Citations

AbstractConstitutively‐active ligand‐independent splice variants of the androgen receptor are an adaptive response by prostate cancer cells to escape androgen deprivation therapy and novel androgen receptor‐directed treatments. Androgen receptor splice variant 7 is the most common splice variant detected in clinical biospecimens, and emerging data now suggest that the presence of tumoral androgen receptor splice variant 7 might be indicative of primary and acquired resistance to next‐generation androgen pathway inhibitors, such as abiraterone and enzalutamide. At the same time, taxane chemotherapy might retain its efficacy regardless of androgen receptor splice variant 7 status, thus suggesting the potential for a predictive biomarker guiding treatment selection in men with metastatic castration‐resistant prostate cancer. Herein, we review the preclinical data elucidating the structure and function of androgen receptor splice variant 7, we describe the existing clinical data using this biomarker in metastatic castration‐resistant prostate cancer, and we highlight potential therapeutic strategies to target androgen receptor splice variant 7‐expressing prostate cancer.

AbstractBackgroundDefecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community.MethodsWe reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography.Key ResultsOf 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age‐ and sex‐adjusted incidence rate per 100 000 person‐years was 19.3 (95% CI: 16.8–21.8). The age‐adjusted incidence per 100 000 person‐years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4–36.1) than in men (6.6, 95% CI: 4.4–8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence.Conclusions & InferencesAmong constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses.

ABSTRACT Injury to the joint provokes a number of local pathophysiological changes, including synthesis of inflammatory cytokines, death of chondrocytes, breakdown of the extra‐cellular matrix of cartilage, and reduced synthesis of matrix macromolecules. These processes combine to engender the subsequent development of post‐traumatic osteoarthritis (PTOA). To prevent this from happening, it is necessary to inhibit these disparate responses to injury; given their heterogeneity, this is challenging. However, dexamethasone has the necessary pleiotropic properties required of a drug for this purpose. Using in vitro models, we have shown that low doses of dexamethasone sustain the synthesis of cartilage proteoglycans while inhibiting their breakdown after injurious compression in the presence or absence of inflammatory cytokines. Under these conditions, dexamethasone is non‐toxic and maintains the viability of chondrocytes exposed chronically to such cytokines as interleukin (IL) ‐1, IL‐6, and tumor necrosis factor‐α. Moreover, the anti‐inflammatory properties of dexamethasone have been appreciated for decades. In view of this information, we have initiated a pilot clinical study to determine whether a single, intra‐articular injection of dexamethasone into the wrist shows promise in preventing PTOA after intra‐articular fracture of the distal radius. CLINICAL SIGNIFICANCE: Suppressing the various etiopathophysiological responses to injury in the joint is an attractive strategy for lowering the clinical burden of PTOA. The intra‐articular administration of dexamethasone soon after injury offers a simple and inexpensive means of accomplishing this. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:406–411, 2017.

Recent combat experience reignited interest in transfusing whole blood (WB) for patients with life‐threatening bleeding. US Army data indicate that WB transfusion is associated with improved or comparable survival compared to resuscitation with blood components. These data complement randomized controlled trials that indicate that platelet (PLT)‐containing blood products stored at 4°C have superior hemostatic function, based on reduced bleeding and improved functional measures of hemostasis, compared to PLT‐containing blood products at 22°C. WB is rarely available in civilian hospitals and as a result is rarely transfused for patients with hemorrhagic shock. Recent developments suggest that impediments to WB availability can be overcome, specifically the misconceptions that WB must be ABO specific, that WB cannot be leukoreduced and maintain PLTs, and finally that cold storage causes loss of PLT function. Data indicate that the use of low anti‐A and anti‐B titer group O WB is safe as a universal donor, WB can be leukoreduced with PLT‐sparing filters, and WB stored at 4°C retains PLT function during 15 days of storage. The understanding that these perceived barriers are not insurmountable will improve the availability of WB and facilitate its use. In addition, there are logistic and economic advantages of WB‐based resuscitation compared to component therapy for hemorrhagic shock. The use of low‐titer group O WB stored for up to 15 days at 4°C merits further study to compare its efficacy and safety with current resuscitation approaches for all patients with life‐threatening bleeding.

Background Incidental mobile thrombi are commonly found on endovascular leads of cardiac implantable electronic devices ( CIED s). Transseptal puncture for catheter ablation of arrhythmia poses a risk for paradoxical embolism. We examined risk of ischemic stroke, transient ischemic attack ( TIA ), or systemic embolism after transseptal ablation in patients with and without CIED s. Methods and Results Using a national administrative claims database, 31 720 patients who underwent a transseptal catheter ablation between January 2004 and September 2014 were identified. Two propensity‐matched cohorts were created by matching demographic variables, administrative variables, Charlson Comorbidity Index, CHA 2 DS 2 ‐Vasc score, and year and indication for ablation (5533 and 11 300 patients with and without CIED s). Incidence rates and Cox proportional hazards models were used to estimate risk of ischemic stroke, TIA , or systemic embolism for patients with and without CIED s. Impact of oral anticoagulation ( OAC ) use on the endpoint was examined. Over a mean follow‐up of 2.1 years, the incidence of the combined endpoint was 1.9 per 100 person‐years in patients with CIED s and 1.5 per 100 person‐years in patients without CIED s ( P =0.03). Among patients not on OAC , presence of a cardiac device was associated with an increased risk (hazard ratio [ HR ], 1.71 [1.24–2.35]; P <0.01), whereas there was no association noted among patients treated with OAC ( HR , 0.98 [0.75–1.28]). Conclusion CIED s are associated with an increased risk of stroke, TIA , or systemic embolism after transseptal ablation, but this risk is attenuated with postablation OAC use. Role of anticoagulation post‐transseptal ablation in patients with CIED warrants further investigation.