Citations

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow–derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c‐Kit+ hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c‐Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c‐Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c‐Kit+ and CD34+ CD133+ hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34+ CD133+ and c‐Kit+ progenitor cells as well as c‐Kit+/CD34+ CD133+ decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c‐Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy.

Background: Management of patients with thyroglobulin (Tg)-positive/scan-negative thyroid cancer remains challenging. American Thyroid Association (ATA) guidelines recommend potential use of empiric 131 I therapy and various scanning modalities, but no standard for managing such cases exists. Methods: We surveyed ATA members to assess current practice in management of patients with Tg-positive/scan-negative disease. Members participated in a web-based survey of six case scenarios of Tg elevations but iodine scan negativity. Results: A total of 288 ATA members (80% male) participated. Patient age, sex, and basal and stimulated Tg varied between the cases. Respondents were asked their opinion regarding empiric 131 I therapy use, including 131 I dose, use and duration of low-iodine diet, thyroxine withdrawal or recombinant human thyrotropin (rhTSH), and utilization of additional imaging (neck ultrasound (US) or positron emission tomography/computed tomography (PET/CT)) and reconsideration of 131 I therapy. Between 16% and 51% recommended initial use of empiric 131 I for the various scenarios. The majority chose a 131 I dose between 75 and 150 mCi, and 73% employed a low-iodine diet for two or more weeks. Preference between thyroxine withdrawal versus rhTSH was evenly split. More than 98% obtained a neck US if empiric 131 I was not given; 52–89% would proceed to PET/CT if US was negative. Only 44% used rhTSH stimulation in PET scan preparation. 131 I use was more common with stimulated Tg significantly >10 ng/mL. 131 I therapy was slightly more likely with PET-positive (56%) than PET-negative status (45%). Respondents were split regarding empiric 131 I if basal and stimulated Tg increased ≥150% over two years. Providers in North America less commonly utilized 131 I treatment than those from other areas. In the face of possible heterophilic antibody interference in the Tg assay, the majority did not recommend 131 I therapy. Conclusions: Empiric 131 I therapy is still utilized for patients with Tg-positive/scan-negative disease. Neck US is frequently used to further evaluate such cases as 18 FDG-PET/CT, albeit the latter is used somewhat less often. Use of 131 I therapy correlated with the degree of Tg elevation or development of Tg antibodies, and was recommended more commonly with PET-positive than PET-negative status in patients with lower Tg levels. 131 I was less commonly used by providers within North America.

Purpose: Dual-energy computed tomography (DECT) is an emerging imaging modality with the unique capability of determining urinary stone composition. This study compares radiation exposure of DECT, standard single-energy CT (SECT), and low-dose renal stone protocol single-energy CT (LDSECT) for the evaluation of nephrolithiasis in a single in vivo patient cohort. Materials and Methods: Following institutional review board (IRB) approval, we retrospectively reviewed 200 consecutive DECT examinations performed on patients with suspected urolithiasis over a 6-month period. Of these, 35 patients had undergone examination with our LDSECT protocol, and 30 patients had undergone examination of the abdomen and pelvis with our SECT imaging protocol within 2 years of the DECT examination. The CT dose index volume (CTDI vol ) was used to compare radiation exposure between scans. Image quality was objectively evaluated by comparing image noise. Statistical evaluation was performed using a Student's t -test. Results: DECT performed at 80/140 kVp and 100/140 kVp did not produce a significant difference in radiation exposure compared with LDSECT ( p =0.09 and 0.18, respectively). DECT performed at 80/140 kVp and 100/140 kVp produced an average 40% and 31%, respectively, reduction in radiation exposure compared with SECT ( p <0.001). For patients imaged with the 100/140 kVp protocol, average values for images noise were higher in the LDSECT images compared with DECT images ( p <0.001) and there was no significant difference in image noise between DECT and SECT images in the same patient ( p =0.88). Patients imaged with the 80/140 kVp protocol had equivocal image noise compared with LDSECT images ( p =0.44), however, DECT images had greater noise compared with SECT images in the same patient ( p <0.001). Of the 75 patients included in the study, stone material was available for 16; DECT analysis correctly predicted stone composition in 15/16 patients (93%). Conclusion: DECT provides knowledge of stone composition in addition to the anatomic information provided by LDSECT/SECT without increasing patient radiation exposure and with minimal impact on image noise.

We treated 26 eyes of 25 young patients having a mean age of 30 years with intravitreal vascular endothelial growth factor (VEGF) inhibitor for choroidal new vessel (CNV) formation overlying choroidal osteoma over a mean follow-up of 26 months. Mean number of injections was 2.4 at 6 months, 3.2 at 12 months, and 5.5 at 24 months. CNV was subfoveal in 14 eyes, juxtafoveal in 5, extrafoveal in 5, and peripapillary in 2. By paired comparison, mean decrease from baseline was 119.7 microns at 6 months (n=15;P=0.001), 105.3 microns at 1 year (n=10;P=0.03), and 157.6 microns at 2 years (n=7;P=0.08). BCVA improved by 3.3 lines at 6 months after therapy (n=26;P<0.001), 2.8 lines (n=20;P=0.01) at 1 year, and 3.1 lines (n=13;P=0.049) at 2 years. We conclude that intravitreal anti-VEGF injections improve vision in majority of eyes with CNV from choroidal osteoma.

Background— There is controversy about the diagnostic and prognostic significance of percutaneous coronary intervention–related myocardial infarction, especially with the use of cardiac troponin T (cTnT). This analysis was designed to address the question of the presence and the level of a prognostic cTnT threshold. Methods and Results— We evaluated 5268 consecutive patients who underwent nonemergent percutaneous coronary intervention between 2000 and 2009 with a preprocedural cTnT level below the upper limit of normal (ULN, ≤0.01 ng/mL). Postprocedural cTnT and creatine kinase-MB mass levels (ULN, 6.7 ng/mL in men and 3.8 ng/mL in women) were found to be associated with 3-month mortality in Cox proportional hazard models (hazard ratio per doubling of cTnT, 1.24; 95% confidence interval, 1.08–1.43; P =0.003 and hazard ratio per doubling of creatine kinase-MB, 1.30; 95% confidence interval, 1.05–1.60; P =0.018), adjusted for the Mayo Clinic risk scores for in-hospital and postdischarge mortality. The optimal prognostic threshold for 3-month mortality was 25× ULN for cTnT (hazard ratio, 4.53; 99% confidence interval, 1.59–12.9; P <0.001), which provided similar information as a value of 5× ULN for creatine kinase-MB (hazard ratio, 4.31; 99% confidence interval, 1.27–14.6; P =0.002). The cumulative mortality rate was 0.6% at 91 days. Conclusions— A significant association of postpercutaneous coronary intervention cardiac biomarker elevation with a small number of postpercutaneous coronary intervention outcomes was noted for the early (first 91 days) follow-up period with an identifiable optimal threshold of 25× ULN (0.25, ng/mL) for cTnT, which provided similar early outcome information as a cutoff of 5× ULN for creatine kinase-MB.

Obesity is often regarded as the primary cause of metabolic syndrome. However, many lines of evidence suggest that obesity may develop as a protective mechanism against tissue damage during caloric surplus and that it is only when the maximum fat accumulation capacity is reached and fatty acid spillover occurs into to peripheral tissues that metabolic diseases develop. In this regard, identifying the molecular mechanisms that modulate adipocyte fat accumulation and fatty acid spillover is imperative. Here we identify the deleted in breast cancer 1 (DBC1) protein as a key regulator of fat storage capacity of adipocytes. We found that knockout (KO) of DBC1 facilitated fat cell differentiation and lipid accumulation and increased fat storage capacity of adipocytes in vitro and in vivo. This effect resulted in a “healthy obesity” phenotype. DBC1 KO mice fed a high-fat diet, although obese, remained insulin sensitive, had lower free fatty acid in plasma, were protected against atherosclerosis and liver steatosis, and lived longer. We propose that DBC1 is part of the molecular machinery that regulates fat storage capacity in adipocytes and participates in the “turn-off” switch that limits adipocyte fat accumulation and leads to fat spillover into peripheral tissues, leading to the deleterious effects of caloric surplus.