Sath Nag

Mitochondrial Oxidative Phosphorylation Is Impaired in Patients with Congenital Lipodystrophy

Objective: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle. Research Design and Methods: Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls. Results: The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P < 0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates. Conclusions: Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

CONTEXT A diagnosis of Addisons disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. OBJECTIVE The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addisons disease could lead to preservation or improvement in adrenal steroidogenesis. DESIGN AND INTERVENTION This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. PATIENTS AND MAIN OUTCOME MEASURES Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. RESULTS Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. CONCLUSION New-onset autoimmune Addisons disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addisons disease may be warranted.

Lesson of the month 2: Catecholamine-induced cardiomyopathy – pitfalls in diagnosis and medical management

Cardiomyopathy as the initial presentation of phaeochromocytoma (PCA) is uncommon. Diagnostic work-up and perioperative management may be challenging within this context. We report three cases of PCA presenting with cardiomyopathy to illustrate the pitfalls in diagnosis and management. None of the patients had typical adrenergic symptoms and all three were established on beta-blockers prior to diagnosis. Their fractionated plasma catecholamine levels were elevated and the diagnosis of PCA was confirmed with various imaging modalities and post adrenalectomy. Interpretation of fractionated catecholamine levels in the context of established cardiomyopathy is difficult as cardiac failure of any aetiology generates an adrenergic response. Hence screening all patients with idiopathic cardiomyopathy is likely to generate a high false-positive rate. However, a high index of suspicion should prompt further diagnostic work-up in patients with idiopathic cardiomyopathy for occult PCAs. Peer-reviewed guidelines are required to guide the investigation and management of suspected catecholamine-induced cardiomyopathy.

Qualitative analysis of ultrasound reports assessing radiological descriptors of thyroid nodules - a retrospective pilot audit

We conducted a retrospective audit at The James cook University Hospital (JCUH) and the University Hospital of North Tees (UHNT) between March 2012 and May 2013. All patients who had a solitary thyroid nodule or a dominant nodule within a multinodular goitre at ultrasound scanning (USS) were included. Patients with multinodular goitre and multiple/incidental asymptomatic nodules or thyroiditis on USS were excluded. The following data for each thyroid USS report was collected from the electronic reporting system:

Incidence of Sunitinib induced thyroid dysfunction in renal cell carcinoma: a pilot retrospective audit

Primary hypothyroidism is a common adverse effect of TKI therapy. The incidence of primary hypothyroidism in this cohort was 20% and is similar to hypothyroidism rates in published data from Sunitinib studies (14-46%). There appeared to be a significant delay between the diagnosis of overt primary hypothyroidism and the start of LT4 therapy. Regular pre-cycle TFT checks and close liaison with Endocrinology will help reduce morbidity from delayed diagnosis and treatment of hypothyroidism. 10% 3%

Emphysematous pyelonephritis: an uncommon fatal complication of type 1 diabetes

Emphysematous urinary tract infections are associated with gas formation within the upper or lower urinary tracts. Diabetes is a major risk factor for these infections which can present as cystitis, pyelitis or pyelonephritis associated with peri nephric abscesses. Emphysematous pyelonephritis (EPN) is a serious, uncommon, necrotising infection affecting the renal parenchyma. The first case of a gas forming renal infection was reported by Kelly and