Patients' attitudes towards cost feedback to doctors to prevent unnecessary testing: a qualitative focus group study.

OBJECTIVES: There is a need to improve efficiency in healthcare delivery without compromising quality of care. One approach is the development and evaluation of behavioural strategies to reduce unnecessary use of common tests. However, there is an absence of evidence on patient attitudes to the use of such approaches in the delivery of care. Our objective was to explore patient acceptability of a nudge-type intervention that aimed to modify blood test requests by hospital doctors. STUDY DESIGN: Single-centre qualitative study. METHODS: The financial costs of common blood tests were presented to hospital doctors on results reports for 1 year at a hospital. Focus group discussions were conducted with recent inpatients at the hospital using a semi-structured question schedule. Discussions were transcribed and analysed using qualitative content analysis to identify and prioritise common themes explaining attitudes to the intervention approach. RESULTS: Three focus groups involving 17 participants were conducted. Patients were generally apprehensive about the provision of blood test cost feedback to doctors. Attitudes were organised around themes representing beliefs about blood tests, the impact on doctors and their autonomy, and beliefs about unnecessary testing. Patients thought that blood tests were important, powerful and inexpensive, and cost information could place doctors under additional pressure. CONCLUSION: The findings identify predominantly positive beliefs about testing and negative attitudes to the use of financial costs in the decision-making of hospital doctors. Public discussion and education about the possible overuse of common tests may allow more resources to be allocated to evidence-based healthcare, by reducing the perception that such strategies to improve healthcare efficiency negatively impact on quality of care.

Pseudohyperkalaemia: a rare complication of splenectomy.

Pseudohyperkalaemia is an uncommon and frequently unrecognised biochemical abnormality. It occurs as a consequence of aggregation and lysis of platelets in vitro. As a result, potassium is released, which causes an elevated serum concentration. We present the case of a 21-year-old man with a traumatic splenic injury necessitating laparotomy and splenectomy. Following surgery he developed hyperkalaemia. Further investigations diagnosed pseudohyperkalaemia, one of the causes of which is thrombocytosis secondary to splenectomy.

Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician. Recommendations • A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R) • Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R) • Patients at high risk should be referred to the dietitian for early intervention. (R) • Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R) • Use a validated nutrition assessment tool (e.g. scored Patient Generated-Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R) • Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G) • Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G) • Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R) • Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R) • Perform nutritional assessment of cancer patients frequently. (G) • Initiate nutritional intervention early when deficits are detected. (G) • Integrate measures to modulate cancer cachexia changes into the nutritional management. (G) • Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R) • Use standard polymeric feed. (G) • Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R) • Monitor nutritional parameters regularly throughout the patient's cancer journey. (G) • Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed. (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R) • Post-operative: ○ Initiate tube feeding within 24 hours of surgery. (R) ○ Consider early oral feeding after primary laryngectomy. (R) • Chyle Leak: ○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons. (R) ○ Commence nutritional intervention with fat free or medium chain triglyceride nutritional supplements either orally or via a feeding tube. (R) ○ Consider parenteral nutrition in severe cases when drainage volume is consistently high. (G) • Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions. (R) • Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate. (R) • Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment. (R) • Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic. (G) • Quality of life parameters including nutritional and swallowing, should be measured at diagnosis and at regular intervals post-treatment. (G).

Evaluation of the limitations of using the University of Washington Quality of Life swallowing domain alone to screen patients in the routine clinical setting.

A broad patient-completed screening tool in routine clinical practice in head and neck oncology has merit, but clinicians should be aware that its simplicity could lead to some patients and the detail of their problems being missed. The purpose of this study was to compare the University of Washington Quality of Life (UWQoL) swallowing domain with the MD Anderson Dysphagia Inventory (MDADI) in relation to the need for interventions for swallowing around one year after treatment. The group comprised 112 consecutively referred patients to speech and language therapy between January 2007 and August 2009 after primary operation for previously untreated oral and oropharyngeal squamous cell carcinoma (SCC). A total of 78 patients completed questionnaires (median time of assessment 11.7 months, IQR 6.1-12.2). There were significant (p<0.001) and moderately strong correlations (rs=0.51-0.62) between the UWQoL swallowing domain score and MDADI subscales and total scores, and also with individual MDADI questions: taking a great deal of effort (rs=0.71); being upset (rs=0.61); and not going out (rs=0.62) were the strongest in regard to swallowing. Use of a gastrostomy tube was associated with worse UWQoL and MDADI scores. In conclusion, patients who score 100 on the UWQoL do not require swallowing to be evaluated further. Those who score 70 could benefit from the detailed MDADI to help to clarify the specific problem and the impact it has before being referred to speech and language therapy. Those who score less than 70 should be brought to the attention of speech and language therapists to confirm that appropriate support and intervention are in place.

Intravasation of barium sulphate at barium enema examination.

We report a case of venous intravasation of barium sulphate occurring during a routine barium enema examination for investigation of rectal bleeding. The patient suffered a cardiopulmonary arrest, but made a full recovery after organ support in intensive care. Review of radiographs from the examination showed intravasated barium in pelvic vessels. We review the literature on this rare, but serious, complication of barium enema examination and suggest measures by which intravasation can be prevented.

Exogenous expression of glucagon-like peptide 1 receptor and human insulin in AtT-20 corticotrophs confers cAMP-mediated gene transcription and insulin secretion.

The insulinotrophic effects of glucagon-like peptide 1 (GLP-1) are mediated by its seven-transmembrane receptor (GLP-1R) in pancreatic beta-cells. We have transiently transfected the GLP-1R and a proopiomelanocortin (POMC) promoter-driven human preproinsulin gene vector (pIRES) into the AtT-20 pituitary corticotrophic cell line, to investigate the possibility of creating a regulated, insulin-expressing cell line. Receptor expression was confirmed by RT-PCR and functionality was demonstrated by measuring changes in cAMP levels in response to GLP-1. Rapid (5 min) stimulation of cAMP production was observed with 100 nM GLP-1, 24 h after transfection of 2 microg GLP-1R DNA. AtT-20 cells co-transfected with GLP-1R and human glycoprotein hormone alpha-subunit or rat POMC promoters revealed GLP-1-stimulated cAMP activation of transcription. Co-transfection of the pIRES vector with the GLP-1R resulted in GLP-1-stimulated activation of POMC promoter-driven preproinsulin gene transcription but insulin secretion was not detected. However, using an adenoviral expression system to infect AtT-20 cells with GLP-1R and the preproinsulin gene (including 120 bp of its own promoter) resulted in a 6.4 +/- 0.6-fold increase in cAMP and a 4.9 +/- 0.8-fold increase in insulin secretion in response to 100 nM GLP-1. These results demonstrate, for the first time, functional GLP-1R-mediated preproinsulin gene transcription and secretion in a transplantable cell line.

The relationship between pituitary tumour transforming gene (PTTG) expression and in vitro hormone and vascular endothelial growth factor (VEGF) secretion from human pituitary adenomas.

OBJECTIVE: Pituitary tumour transforming gene (PTTG) is a recently identified protooncogene, ubiquitously expressed in pituitary tumours at levels higher than those detected in normal pituitary. Although the precise function of PTTG protein is unknown, in vitro experiments have shown that it induces angiogenesis. In this study, we have examined the potential relationship between the level of PTTG expression and tumour phenotype, tumour size, in vitro pituitary hormone secretion and release of vascular endothelial growth factor (VEGF), a potent angiogenic factor. METHODS: Pituitary tumours (12 somatotroph, five lactotroph, five corticotroph and 18 non-functioning) were studied by cell culture, measuring the basal secretion of anterior pituitary hormones and VEGF in vitro. Immunocytochemistry was used to confirm the clinical diagnosis and tumour phenotype. PTTG mRNA expression was investigated by comparative RT-PCR. Tumour Volume was quantitated from pre-operative MRI scans. RESULTS: PTTG expression was significantly increased 2.7-fold in somatotroph tumours compared with non-functioning adenomas (P<0.01, ANOVA). A positive correlation was demonstrated between PTTG expression and in vitro GH secretion (r=0.41, P<0.01, Spearman) but no correlations were found for any of the other pituitary hormones. In 16 out of 40 pituitary tumours, we were able to determine the in vitro secretion of VEGF and relate this to PTTG expression. All of the adenomas tested secreted measurable VEGF but there was no correlation between the amount of VEGF secreted and either the tumour phenotype or PTTG expression. Neither PTTG expression nor VEGF secretion correlated with tumour Volume. CONCLUSIONS: Our studies have confirmed the presence of PTTG in pituitary adenomas and demonstrated a higher level of expression in somatotroph tumours and a significant correlation with GH secretion. We failed to demonstrate a relationship between PTTG expression and production of the angiogenic factor, VEGF, or tumour Volume. Thus, although PTTG induces angiogenesis experimentally, it seems unlikely that a VEGF-mediated angiogenic mechanism occurs during pituitary tumour progression.

Percutaneous endoscopic gastrostomy (PEG): change in practice since 1988.

BACKGROUND AND AIMS: We previously reported a 30-day mortality following percutaneous endoscopic gastrostomy (PEG) of 8% (1988-92). Concerns over increasing mortality rates prompted us to survey current practice compared with 1988-92: assess case mix, outcome, risk factors for early death, and review practice guidelines. METHODS: 78 consecutive adults were referred for PEG over 7 months. Baseline characteristics, including age and functional status (Barthel Index), and outcome at 30 and 180 days were prospectively evaluated. RESULTS: 74 patients. Median age 69 years; male 55%. Major underlying diagnoses: cerebrovascular disease 42%, head and neck tumours 19%, motor neurone disease 4% (33%, 16% and 27% in 1988-92). Mortality rates at 30, 90 and 180 days were 19%, 35% and 42% respectively (8%, 20% and 37% in 1988-92). Univariate analysis showed that age >75 years, Barthel Index <1 and Glasgow Coma Scale < or =10 were significant risk factors for death at 30 days: odds ratios (95% confidence intervals) 3.9 (1.1-13), 5.9 (1.4-25) and 4.4 (1.2-15) respectively. CONCLUSIONS: 30-day mortality was increased from 8% to 19% between 1988-92 and 1998-99 reflecting a change in referral patterns: more elderly with cerebrovascular disease and fewer with motor neurone disease. Age and functional status should be considered when advising on PEG feeding.

Glycerol-stimulated proinsulin biosynthesis in isolated pancreatic rat islets via adenoviral-induced expression of glycerol kinase is mediated via mitochondrial metabolism.

In this study, we examined whether adenoviral-mediated glycerol kinase (AdV-CMV-GlyK) expression in isolated rat pancreatic islets could introduce glycerol-induced proinsulin biosynthesis. In AdV-CMV-GlyK-infected islets, specific glycerol-induced proinsulin biosynthesis translation and insulin secretion were observed in parallel from the same islets. The threshold concentration of glycerol required to stimulate proinsulin biosynthesis was lower (0.25-0.5 mmol/l) than that for insulin secretion (1.0-1.5 mmol/l), reminiscent of threshold differences for glucose-stimulated proinsulin biosynthesis versus insulin secretion. The dose-dependent glycerol-induced proinsulin biosynthesis correlated with the rate of glycerol oxidation in AdV-CMV-GlyK-infected islets, indicating that glycerol metabolism was required for the response. However, glycerol did not significantly increase lactate output from AdV-CMV-GlyK-infected islets, but the dihydroxyacetone phosphate (DHAP) to alpha-glycerophosphate (alpha-GP) ratio significantly increased in AdV-CMV-GlyK-infected islets incubated at 2 mmol/l glycerol compared with that at a basal level of 2.8 mmol/l glucose (P < or = 0.05). The DHAP:alpha-GP ratio was unaffected in AdV-CMV-GlyK-infected islets incubated at 2 mmol/l glycerol in the added presence of alpha-cyanohydroxycinnaminic acid (alpha-CHC), an inhibitor of the plasma membrane and mitochondrial lactate/pyruvate transporter. However, alpha-CHC inhibited glycerol-induced proinsulin biosynthesis and insulin secretion in AdV-CMV-GlyK-infected islets (>75%; P = 0.05), similarly to glucose-induced proinsulin biosynthesis and insulin secretion in AdV-CMV-GlyK-infected and control islets. These data indicated that in AdV-CMV-GlyK-infected islets, the importance of mitochondrial metabolism of glycerol was required to generate stimulus-response coupling signals to induce proinsulin biosynthesis and insulin secretion.

Expression of the pituitary transcription factor Ptx-1, but not that of the trans-activating factor prop-1, is reduced in human corticotroph adenomas and is associated with decreased alpha-subunit secretion.

We have studied the expression of the pituitary transcription factors Ptx-1 and Prop-1 in a series of 34 pituitary adenomas fully characterized for in vitro hormone secretion and histological staining. In studies involving mammalian cell lines, the pituitary transcription factor Ptx-1 has been shown to be a pituitary hormone panactivator, whereas more recent studies have shown that it plays an important role in alpha-subunit gene expression. Its expression has not been examined previously in human pituitary adenomas characterized by in vitro hormone secretory profiles. Of the 34 pituitary adenomas studied, Ptx-1 expression was reduced by more than 50% compared to that of the housekeeping gene human glyceraldehyde-3-phosphate dehydrogenase in the 6 corticotroph adenomas, which also had significantly reduced alpha-subunit production (all 6 tumors secreting < or =0.5 ng/24 h). Mutations of the pituitary transcription factor Prop-1, which is responsible for the syndrome of Ames dwarfism in mice, are being increasingly recognized as a cause of combined pituitary hormone deficiency in humans, although ACTH deficiency has been described only once. Prop-1 expression was detected in all 34 pituitary adenomas, including 6 corticotroph adenomas and 5 gonadotroph adenomas. The expression of Prop-1 has not been described previously in these cell phenotypes.

Visceral leishmaniasis (Kala-azar) in two patients with HIV-1 infection: atypical features and response to therapy.

Visceral leishmaniasis (VL) is a well recognized opportunistic infection in patients with HIV-1 infection, which may occasionally present with atypical features. We describe two patients with advanced HIV-1 infection (CD4<100/ mm3) in whom visceral leishmaniasis presented with atypical features, and their response to therapy. Atypical features of visceral leishmaniasis in the two infected patients include absence of fever, dissemination to the duodenal mucosa and to the skin as xanthoma-like lesions. Therapy and secondary prophylaxis remain unsatisfactory, and studies to evaluate combinations of amphotericin B and immunotherapy are needed.

A distinct difference in the metabolic stimulus-response coupling pathways for regulating proinsulin biosynthesis and insulin secretion that lies at the level of a requirement for fatty acyl moieties.

The regulation of proinsulin biosynthesis in pancreatic beta-cells is vital for maintaining optimal insulin stores for glucose-induced insulin release. The majority of nutrient fuels that induce insulin release also stimulate proinsulin biosynthesis, but since insulin exocytosis and proinsulin synthesis involve different cellular mechanisms, a point of divergence in the respective metabolic stimulus-response coupling pathways must exist. A parallel examination of the metabolic regulation of proinsulin biosynthesis and insulin secretion was undertaken in the same beta-cells. In MIN6 cells, glucose-induced proinsulin biosynthesis and insulin release shared a requirement for glycolysis to generate stimulus-coupling signals. Pyruvate stimulated both proinsulin synthesis (threshold 0.13-0.2 mM) and insulin release (threshold 0.2-0.3 mM) in MIN6 cells, which was eliminated by an inhibitor of pyruvate transport (1 mM alpha-cyano-4-hydroxycinnamate). A combination of alpha-oxoisohexanoate and glutamine also stimulated proinsulin biosynthesis and insulin release in MIN6 cells, which, together with the effect of pyruvate, indicated that anaplerosis was necessary for instigating secondary metabolic stimulus-coupling signals in the beta-cell. A consequence of increased anaplerosis in beta-cells is a marked increase in malonyl-CoA, which in turn inhibits beta-oxidation and elevates cytosolic fatty acyl-CoA levels. In the beta-cell, long-chain fatty acyl moieties have been strongly implicated as metabolic stimulus-coupling signals for regulating insulin exocytosis. Indeed, it was found in MIN6 cells and isolated rat pancreatic islets that exogenous oleate, palmitate and 2-bromopalmitate all markedly potentiated glucose-induced insulin release. However, in the very same beta-cells, these fatty acids in contrast inhibited glucose-induced proinsulin biosynthesis. This implies that neither fatty acyl moieties nor beta-oxidation are required for the metabolic stimulus-response coupling pathway specific for proinsulin biosynthesis, and represent an early point of divergence of the two signalling pathways for metabolic regulation of proinsulin biosynthesis and insulin release. Therefore alternative metabolic stimulus-coupling factors for the specific control of proinsulin biosynthesis at the translational level were considered. One possibility examined was an increase in glycerophosphate shuttle activity and change in cytosolic redox state of the beta-cell, as reflected by changes in the ratio of alpha-glycerophosphate to dihydroxyacetone phosphate. Although 16.7 mM glucose produced a significant rise in the alpha-glycerophosphate/dihydroxyacetone phosphate ratio, 1 mM pyruvate did not. It follows that the cytosolic redox state and fatty acyl moieties are not necessarily involved as secondary metabolic stimulus-coupling factors for regulation of proinsulin biosynthesis. However, the results indicate that glycolysis and the subsequent increase in anaplerosis are indeed necessary for this signalling pathway, and therefore an extramitochondrial product of beta-cell pyruvate metabolism (that is upstream of the increased cytosolic fatty acyl-CoA) acts as a key intracellular secondary signal for specific control of proinsulin biosynthesis by glucose at the level of translation.

Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation.

The pancreatic beta cell normally maintains a stable balance among insulin secretion, insulin production, and insulin degradation to keep optimal intracellular stores of the hormone. Elevated levels of FFA markedly enhance insulin secretion; however, the effects of FFA on insulin production and intracellular stores remain unclear. In this study, twofold elevation in total circulating FFA effected by infusion of lard oil and heparin into rats for 6 h under normoglycemic conditions resulted in a marked elevation of circulating insulin levels evident after 4 h, and a 30% decrease in pancreatic insulin content after a 6-h infusion in vivo. Adding 125 muM oleate to isolated rat pancreatic islets cultured with 5.6 mM glucose caused a 50% fall in their insulin content over 24 h, coupled with a marked enhancement of basal insulin secretion. Both effects of fatty acid were blocked by somatostatin. In contrast to the stimulatory effects of oleate on insulin secretion, glucose-induced proinsulin biosynthesis was inhibited by oleate up to 24 h, but was unaffected thereafter. This result was in spite of a two- to threefold oleate-induced increase in preproinsulin mRNA levels, underscoring the importance of translational regulation of proinsulin biosynthesis in maintaining beta cell insulin stores. Collectively, these results suggest that chronically elevated FFA contribute to beta cell dysfunction in the pathogenesis of NIDDM by significantly increasing the basal rate of insulin secretion. This increase in turn results in a decrease in the beta cell's intracellular stores that cannot be offset by commensurate FFA induction of proinsulin biosynthesis.

Insulin-secreting non-islet cells are resistant to autoimmune destruction.

Transgenic nonobese diabetic mice were created in which insulin expression was targeted to proopiomelanocortin-expressing pituitary cells. Proopiomelanocortin-expressing intermediate lobe pituitary cells efficiently secrete fully processed, mature insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing intermediate lobe pituitaries are not targeted or destroyed by cells of the immune system. Transplantation of the transgenic intermediate lobe tissues into diabetic nonobese diabetic mice resulted in the restoration of near-normoglycemia and the reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bona fide insulin raises the potential of these cell types for beta-cell replacement therapy for the treatment of insulin-dependent diabetes mellitus.

Glucose-regulated translational control of proinsulin biosynthesis with that of the proinsulin endopeptidases PC2 and PC3 in the insulin-producing MIN6 cell line.

In the short term (< 2 h), proinsulin biosynthesis is predominately glucose regulated at the translational level; however, the details at the molecular level behind this mechanism are not well defined. One of the major hindrances for gaining a better understanding of the proinsulin biosynthetic mechanism has been a lack of an abundant source of beta-cells that express a phenotype of regulated proinsulin biosynthesis in the appropriate 2.8-16.7 mmol/l glucose range as defined in normal pancreatic islets. In this study, we demonstrate that in the MIN6 cell line, specific glucose-regulated translational control of proinsulin biosynthesis is present in the appropriate glucose concentration range. In addition to that of proinsulin, the biosynthesis of the two proinsulin conversion endopeptidases, PC2 and PC3, was coordinately glucose regulated in MIN6 cells, whereas that of the exopeptidase, carboxypeptidase H, was unaffected by glucose. Proinsulin, PC2 and PC3 biosynthesis was specifically stimulated over that of total MIN6 cell protein synthesis above a threshold of 4 mmol/l glucose that reached a maximum rate between 8 and 10 mmol/l glucose. Glucose-induced proinsulin, PC2, and PC3 biosynthesis was rapid (occurring after a 20-min lag period but reaching a maximum by 60 min), unaffected by the presence of actinomycin D; and in parallel experiments, stimulatory glucose concentrations did not alter MIN6 cell total preproinsulin, PC2, or PC3 mRNA levels. Thus, short-term (< 2 h) glucose stimulation of proinsulin, PC2 and PC3 biosynthesis in MIN6 cells, like that in isolated islets, was mediated at the translational level. Intracellular signals for mediating glucose-stimulated proinsulin PC2 and PC3 biosynthesis translation in MIN6 cells also appeared to be similar to those in pancreatic islets, requiring glucose metabolism and a supporting role for protein kinase A. However, protein kinase C or a Ca(2+)-dependent protein kinase did not appear to be required for glucose-regulated proinsulin biosynthesis in MIN6 cells, as in islets. MIN6 cells are the first beta-cell line that indicate glucose-regulated proinsulin biosynthesis translation essentially identical to that in differentiated islet beta-cells and will be an important experimental model to better define the mechanism of proinsulin biosynthesis in detail.