Citations

To determine the role insulin resistance may play in the catabolic effect of high-dose prednisone therapy, healthy volunteers were studied on four occasions with the hormone-clamp technique at two insulin infusion rates. Subjects were studied after 5 days of prednisone (60 mg/day) or no steroid treatment and were infused with somatostatin, glucagon, growth hormone, [3H]glucose, [14C]leucine, and insulin (0.1 or 0.2 mil · kg1 · min1). At each rate of insulin infusion, the rate of leucine oxidation was increased (P < .001) after steroid treatment. Leucine flux, an indicator of whole-body proteolysis, was similar in the presence or absence of steroid treatment (2.26 ± 0.08 vs. 2.13 ± 0.04 μmol · kg1 · min1 respectively) at the lower rate of insulin infusion but was higher during steroid treatment (2.18 ± 0.06 vs. 1.84 ± 0.13 μmol · kg1 · min1) at the 0.2-mU · kg1 · min1 insulin infusion. Steroid pretreatment had no significant effect on the nonoxidative rates of leucine disappearance. These data provide strong evidence that the protein wasting associated with glucocorticosteroid therapy is in part the result of steroid-induced resistance to the antiproteolytic effect of insulin and an increase in the oxidation (and thus wasting) of one essential amino acid, leucine.

Recent studies indicate that hydrogen-labeled glucose tracers underestimate glucose turnover in humans under conditions of high flux. The cause of this underestimation is unknown. To determine whether the error is time-, pool-, model-, or insulin-dependent, glucose turnover was measured simultaneously with [6-3H]-, [6,6-2H2]-, and [6-14C]glucose during a 7-h infusion of either insulin (1 mU · kg−1 · min−1) or saline. During the insulin infusion, steady-state glucose turnover measured with both [6-3H]glucose (8.0 ± 0.5 mg · kg−1 · min−1) and [6,6-2H2]glucose (7.6 ± 0.5 mg kg−1 min−1) was lower (P < .01) than either the glucose infusion rate required to maintain euglycemia (9.8 ± 0.6 mg · kg−1 · min−1) or glucose turnover determined with [6-14 C]glucose and corrected for Cori cycle activity (9.8 ± 0.7 mg · kg−1 · min1). Consequently “negative” glucose production rates (P <.01) were obtained with either [6-3 H]- or [6,6-2 H2]-but not [6-14 C]glucose. The difference between turnover estimated with [6-3 H]glucose and actual glucose disposal (or 14C glucose flux) did not decrease with time and was not dependent on duration of isotope infusion. During saline infusion, estimates of glucose turnover were similar regardless of the glucose tracer used. High-performance liquid chromatography of the radioactive glucose tracer and plasma revealed the presence of a tritiated nonglucose contaminant. Although the contaminant represented only 1.5% of the radioactivity in the [6-3H]glucose infusate, its clearance was 10-fold less (P <.001) than that of [6-3H]glucose. This resulted in accumulation in plasma, with the contaminant accounting for 16.6 ± 2.09 and 10.8 ± 0.9% of what customarily is assumed to be plasma glucose radioactivity during the insulin or saline infusion, respectively (P < .01). When corrected for the presence of the contaminant, glucose turnover determined with [6-3H]glucose during insulin infusion (9.5 ± 0.6 mg · kg−1 · min−1) no longer differed from either the glucose infusion rate or that determined with [6-14C]glucose. Therefore, the underestimation of glucose turnover during insulin infusion and negative glucose production rates observed with traditional methods to analyze plasma radioactivity and commercially available tracers is the result of an artifactual increase in [6-3H]glucose specific activity. The etiology of the underestimation of glucose turnover with [6,6-2H2]glucose remains to be determined.

Competition between glucose and free fatty acids as metabolic fuels is supported by both in vitro and in vivo data, but whether amino acids can also compete with glucose as a source of energy in vivo remains to be established. To determine the effect of increased availability of an amino acid on whole-body glucose flux and glucose carbon uptake by the human forearm, five groups of overnight-fasted normal subjects were infused with either saline, leucine (at 0.5 or 1.0μmol · kg−1 · min−1), isoleucine (0.5 μmol · kg−1 · min−1), or threonine (0.5 μmol · kg−1 · min−1). Plasma glucose concentrations and glucose flux decreased similarly in all groups. No significant changes in forearm output of leucine carbon, isoleucine carbon, or threonine were seen during saline infusion. In contrast, during leucine infusion there was a dose-dependent increase (r = .86, P < .001) in leucine carbon uptake with increased arterial leucine and a-ketoisocaproate concentrations. During infusions of isoleucine and threonine, increases (P < .05) in isoleucine carbon uptake and threonine uptake, respectively, were observed. Glucose uptake by forearm tissues did not change during the saline infusion, but it decreased (P < .05) in all four groups receiving an amino acid infusion. Changes in leucine carbon uptake were strongly correlated (r = −.76, P < .001) with changes in glucose uptake. Therefore, amino acids affect glucose uptake in human forearm tissue and presumably compete as oxidative fuels.

Type A insulin resistance, associated with acanthosis nigricans and menstrual irregularity, has been ascribed to a decreased concentration of insulin receptors. We now report four affected females from one family, a mother and three daughters (including identical twins) who appear to have the type A syndrome. Two of the kindred had no apparent ovarian dysfunction, while the other two had hyperprolactinemia without other findings of polycystic ovary disease, suggesting a genetic disease with variable penetrance. All had normal erythrocyte and monocyte insulin binding. Insulin dose-response studies to assess glucose metabolism and insulinsensitivity were performed in the affected twins. The dose response to insulin was shifted to the right with a decrease in maximal response. These results are consistent with a postbinding defect in insulin action in these patients.

ObjectiveTo identify new genetic associations with juvenile and adult dermatomyositis (DM).MethodsWe performed a genome‐wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single‐nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS‐level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non‐MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C–like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C‐C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM.ConclusionOur findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non‐MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

SummaryDetection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1‐ (17p‐) and 11q22.3‐ (11q‐) occurring in the same cell (clonal 17p‐/11q‐) would confer a worse prognosis than either 17p‐ or 11q‐. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p‐, 11q‐, or clonal 17p‐/11q‐. Twenty (1%) patients had clonal 17p–/11q‐, 158 (7%) had 17p‐ (including 4 with 17p‐ and 11q‐ in separate clones), 247 (11%) had 11q‐, and 1759 (81%) had neither 17p‐ nor 11q‐. Eleven of 15 (73%) tested patients with clonal 17p‐/11q‐ had dysfunctional TP53 mutations. Overall survival for clonal 17p‐/11q‐ was significantly shorter (1·9 years) than 17p‐ (3·1 years, P = 0·04), 11q‐ (4·8 years, P ≤ 0·0001), or neither 17p‐ nor 11q‐ (9·3 years, P ≤ 0·0001). Clonal 17p‐/11q‐ thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very‐high risk patients.

ObjectiveIt is unclear why despite a comparable cardiometabolic risk profile, “metabolically benign” overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals.Design and MethodsIn cross‐sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at‐risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined “metabolically benign” with ≤ 1, and “at‐risk” with ≥2 components of the metabolic syndrome.ResultsCompared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04‐2.99), hepatic fat (OR: 1.90, 95% CI:1.12‐3.24) and leptin (OR: 2.15, 95% CI: 1.23‐3.76), and the bottom tertile of HMW‐adiponectin (OR: 2.90, 95% CI: 1.62‐5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22‐8.29), pericardial fat (OR: 9.27, 95% CI: 5.52‐15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77‐4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60‐3.94).ConclusionsLevels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state.

Abstract Interleukin-2 (IL-2), a product of activated T-cells, is now being used in a number of protocols for cancer immunotherapy. In one stem cell transplantation protocol for breast cancer, IL-2 is used together with interferon- γ (IFN- γ ) and cyclosporine to stimulate a graft-versus-tumor response and improve the likelihood of a prolonged remission. We present the case of a patient who developed peripheral eosinophilia, perihilar infiltrates, and hypoxemia after autologous stem cell transplantation and the use of recombinant IL-2 and IFN- γ. Histologic analysis of transbronchial lung biopsies demonstrated a few eosinophils within the bronchial submucosa. Immunostaining using antibodies directed against eosinophil major basic protein (MBP), however, revealed massive extracellular deposition of this toxic granule protein throughout the lung parenchyma. IL-2 therapy is well known to induce a peripheral eosinophilia and to be associated with the capillary leak syndrome characterized by weight gain, edema, and oliguria. The findings noted in this case report suggest that the eosinophil activation that accompanies immunologic therapy with IL-2 can result in direct toxicity to the lung and a localized vascular leak syndrome. This syndrome should be considered in the differential diagnosis of pulmonary infiltrates that occur acutely after bone marrow transplantation with cytokine augmentation.

Aims: The NCDR CathPCI Registry collects detailed clinical, process-of-care and outcomes data for patients undergoing coronary angiography and percutaneous coronary intervention (PCI) in the USA. The registry contributes to quality of care by providing data feedback on a wide range of performance metrics to participating centres and by facilitating local and national quality improvement efforts. Interventions: No treatments are mandated, participating centres receive routine quality-of-care and outcomes performance feedback reports and access to a quality dashboard for personalized performance reports. Population: Patients undergoing cardiac catheterization and PCI are retrospectively identified. No informed consent is required, as data are anonymised. From inception in 1998, more than 12 million records have been submitted from 1577 participating US centres. Baseline data: Approximately 250 fields encompassing patient demographics, medical history and risk factors, hospital presentation, initial cardiac status, procedural details, medications, laboratory values, and in-hospital outcomes. Linkages with outside sources of data have permitted longitudinal outcomes assessment in some cases. Centre personnel enter the data into the registry, in some cases facilitated by software vendors. There are non-financial incentives for centre participation. Data completeness is noteworthy with most fields missing at rates less than 5%. A comprehensive data quality program is employed to enhance data validity. Endpoints: Main outcome measures include quality process metrics and in-hospital patient outcomes. Data are available for research by application to: http://www.ncdr.com