application of both insulin and leptin could be prevented by pre-treatment with the combination of p110alpha and p110beta inhibitors. The data suggest that p110alpha and p110beta isoforms of PI3K are necessary to mediate insulin action in the hypothalamus. The role of PI3K in leptin action is less clear, but it may be involved by means of an insulin-dependent sensitisation of leptin action.

Caffeine and theophylline block insulin-stimulated glucose uptake and PKB phosphorylation in rat skeletal muscles.

AIM: Caffeine and theophylline inhibit phosphatidylinositol 3-kinase (PI3-kinase) activity and insulin-stimulated protein kinase B (PKB) phosphorylation. Insulin-stimulated glucose uptake involves PI3-kinase/PKB, and the aim of the present study was to test the hypothesis that caffeine and theophylline inhibit insulin-stimulated glucose uptake in skeletal muscles. METHODS: Rat epitrochlearis muscles and soleus strips were incubated with insulin and different concentrations of caffeine and theophylline for measurement of glucose uptake, force development and PKB phosphorylation. The effect of caffeine was also investigated in muscles stimulated electrically. RESULTS: Caffeine and theophylline completely blocked insulin-stimulated glucose uptake in both soleus and epitrochlearis muscles at 10 mm. Furthermore, insulin-stimulated PKB Ser(473) and Thr(308) and GSK-3beta Ser(9) phosphorylation were blocked by caffeine and theophylline. Caffeine reduced and theophylline blocked insulin-stimulated glycogen synthase activation. Caffeine stimulates Ca(2+) release and force development increased rapidly to 10-20% of maximal tetanic contraction. Dantrolene (25 microm), a well-known inhibitor of Ca(2+)-release, prevented caffeine-induced force development, but caffeine inhibited insulin-stimulated glucose uptake in the presence of dantrolene. Contraction, like insulin, stimulates glucose uptake via translocation of glucose transporter-4 (GLUT4). Caffeine and theophylline reduced contraction-stimulated glucose uptake by about 50%, whereas contraction-stimulated glycogen breakdown was normal. CONCLUSION: Caffeine and theophylline block insulin-stimulated glucose uptake independently of Ca(2+) release, and the likely mechanism is via blockade of insulin-stimulated PI3-kinase/PKB activation. Caffeine and theophylline also reduced contraction-stimulated glucose uptake, which occurs independently of PI3-kinase/PKB, and we hypothesize that caffeine and theophylline also inhibit glucose uptake in skeletal muscles via an additional and hitherto unknown molecule involved in GLUT4 translocation.

Systemic mastocytosis presenting as osteoporosis--a case report.

Mastocytosis is a clonal disorder of the mast cell and its precursor cells, and is characterised by proliferation and accumulation of mast cells within various organs, most commonly the skin. Systemic mastocytosis is a rare but well-recognised cause of secondary osteoporosis, accounting for about 1.25% of cases. The pathophysiological mechanism is probably multifactorial, including increased osteoclastic activity, and a direct effect of mast cell mediators like histamine, heparin, tryptase and cytokines. Here, we report the case of a middle-aged male patient with osteoporotic vertebral fractures as a rare presenting manifestation of systemic mastocytosis. In summary, systemic mastocytosis, although rare, should be considered as a cause in patients with idiopathic osteoporosis.

Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat.

AIMS/HYPOTHESIS: Use of the second-generation antipsychotic drugs (SGAs) results in the development of obesity and a type 2 diabetes-like syndrome. We hypothesised that, in addition to the insulin resistance associated with the obesity, the SGAs might have acute effects on glucose metabolism that could contribute to the derangements in glucose metabolism. METHODS: We investigated the effects of therapeutically relevant levels of three different antipsychotic medications (haloperidol, quetiapine and clozapine) on glucose tolerance, measures of insulin resistance and hepatic glucose production, and on insulin and glucagon secretion in rats. RESULTS: We found that these drugs induce impaired glucose tolerance in rats that is associated with increased insulin secretion (clozapine>quetiapine>haloperidol) but is independent of weight gain. However, Akt/protein kinase B activation is normal, and at these levels of drug there was no effect on insulin action in fat cells or soleus muscle, and no effect on insulin sensitivity as evaluated by insulin tolerance tests. We show that clozapine induces increased glucose levels following pyruvate and glycerol challenges, indicating an increase in hepatic glucose output (HGO). Increased HGO would in turn increase insulin release and would explain the apparent phenotype mimicking insulin resistance. We provide evidence that this effect could at least in part be mediated by a stimulation of glucagon secretion. CONCLUSIONS/INTERPRETATION: Our findings indicate that SGAs can cause acute derangements in glucose metabolism that are not caused by a direct induction of insulin resistance but act via an increase in glucagon secretion and thus stimulation of hepatic glucose production.

Successful use of National Cancer Registry data to monitor the effective use of imatinib for treating chronic myeloid leukaemia.

UNLABELLED: Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources. METHODS: All imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML. RESULTS: One hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases. CONCLUSIONS: We believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases.

Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort.

OBJECTIVE: A biomedical survey of the 1958 British birth cohort at age 45 years provides a baseline for future studies of chronic disease. The extent and nature of bias in this sample was examined. METHODS: Follow-up of all births in Great Britain in one week in March 1958. At 45 years the sample was compared with the surviving cohort on characteristics recorded at birth and seven years, and in adulthood (42 years). RESULTS: Sample attrition to age 45 years was chiefly through avoidable (35.8%) than unavoidable loss through death or emigration (13.7%). 11 971 individuals were invited to participate at 45 years. Of 9377 participants (78.3%), most consented to, and had valid values for, physical and mental measurements, survey questionnaires, and blood and saliva sampling; 8302 (88.5%) provided a blood sample. Groups moderately underrepresented in the 45-year sample included those with externalizing or internalizing behaviours, poor reading or math scores, and shorter stature. For example, 8.8% of the 45-year sample had been poor readers at age seven years compared with 11.1% of the total surviving cohort; for shorter stature the figures were 7.2% versus 8.4%, respectively. There was also underrepresentation of some minority groups (non-whites, births in households with no male head and children in social care). Most bias was present before the 45-year survey. CONCLUSION: The 45-year sample remains broadly representative of the surviving cohort, but specific biases may need to be taken into account in future research. Renewed efforts to re-engage all cohort members will improve the representativeness and value of the study.

Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues.

A great deal of evidence has accumulated indicating that the activity of PI 3-kinase is necessary, and in some cases sufficient, for a wide range of insulin's actions in the cell. Most biochemical, genetic and pharmacological studies have focused on identifying potential roles for the class-Ia PI 3-kinases which are rapidly activated following insulin stimulation. However, recent evidence indicates the alpha isoform of class-II PI 3-kinase (PI3K-C2alpha) may also play a role as insulin causes a very rapid activation of this as well. The basic mechanisms by which insulin activates the various members of the PI 3-kinase family are increasingly well understood and these studies reveal multiple mechanisms for modulating the activity and functionality of PI 3-kinase and for down regulating the signals they generate. These include inhibitory phosphorylation events, lipid phosphatases such as PTEN and SHIP2 and inhibitor proteins of the suppressors of cytokine signalling (SOCS) family. The current review will focus on these mechanisms and how defects in these might contribute to the development of insulin resistance.

Phosphoinositide 3-kinase: the protein kinase that time forgot.

Class I phosphoinositide 3-kinases were originally characterized as lipid kinases, although more than 10 years ago they were also found to phosphorylate protein serine residues. However, while there is a vast amount of data on the function of this lipid kinase activity, relatively little is known about the function of the protein kinase activity. We discuss the evidence that suggests that the protein kinase activity of phosphoinositide 3-kinases mediates important signalling functions in cells.

Saturated-fat diet induces moderate diabetes and severe glomerulosclerosis in hamsters.

AIMS/HYPOTHESIS: Diets high in saturated fat are thought to be a risk factor for Type 2 diabetes and associated complications. We investigated effects of a medium and high saturated fat diet on the development of diabetes-associated pathologies in Golden Syrian hamsters, an animal that reacts to dietary lipids in a fashion similar to humans. METHODS: Three diets containing 46.5 kcal %, 267.3 kcal %, and 488.2 kcal % as saturated fat respectively, were studied. Metabolic parameters were measured up to 20 weeks. Electron microscopy was used to examine the structure of the pancreas, aorta and kidney. RESULTS: Increased saturated fat consumption was associated with: (i) gradual imbalance of homeostasis, and severe structural alterations of acinar, beta cells and capillaries in the pancreas, and of the kidney glomeruli; (ii) severe hypertriglyceridaemia and augmented creatinine concentrations related to disturbances of the renal function, progressing to nodular glomerulosclerosis and nephropathy; (iii) reduced early insulin secretion in response to glucose; (iv) switch of the aortic endothelium to a secretory phenotype. CONCLUSION/INTERPRETATION: The results show that high-caloric saturated fat intake induced diabetes in hamsters, probably linked to delayed insulin secretion. The model was also associated with the development of a range of pathologies characteristic to human diabetes, including nephropathy and defects in vasculature. Thus, high-fat fed hamsters provide a new model that is likely to be useful in understanding the cellular and molecular mechanisms involved in the pathogenesis of diabetes.