Factors influencing nurse and pharmacist willingness to take or not take responsibility for non-medical prescribing.

BACKGROUND: In the UK, the majority of non-medical prescribers (NMPs) are nurses or pharmacists working in community or primary care. However, little is known about what influences their decisions to prescribe, unlike with medical prescribing. It is also unclear whether the medical findings can be extrapolated, given their very different prescribing training. OBJECTIVES: To explore the factors influencing whether nurse and pharmacist NMPs in community and primary care settings take responsibility for prescribing. METHODS: Initially, 20 NMPs (15 nurses and 5 pharmacists) were purposively selected and interviewed using the critical incident technique about situations where they felt it was inappropriate for them to take responsibility for prescribing or where they were uneasy about doing so. In addition, more general factors influencing their decision to take or not take prescribing responsibility were discussed. Subsequently, the themes from the interview analysis were validated in three focus groups with a total of 10 nurse NMPs. All data were analyzed using a constant comparison approach. RESULTS: Fifty-two critical incidents were recorded--12 from pharmacist NMPs and 40 from nurse NMPs. Participants experienced situations where they were reluctant to accept responsibility for prescribing. Perceptions of competency, role and risk influenced their decision to prescribe. Workarounds such as delaying the prescribing decision or refer the patient to a doctor were used. CONCLUSIONS: For NMPs to feel more confident about taking responsibility for prescribing, these issues of competency, role and perceived risk need to be addressed. Roles of NMPs must be clear to colleagues, doctors and patients. Training and support must be provided to enable professional development and increasing competence of NMPs.

Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome.

UNLABELLED: A lean 15-year-old girl was diagnosed with type 1 diabetes based on symptomatic hyperglycaemia and positive anti-islet cell antibodies. Glycaemia was initially stabilised on twice-daily mixed insulin. After 11 months from the time of diagnosis, she complained of hyperglycaemia and ketosis alternating with hypoglycaemia. This progressively worsened until prolonged hospital admission was required for treatment of refractory hypoglycaemia. A high titre of anti-insulin antibodies was detected associated with a very low recovery of immunoreactive (free) insulin from plasma after precipitation with polyethylene glycol, suggesting the presence of insulin in bound complexes. Insulin autoimmune syndrome was diagnosed and metabolic fluctuations were initially managed supportively. However, due to poor glucose control, immunosuppressive therapy was initiated first with steroids and plasmapheresis and later with anti-CD20 antibody therapy (Rituximab). This treatment was associated with a gradual disappearance of anti-insulin antibodies and her underlying type 1 diabetes has subsequently been successfully managed with an insulin pump. LEARNING POINTS: Anti-insulin antibodies may result in low levels of free insulin.Polyclonal anti-insulin antibodies can interfere with the pharmacological action of administered insulin, resulting in hypoglycaemia and insulin resistance, due to varying affinities and capacities.In this patient, rituximab administration was associated with a gradual disappearance of anti-insulin antibodies.It is hypothesised that this patient had subcutaneous insulin resistance (SIR) caused by insulin capture at the tissue level, either by antibodies or by sequestration.A prolonged tissue resistance protocol may be more appropriate in patients with immune-mediated SIR syndrome.

Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

Cortisol measurement in patients receiving metyrapone therapy.

Current guidance recommends titrating the dose of metyrapone against serum cortisol concentration, in patients under medical management of Cushing's syndrome. In the UK, this almost always involves measuring serum cortisol concentration by immunoassay, the performance of which is questionable in the presence of altered steroid metabolism. Sera from two patients receiving metyrapone were analysed using a liquid chromatography tandem mass spectrometry (MS) steroid assay to identify which steroids, if any, were elevated in these patients. In addition, control serum was spiked with a series of steroids to identify any potential positive interferences in a cortisol immunoassay. Serum 11-deoxycortisol concentration was elevated in both of the patients studied. One patient also had an elevated serum 17-hydroxyprogesterone concentration and the other an elevated androstenedione. In addition, the results of the interference studies indicated that the cortisol immunoassay was susceptible to interference from 11-deoxycortisol, 17-hydroxyprogesterone and 21-deoxycortisol. However, the magnitude of interference, in the serum cortisol immunoassay, due to these three steroids could not account for the discrepancy between the cortisol concentrations measured by immunoassay and those measured by MS. Both clinicians and laboratory staff should be aware of these interferences when monitoring patients undergoing treatment with metyrapone, and consequently serum should be measured in these patients by MS, not by immunoassay.

Low-dose and high-dose synacthen tests and the hemodynamic response to hydrocortisone in acute traumatic brain injury.

INTRODUCTION: In order to identify whether low-dose (1 microg) tetracosactide (Synacthen) testing may be preferable to high-dose (250 microg) testing in the diagnosis of adrenal insufficiency in traumatic brain injury (TBI), as suggested by studies in other forms of critical illness. METHODS: We retrospectively reviewed the results of modified tetracosactide tests (involving administration of both low-dose and high-dose tetracosactide) conducted for clinical indications in patients in a neurocritical care unit within 10 days of TBI. Sixty-three modified tests were included and cortisol concentrations before and after administration of tetracosactide were extracted from the hospital records. Data were also extracted regarding hemodynamic response to empirical corticosteroid therapy, based on rapid weaning from vasoactive drugs. RESULTS: Cortisol increments at 30 and 60 min following tetracosactide correlated well in the low-dose test (r(2) = 0.875, P < 0.0001). The mean cortisol concentration was 581 nmol/l at 30 min and 556 nmol/l at 60 min in the low-dose test. Cortisol increments following low-dose and high-dose testing correlated well overall (r(2) = 0.839, P < 0.0001), but results were discordant in 27 of 63 cases (43%) when the same diagnostic threshold was used. ROC curve analysis showed that both tests performed poorly in identifying hemodynamic steroid responsiveness (AUC 0.553 and 0.502, respectively). CONCLUSIONS: In the low-dose tetracosactide test, it is sufficient to determine cortisol concentrations at baseline and at 30 min. Low-dose and high-dose tests give discordant results in a significant proportion of cases when using the same diagnostic threshold. Neither test can be used to guide the initiation of corticosteroid therapy in acute TBI.

Severe insulin resistance due to anti-insulin antibodies: response to plasma exchange and immunosuppressive therapy.

Anti-insulin antibodies have been described in two contexts: in insulin-naive individuals (so-called 'insulin autoimmune syndrome') and in patients with insulin-treated diabetes, in whom antibodies are rarely of clinical significance. We report the case of an 68-year-old woman who exhibited a local allergic reaction to subcutaneous insulin followed by severe insulin resistance, evidenced by poor glycaemic control despite treatment with > 3.5 U/kg of insulin per day. She was found to have circulating polyclonal anti-insulin antibodies of the IgG subtype and responded clinically to a course of plasma exchange and immunosuppression with mycophenolate mofetil and, subsequently, intravenous immunoglobulin. Falling titres of antibodies on this regimen correlated with improved glycaemic control. This case suggests that clinicians should be alert to the possibility of insulin resistance due to anti-insulin antibodies and that immunosuppression in this situation may be a valuable therapeutic option.

Augmentation index in resistance to thyroid hormone (RTH).

OBJECTIVE: Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes. DESIGN: An observational study. PATIENTS: Twelve RTH patients were recruited from the thyroid clinic (mean value +/- SD), age 40.8 +/- 18.7 years; BMI 27.2 +/- 4.2 kg/m(2) and compared with 12 healthy, euthyroid, age-matched controls (age 41.4 +/- 19.3; BMI 24.8 +/- 4.4 kg/m(2)) with no history of cardiovascular disease. No interventional measures were instituted. MEASUREMENTS: Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls. Results The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21.0% +/- 14.1%vs. 5.4% +/- 18.2%, P < 0.03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3.0 +/- 0.6 vs. 2.1 +/- 0.5 mmol/l; P < 0.002). CONCLUSION: RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.

Hypovitaminosis D among rheumatology outpatients in clinical practice.

OBJECTIVES: A role for vitamin D in the pathogenesis of autoimmune and inflammatory diseases is emerging. We undertook an audit of 25-hydroxyvitamin D (25OHD) investigation and treatment in rheumatology outpatients. METHODS: Serum 25OHD requests were matched to electronic medical records from rheumatology and metabolic bone clinics (April 2006-March 2007). Data were analysed separately for two groups, 'Documented osteoporosis/osteopaenia' (Group 1) and 'General rheumatology outpatients' (Group 2, sub-divided by diagnosis). Hypovitaminosis D was defined by 25OHD levels <50 nmol/l. Values were compared with healthy adults to calculate geometric z-scores. RESULTS: A total of 263 patients were included (Group 1, n = 122; Group 2, n = 141) with an overall median 25OHD of 44 nmol/l. The 25OHD level among general rheumatology patients (median 39 nmol/l, mean z score -1.2, was statistically significantly lower than among osteoporotic/osteopaenic patients (median 49 nmol/l, mean z score of -0.9, p < 0.05 for the difference). 25OHD was lower in inflammatory arthritis and chronic pain/fibromyalgia than in other groups. Prescribing was recorded in 100 in Group 1 (of whom 95% were prescribed calcium/800 IU cholecalciferol) and 83 in Group 2 (91% calcium/800 IU). Only 31% of the patients with 25OHD <50 nmol/l would have been identified using general guidelines for screening patients at 'high risk' of hypovitaminosis D. CONCLUSIONS: Improved guidelines for managing hypovitaminosis D in rheumatology patients are needed. We found a high prevalence of hypovitaminosis D among secondary care patients in rheumatology and widespread supplementation with 800 IU cholecalciferol. Substantially reduced levels of serum 25OHD were identified among patients with inflammatory arthritis and chronic pain.

Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma.

CONTEXT: Autoantibodies to insulin have been described to cause spontaneous hypoglycemia in nondiabetic subjects. There have been occasional reports of spontaneous hypoglycemia due to monoclonal anti-insulin antibodies. We present the first report of a patient with an IgA-kappa myeloma in whom frequent hypoglycemia resulted from the ability of the monoclonal IgA-kappa to bind insulin. OBJECTIVES: The aim of this study was to describe the occurrence of profound hypoglycemia in a patient with IgA-kappa myeloma, characterize biochemically the nature of the IgA:insulin complex present, and place this case in the context of the published literature on hypoglycemia resulting from autoantibodies to insulin. DESIGN: A case study was performed. PATIENTS: A single case of profound hypoglycemia associated with IgA-kappa myeloma was studied. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: A case study was performed. RESULTS: Polyethylene glycol precipitation and gel filtration chromatography were used to demonstrate high-molecular weight insulin immunoreactivity in the patient's plasma. This was characterized as an insulin binding IgA-kappa paraprotein present at 4200 mg/dl (42 g/liter) with a relatively high insulin dissociation constant of 0.32 microm/liter using radiolabelled insulin binding studies. CONCLUSIONS: We present the first case of hypoglycemia due to IgA binding insulin antibodies in a patient with an IgA-kappa paraprotein myeloma. The hypoglycemia was associated with high-plasma insulin levels and relatively low C-peptide levels. A plausible mechanism for the hypoglycemia is the delayed clearance of insulin. This case broadens the spectrum of monoclonal gammopathies that have been associated with anti-insulin reactivity and spontaneous hypoglycemia.

Hypercalcaemia associated with granulomatous lymphadenitis and elevated 1,25 dihydroxyvitamin D concentration in a dog.

A seven-year-old Labrador was presented with weight loss and mild generalised lymphadenopathy. Histopathology of an excised lymph node by the referring veterinarian demonstrated granulomatous lymphadenitis. At the time of referral, fine-needle aspirates of the lymph nodes confirmed the presence of ongoing granulomatous inflammation. Further investigations revealed marked hypercalcaemia, a low parathyroid hormone concentration, a parathyroid hormone related protein concentration within the reference range, and an elevated serum concentration of 1,25 dihydroxyvitamin D. An underlying cause of the granulomatous lymphadenitis could not be identified. The clinical signs, hypercalcaemia and elevated serum concentrations of 1,25 dihydroxyvitamin D resolved following prednisolone treatment. In contrast to dogs, hypercalcaemia occurred secondarily to granulomatous disease and elevated 1,25 dihydroxyvitamin D concentrations is a well-recognised condition in human beings. To the authors' knowledge, this is the first case report to describe elevated serum calcium and 1,25 dihydroxyvitamin D concentrations in a dog with histologically confirmed granulomatous disease.

Monitoring enzyme replacement therapy in Fabry disease--role of urine globotriaosylceramide.

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb(3)), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant alpha-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb(3)) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb(3) concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant alpha-galactosidase A. The marked decline in urine Gb(3) on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment.

Twin pairs showing discordance of phenotype in adult Gaucher's disease.

BACKGROUND: Non-neuronopathic (type 1) Gaucher's disease, a recessive disorder caused by glucocerebrosidase deficiency, shows marked variability in the severity and extent of clinical expression: many individuals who harbour two mutant alleles remain mildly affected or asymptomatic. Despite much effort, it is not possible accurately to predict disease severity from the genotype, or to identify those patients destined to develop severe disease and meriting early treatment. AIM: To determine the degree to which variance in Gaucher disease is determined by non-heritable factors. DESIGN: Case reports of monozygotic and dizygotic twin pairs. RESULTS: For the monozygotic twin pair, homozygous for the frequent N370S glucocerebrosidase allele, there was no evidence that significant lipid storage was ever initiated in the unaffected twin. In contrast, pathological storage of glucocerebroside has been present in the macrophages of both members of the dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles) from an early age but, by the age of 57 years, only one has developed symptoms. DISCUSSION: Non-heritable factors influence Gaucher disease expression in genetically predisposed individuals. Understanding the interactions between heritable and non-heritable factors will be critical for an analysis of pathogenesis, and the treatment of individuals predisposed to Gaucher disease.

The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity.

The lipolytic effects of catecholamines are mediated through members of the beta(2)-adrenergic receptor (BAR-2) family. Previous studies have suggested that genetic variants in the BAR-2 gene may be associated with obesity in some populations. To our knowledge, no studies have directly examined the effects of this polymorphism on circulating nonesterified fatty acid (NEFA) levels. To explore this issue further, a cohort of 604 Caucasian individuals (aged 40-65 yr) was genotyped for a common polymorphism in the BAR-2 gene (Gly16Arg), and the relationships between genotype, body mass index (BMI), NEFA, and lipid levels were examined. Women bearing the Arg16 allele had higher BMI values (P < 0.01) than Gly16Gly women. Women carriers of the Arg16Arg genotype had lower fasting plasma NEFAs (P < 0.01) and greater suppression of NEFAs (P < 0.01) after an oral glucose load than women bearing the Gly16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the BAR-2 genotype and BMI in determining fasting NEFA concentrations was statistically significant (P < 0.05). The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the Arg16Arg genotype on the suppression of NEFA levels was modified by physical activity level (P for interaction <0.05). These data suggest the existence in this population of a gene-physical activity interaction on NEFA levels.

Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population.

OBJECTIVE: To investigate whether genetic variation at the UCP3 locus contributes to human obesity. SUBJECTS: Ninety-one obese children (BMI>4 standard deviations from age related mean) and 419 Caucasian adults from the Isle of Ely Study. DESIGN: Single strand conformation polymorphism (SSCP) analysis was used to scan the coding region of the UCP3 gene in 91 severely obese children. A common polymorphism identified in this gene (c-55t) has been shown to associate with lower UCP3 mRNA expression. Polymerase chain reaction-based forced restriction digestion was used to detect this allele in Caucasian adults. Multiple regression analysis was used to determine associations between the c-55t genotype and anthropometric, energetic and biochemical indices relevant to obesity. MEASUREMENTS: For the obese children, SSCP analysis and sequencing of variants were carried out. For the Isle of Ely Study, c-55t genotype and anthropometric (body mass index, waist-hip ratio, percentage body fat), energetic (dietary fat intake, physical activity index, adjusted metabolic rate, maximum oxygen consumption) and biochemical indices (pre- and post-glucose challenge plasma triglycerides, non-esterified fatty acids, insulin and glucose) were determined. RESULTS: A previously reported missense mutation (V102I) was detected in a single obese Afro-Carribean child. Twenty-one percent of the genes examined in the Isle of Ely study carried the c-55t promoter variant. Age-adjusted body mass index (BMI) was significantly (P=0.0037) lower in carriers of this variant. CONCLUSION: Mutations in the coding sequence of UCP3 are unlikely to be a common monogenic cause of severe human obesity. In a Caucasian population the UCP3 c-55t polymorphism is negatively associated with BMI.