Duncan J. Topliss

Reduced bone density in cystic fibrosis: ΔF508 mutation is an independent risk factor

The aim of this cross-sectional study was to determine the prevalence and identify determinants of reduced bone mineral density (BMD) in adults with cystic fibrosis (CF). Adults (88) with CF (mean±sd age 29.9±7.7 yrs; forced expiratory volume in one second (FEV1) 58.2±21.5% of the predicted value) were studied. BMD at the lumbar spine (LS) and femoral neck (FN) and body composition were measured using dual-energy X-ray absorptiometry. Blood and urine were analysed for hormones, bone turnover markers, and the cytokines tumour necrosis factor-α, and interleukin-6 and -1β. FEV1 (% pred); CF genotype; malnutrition; history of growth, development or weight gain delays; and corticosteroid use were analysed. BMD Z-scores were −0.58±1.30 (mean±sd) at the LS and −0.24±1.19 at the FN. Z-scores of <−2.0 were found in 17% of subjects. Subjects who were homozygous or heterozygous for the ΔF508 mutation exhibited significantly lower Z-scores than those with no ΔF508 allele. Multiple linear regression showed that the ΔF508 genotype and male sex were independently associated with lower BMD at both sites. Other factors also independently associated with lower BMD included malnutrition, lower 25-hydroxyvitamin D level, lower fat-free mass and lower FEV1 (% pred). In conclusion, reduced bone mineral density in cystic fibrosis is associated with a number of factors, including ΔF508 genotype, male sex, greater lung disease severity and malnutrition.

A New Monitoring Protocol for Clozapine-Induced Myocarditis Based on an Analysis of 75 Cases and 94 Controls:

Objective: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. Methods: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients’ medical records. Results: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10–33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown. Conclusion: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.

Well‐being, health‐related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease – a community‐based study

Objectives  The aim of this study was to evaluate whether subclinical thyroid disease is associated with impaired health‐related quality of life and a more adverse cardiovascular disease risk profile.

Serum 25-Hydroxyvitamin D: A Predictor of Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes

OBJECTIVE People with diabetes frequently develop vascular disease. We investigated the relationship between blood 25-hydroxyvitamin D (25OH-D) concentration and vascular disease risk in type 2 diabetes. RESEARCH DESIGN AND METHODS The relationships between blood 25OH-D concentration at baseline and the incidence of macrovascular (including myocardial infarction and stroke) and microvascular (retinopathy, nephropathy, neuropathy, and amputation) disease were analyzed with Cox proportional hazards models and logistic regression in an observational study of patients in the 5-year Fenofibrate Intervention and Event Lowering in Diabetes trial. RESULTS A total of 50% of the patients had low vitamin D concentrations, as indicated by median blood 25OH-D concentration of 49 nmol/L. These patients with a blood 25OH-D concentration <50 nmol/L had a higher cumulative incidence of macrovascular and microvascular events than those with levels ≥50 nmol/L. Multivariate analysis, stratified by treatment and adjusted for relevant confounders, identified blood 25OH-D concentration as an independent predictor of macrovascular events. A 50 nmol/L difference in blood 25OH-D concentration was associated with a 23% (P = 0.007) change in risk of macrovascular complications during the study, and further adjustments for seasonality, hs-CRP, and physical activity level had little impact. The unadjusted risk of microvascular complications was 18% (P = 0.006) higher during the study, though the excess risk declined to 11–14% and lost significance with adjustment for HbA1c, seasonality, or physical activity. CONCLUSIONS Low blood 25OH-D concentrations are associated with an increased risk of macrovascular and microvascular disease events in type 2 diabetes. However, a causal link remains to be demonstrated.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine‐refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1‐VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1‐FGFR4), platelet‐derived growth factor receptor α (PDGFRα), ret proto‐oncogene (RET), and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine‐refractory, differentiated thyroid cancer (RR‐DTC).

Renin and renin substrate in primary adrenal insufficiency: Contrasting effects of glucocorticoid and mineralocorticoid deficiency

Abstract Overactivity of the renin-angiotensin system has recently been shown to be important in circulatory homeostasis in adrenocortical failure. However, renin substrate levels decrease in experimentally induced glucocorticoid deficiency, and this can impair both the function of the renin-angiotensin system and its accurate assessment by measurement of renin activity. In order to define the effects of spontaneous steroid deficiency, renin concentration activity and renin substrate were assessed before and after treatment in seven patients with Addisons disease who showed varying degrees of aldosterone and cortisol deficiency. Severe adrenocortical failure, affecting both aldosterone and cortisol, resulted in a gross increase in renin concentration with substrate levels reduced to less than 10 per cent of the mean normal level. Renin excess was poorly reflected by measurement of renin activity when substrate depletion was severe. Substrate deficiency was closely related to the degree of cortisol lack, i.e., renin substrate showed a positive correlation with the level of plasma cortisol before treatment (r = 0.94, p These findings indicate that although mineralocorticoid failure stimulates renin release, adequate glucocorticoid production is crucial in preventing substrate depletion. The homeostatic role of the renin-angiotensin system may be impaired in severe adrenal failure despite an appropriate renin response to mineralocorticoid deficiency. Depletion of substrate may be a factor which contributes to circulatory failure in glucocorticoid deficiency.

Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases

BACKGROUND Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality. METHODS Cases of myocarditis were documented from the patients medical records and fatal cases also from autopsy reports. RESULTS The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004). CONCLUSIONS Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.

Fine Needle Aspiration and Medullary Thyroid Carcinoma: The Risk of Inadequate Preoperative Evaluation and Initial Surgery When Relying Upon FNAB Cytology Alone

OBJECTIVES To evaluate the diagnostic accuracy of fine-needle aspiration biopsy (FNAB) to preoperatively diagnose medullary thyroid cancer (MTC) among multiple international centers and evaluate how the cytological diagnosis alone could impact patient management. METHODS We performed a retrospective chart review of sporadic MTC (sMTC) patients from 12 institutions over the last 29 years. FNAB cytology results were compared to final pathologic diagnoses to calculate FNAB sensitivity. To evaluate the impact of cytology sensitivity for MTC according to current practice and to avoid confounding results by local treatment protocols, changes in treatment patterns over time, and the influence of ancillary findings (e.g., serum calcitonin), therapeutic interventions based on FNAB cytology alone were projected into 1 of 4 treatment categories: total thyroidectomy (TT) and central neck dissection (CND), TT without CND, diagnostic hemithyroidectomy, or observation. RESULTS A total of 313 patients from 4 continents and 7 countries were included, 245 of whom underwent FNAB. FNAB cytology revealed MTC in 43.7% and possible MTC in an additional 2.4%. A total of 113 (46.1%) patients with surgical pathology revealing sMTC had FNAB findings that supported TT with CND, while 37 (15.1%) supported TT alone. In the remaining cases, diagnostic hemithyroidectomy and observation were projected in 32.7% and 6.1%, respectively. CONCLUSION FNAB is an important diagnostic tool in the evaluation of thyroid nodules, but the low sensitivity of cytological evaluation alone in sMTC limits its ability to command an optimal preoperative evaluation and initial surgery in over half of affected patients.

Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF).

Objective  Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia.

Post-partum hypercalcemia in hereditary hyperphosphatasia (juvenile Paget’s disease)

Hereditary hyperphosphatasia is a rare bone disorder characterized by increased bone turnover, elevated alkaline phosphatase (ALP) and bone deformity. We describe a patient with a mild form of hereditary hyperphosphatasia who was initially hypercalcemic in childhood with remission after puberty. Symptomatic hypercalcemia recurred during lactation after each of two pregnancies, associated with increased bone turnover (rise in ALP, osteocalcin, and urine hydroxyproline excretion) which appeared to be independent of changes in major calcium-regulating hormones. The mechanism for the development of post-partum hypercalcemia remains unclear but may relate to the relative estrogen deficiency of lactation. We postulate that acute estrogen withdrawal may result in hypercalcemia in the presence of markedly increased bone turnover.