Pippa Powell - Academia.edu (original) (raw)

Papers by Pippa Powell

BMC Pulmonary Medicine

Background Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic b... more Background Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs...

Archives of Disease in Childhood-fetal and Neonatal Edition, Mar 1, 2000

Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the ... more Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the islets of Langerhans, which are distributed throughout the pancreas. Less than 2% of the total pancreas is devoted to an endocrine function. When the mechanisms that control insulin release are compromised, potentially lethal diseases such as diabetes and neonatal hypoglycaemia are manifest. This article reviews the physiology of insulin release and illustrates how defects in these processes will result in the pathophysiology of hyperinsulinism of infancy.

Journal of Biological Chemistry, Nov 1, 1999

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by... more Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta celllike phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K ATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K ATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K ATP channel activity, and as a result of changes in intracellular Ca 2؉ homeostasis ([Ca 2؉ ] i) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.

21st Joint Meeting of the British Endocrine Societies, Mar 1, 2002

The Journal of Physiology, 2002

Peer reviewe

European Journal of Pharmacology, Feb 1, 2004

The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2... more The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K + (K ATP) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose-and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic h-cells which express K ATP channels comprised of Kir6.2 and SUR1, and the NES2Y human h-cell line, transfected with Kir6.2DC26. Y-26763 activated K ATP channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K ATP channels in human h-cells.

Pflügers Archiv: European Journal of Physiology, Mar 1, 2002

Peer reviewe

npj Primary Care Respiratory Medicine, 2020

Nature genetics, 2000

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, v... more Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The patter...

The Journal of Clinical Endocrinology & Metabolism, 2002

European Journal of Pharmacology, 2004

The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2... more The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K + (K ATP) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose-and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic h-cells which express K ATP channels comprised of Kir6.2 and SUR1, and the NES2Y human h-cell line, transfected with Kir6.2DC26. Y-26763 activated K ATP channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K ATP channels in human h-cells.

Diabetes, 2000

NES2Y is a proliferating human insulin-secreting cell line that we have derived from a patient wi... more NES2Y is a proliferating human insulin-secreting cell line that we have derived from a patient with persistent hyperinsulinemic hypoglycemia of infancy. This disease is characterized by unregulated insulin release despite profound hypoglycemia. NES2Y cells, like beta-cells isolated from the patient of origin, lack functional ATP-sensitive potassium channels (KATP) and also carry a defect in the insulin gene-regulatory transcription factor PDX1. Here, we report that the NES2Y beta-cells that are transfected with the genes encoding the components of KATP channels in beta-cells, sulfonylurea receptor (SUR) 1 and Kir6.2, have operational KATP channels and show normal intracellular Ca2+ and secretory responses to glucose. However, these cells, designated NESK beta-cells, have impaired insulin gene transcription responses to glucose. NES2Y beta-cells that are transfected with either Kir6.2 or SUR1 alone do not express functional KATP channels and have impaired intracellular free Ca2+ conc...

Diabetes, 2011

OBJECTIVE Congenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin sec... more OBJECTIVE Congenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin secretion from pancreatic β-cells; severe forms are associated with defects in ABCC8 and KCNJ11 genes encoding sulfonylurea receptor 1 (SUR1) and Kir6.2 subunits, which form ATP-sensitive K+ (KATP) channels in β-cells. Diazoxide therapy often fails in the treatment of CHI and may be a result of reduced cell surface expression of KATP channels. We hypothesized that conditions known to facilitate trafficking of cystic fibrosis transmembrane regulator (CFTR) and other proteins in recombinant expression systems might increase surface expression of KATP channels in native CHI β-cells. RESEARCH DESIGN AND METHODS Tissue was isolated during pancreatectomy from eight patients with CHI and from adult cadaver organ donors. Patients were screened for mutations in ABCC8 and KCNJ11. Isolated β-cells were maintained at 37°C or 25°C and in the presence of 1) phorbol myristic acid, forskolin and 3-isobutyl...

British Journal of Pharmacology, 2001

Original quinolinone derivatives structurally related to diazoxide were synthesized and their eff... more Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration‐dependent decrease of insulin release was induced by 6‐chloro‐2‐methylquinolin‐4(1H)‐one (HEI 713). The average IC50 values were 16.9±0.8 μM for HEI 713 and 18.4±2.2 μM for diazoxide. HEI 713 increased the rate of 86Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca2+ but was inhibited by glibenclamide, a KATP channel blocker. Inside‐out patch‐clamp experiments revealed that HEI 713 increased KATP channel openings. HEI 713 decreased 45Ca outflow, insulin output and cytosolic free Ca2+ concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca2+. The drug did not affect the K+(50 mM)‐induced increase in 45Ca outflow. In aortic rings, the vasorelaxant ef...

Archives of Disease in Childhood - Fetal and Neonatal Edition, 2000

Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the ... more Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the islets of Langerhans, which are distributed throughout the pancreas. Less than 2% of the total pancreas is devoted to an endocrine function. When the mechanisms that control insulin release are compromised, potentially lethal diseases such as diabetes and neonatal hypoglycaemia are manifest. This article reviews the physiology of insulin release and illustrates how defects in these processes will result in the pathophysiology of hyperinsulinism of infancy.

The Cochrane library, Oct 1, 2019

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To assess ... more This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To assess the efficacy, safety and acceptability of individual‐level interventions that aim to help people with or without chronic respiratory conditions to reduce their exposure to outdoor air pollution.To assess the efficacy, safety and acceptability of individual‐level interventions that aim to help people with chronic respiratory condition reduce the personal impact of outdoor air pollution and improve health outcomes.

BMC Pulmonary Medicine

Background Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic b... more Background Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs...

Archives of Disease in Childhood-fetal and Neonatal Edition, Mar 1, 2000

Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the ... more Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the islets of Langerhans, which are distributed throughout the pancreas. Less than 2% of the total pancreas is devoted to an endocrine function. When the mechanisms that control insulin release are compromised, potentially lethal diseases such as diabetes and neonatal hypoglycaemia are manifest. This article reviews the physiology of insulin release and illustrates how defects in these processes will result in the pathophysiology of hyperinsulinism of infancy.

Journal of Biological Chemistry, Nov 1, 1999

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by... more Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta celllike phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K ATP channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K ATP channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K ATP channel activity, and as a result of changes in intracellular Ca 2؉ homeostasis ([Ca 2؉ ] i) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.

21st Joint Meeting of the British Endocrine Societies, Mar 1, 2002

The Journal of Physiology, 2002

Peer reviewe

European Journal of Pharmacology, Feb 1, 2004

The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2... more The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K + (K ATP) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose-and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic h-cells which express K ATP channels comprised of Kir6.2 and SUR1, and the NES2Y human h-cell line, transfected with Kir6.2DC26. Y-26763 activated K ATP channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K ATP channels in human h-cells.

Pflügers Archiv: European Journal of Physiology, Mar 1, 2002

Peer reviewe

npj Primary Care Respiratory Medicine, 2020

Nature genetics, 2000

Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, v... more Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The patter...

The Journal of Clinical Endocrinology & Metabolism, 2002

European Journal of Pharmacology, 2004

The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2... more The effect of Y-26763 [(À)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol], a novel ATP-sensitive K + (K ATP) channel activator, was tested on insulin secretion from human pancreatic islets in vitro. Y-26763 was able to inhibit both glucose-and tolbutamide-induced insulin secretion from islets as assessed by radioimmunoassay. The mechanism for inhibition of insulin secretion was characterised using patch clamp electrophysiology on dispersed human pancreatic h-cells which express K ATP channels comprised of Kir6.2 and SUR1, and the NES2Y human h-cell line, transfected with Kir6.2DC26. Y-26763 activated K ATP channels in a reversible manner with a similar activity to diazoxide. This required the presence of hydrolysable nucleotides and appeared to be mediated by interaction of Y-26763 with SUR1 since: (a) tolbutamide was able to reverse the actions of Y-26763 and (b) Y-26763 failed to activate Kir6.2DC26 in the absence of SUR1. We conclude that Y-26763-induced inhibition of insulin release is dependent upon the activation of K ATP channels in human h-cells.

Diabetes, 2000

NES2Y is a proliferating human insulin-secreting cell line that we have derived from a patient wi... more NES2Y is a proliferating human insulin-secreting cell line that we have derived from a patient with persistent hyperinsulinemic hypoglycemia of infancy. This disease is characterized by unregulated insulin release despite profound hypoglycemia. NES2Y cells, like beta-cells isolated from the patient of origin, lack functional ATP-sensitive potassium channels (KATP) and also carry a defect in the insulin gene-regulatory transcription factor PDX1. Here, we report that the NES2Y beta-cells that are transfected with the genes encoding the components of KATP channels in beta-cells, sulfonylurea receptor (SUR) 1 and Kir6.2, have operational KATP channels and show normal intracellular Ca2+ and secretory responses to glucose. However, these cells, designated NESK beta-cells, have impaired insulin gene transcription responses to glucose. NES2Y beta-cells that are transfected with either Kir6.2 or SUR1 alone do not express functional KATP channels and have impaired intracellular free Ca2+ conc...

Diabetes, 2011

OBJECTIVE Congenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin sec... more OBJECTIVE Congenital hyperinsulinism in infancy (CHI) is characterized by unregulated insulin secretion from pancreatic β-cells; severe forms are associated with defects in ABCC8 and KCNJ11 genes encoding sulfonylurea receptor 1 (SUR1) and Kir6.2 subunits, which form ATP-sensitive K+ (KATP) channels in β-cells. Diazoxide therapy often fails in the treatment of CHI and may be a result of reduced cell surface expression of KATP channels. We hypothesized that conditions known to facilitate trafficking of cystic fibrosis transmembrane regulator (CFTR) and other proteins in recombinant expression systems might increase surface expression of KATP channels in native CHI β-cells. RESEARCH DESIGN AND METHODS Tissue was isolated during pancreatectomy from eight patients with CHI and from adult cadaver organ donors. Patients were screened for mutations in ABCC8 and KCNJ11. Isolated β-cells were maintained at 37°C or 25°C and in the presence of 1) phorbol myristic acid, forskolin and 3-isobutyl...

British Journal of Pharmacology, 2001

Original quinolinone derivatives structurally related to diazoxide were synthesized and their eff... more Original quinolinone derivatives structurally related to diazoxide were synthesized and their effects on insulin secretion from rat pancreatic islets and the contractile activity of rat aortic rings determined. A concentration‐dependent decrease of insulin release was induced by 6‐chloro‐2‐methylquinolin‐4(1H)‐one (HEI 713). The average IC50 values were 16.9±0.8 μM for HEI 713 and 18.4±2.2 μM for diazoxide. HEI 713 increased the rate of 86Rb outflow from perifused pancreatic islets. This effect persisted in the absence of external Ca2+ but was inhibited by glibenclamide, a KATP channel blocker. Inside‐out patch‐clamp experiments revealed that HEI 713 increased KATP channel openings. HEI 713 decreased 45Ca outflow, insulin output and cytosolic free Ca2+ concentration in pancreatic islets and islet cells incubated in the presence of 16.7 or 20 mM glucose and extracellular Ca2+. The drug did not affect the K+(50 mM)‐induced increase in 45Ca outflow. In aortic rings, the vasorelaxant ef...

Archives of Disease in Childhood - Fetal and Neonatal Edition, 2000

Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the ... more Insulin is synthesised, stored, and secreted from pancreatic cells. These are located within the islets of Langerhans, which are distributed throughout the pancreas. Less than 2% of the total pancreas is devoted to an endocrine function. When the mechanisms that control insulin release are compromised, potentially lethal diseases such as diabetes and neonatal hypoglycaemia are manifest. This article reviews the physiology of insulin release and illustrates how defects in these processes will result in the pathophysiology of hyperinsulinism of infancy.

The Cochrane library, Oct 1, 2019

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To assess ... more This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:To assess the efficacy, safety and acceptability of individual‐level interventions that aim to help people with or without chronic respiratory conditions to reduce their exposure to outdoor air pollution.To assess the efficacy, safety and acceptability of individual‐level interventions that aim to help people with chronic respiratory condition reduce the personal impact of outdoor air pollution and improve health outcomes.