Citations

ABSTRACTThe primary objective of this study was to test the hypothesis that gleno‐humeral deformity in children and adolescent with obstetrical brachial plexus palsy is three‐dimensional (3D). The study also compared the metrological properties of typical two‐dimensional gleno‐humeral measures to the newly developed 3D measures. Thirteen individuals (age = 11.8 ± 3.3 years) with obstetrical brachial plexus palsy participated in this IRB‐approved study. 3D axial magnetic resonance images were acquired for both shoulders. Glenoid and humeral models were created in order to quantify 3D glenoid version, humeral head migration, and glenoid concavity. Two‐dimensional (2D) measures were acquired as recommended in the literature. All measures were completed by two observers in this observer‐blind study. Compared to the non‐involved side, the glenoid was more retroverted (7.91°, p = 0.003) and inferiorly oriented (7.28°, p = 0.009). The humeral head was migrated more posteriorly (5.54 mm, p = 0.007), inferiorly (−3.96 mm, p = 0.013), and medially (−3.63 mm,p = 0.002). Eleven of the 13 glenoids were concave, based on the 3D glenoid models. The concurrent validity between three‐ and 2D measures were highly dependent of the parameter measured, the slice level used for the 2D analysis, and the presence/absence of pathology (0.63 < r < 0.91). The standard error of measurement for the 2D anterior–posterior version (>3°) was larger than that for the 3D measure of version (<1°) on the involved side. This study clearly demonstrated that the gleno‐humeral deformation in obstetrical brachial plexus palsy is 3D, emphasizing the need for 3D subject specific gleno‐humeral shape analysis for follow‐up and treatment plans in children with obstetrical brachial plexus palsy. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:675–682, 2016.

Abstract The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell-cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early-phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies. Clin Cancer Res; 21(21); 4780–5. ©2015 AACR.

Whether or not recurrent tumefactive demyelinating lesions are a unique form of CNS demyelinating disease or part of the continuum of multiple sclerosis is a question raised by the case report on which this commentary is based. Detailed review and immunopathologic study of biopsy material may not only confirm or refute a diagnosis of demyelinating disease, but potentially uncover unique features that may assist in understanding pathophysiology and nosology of rare cases with recurrent tumefactive demyelination.

Abstract Background Renal imaging examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) patients. TKV has become the gold-standard image biomarker for ADPKD progression at early stages of the disease and is used in clinical trials to characterize treatment efficacy. Automated methods to segment the kidneys and measure TKV are desirable because of the long time requirement for manual approaches such as stereology or planimetry tracings. However, ADPKD kidney segmentation is complicated by a number of factors, including irregular kidney shapes and variable tissue signal at the kidney borders. Methods We describe an image processing approach that overcomes these problems by using a baseline segmentation initialization to provide automatic segmentation of follow-up scans obtained years apart. We validated our approach using 20 patients with complete baseline and follow-up T1-weighted magnetic resonance images. Both manual tracing and stereology were used to calculate TKV, with two observers performing manual tracings and one observer performing repeat tracings. Linear correlation and Bland–Altman analysis were performed to compare the different approaches. Results Our automated approach measured TKV at a level of accuracy (mean difference ± standard error = 0.99 ± 0.79%) on par with both intraobserver (0.77 ± 0.46%) and interobserver variability (1.34 ± 0.70%) of manual tracings. All approaches had excellent agreement and compared favorably with ground-truth manual tracing with interobserver, stereological and automated approaches having 95% confidence intervals ∼±100 mL. Conclusions Our method enables fast, cost-effective and reproducible quantification of ADPKD progression that will facilitate and lower the costs of clinical trials in ADPKD and other disorders requiring accurate, longitudinal kidney quantification. In addition, it will hasten the routine use of TKV as a prognostic biomarker in ADPKD.

Abstract Environmental, genetic, and immune factors are at play in the development of the variable clinical manifestations of Graves’ ophthalmopathy (GO). Among the environmental contributions, smoking is the risk factor most consistently linked to the development or worsening of the disease. The close temporal relationship between the diagnoses of Graves’ hyperthyroidism and GO have long suggested that these 2 autoimmune conditions may share pathophysiologic features. The finding that the thyrotropin receptor (TSHR) is expressed in orbital fibroblasts, the target cells in GO, supported the notion of a common autoantigen. Both cellular and humeral immunity directed against TSHR expressed on orbital fibroblasts likely initiate the disease process. Activation of helper T cells recognizing TSHR peptides and ligation of TSHR by TRAb lead to the secretion of inflammatory cytokines and chemokines, and enhanced hyaluronic acid (HA) production and adipogenesis. The resulting connective tissue remodeling results in varying degrees extraocular muscle enlargement and orbital fat expansion. A subset of orbital fibroblasts express CD34, are bone-marrow derived, and circulate as fibrocytes that infiltrate connective tissues at sites of injury or inflammation. As these express high levels of TSHR and are capable of producing copious cytokines and chemokines, they may represent an orbital fibroblast population that plays a central role in GO development. In addition to TSHR, orbital fibroblasts from patients with GO express high levels of IGF-1R. Recent studies suggest that these receptors engage in cross-talk induced by TSHR ligation to synergistically enhance TSHR signaling, HA production, and the secretion of inflammatory mediators.

AbstractObjectivesCaregiving can negatively impact well‐being. Cancer caregivers face unique challenges given the intense nature of cancer and treatment, which increases their risk for burden, poor quality of life (QOL), and burnout. Studies to reduce caregiver burden demonstrate QOL improvement and distress reduction in the short term. However, few studies exist to address long‐term benefits. We assessed changes in various QOL domains after participation in a QOL intervention for caregivers of patients having newly diagnosed advanced cancer.MethodsOur institutional review board‐approved study randomized patient–caregiver dyads to either usual care or an in‐person group intervention composed of six 90‐min sessions of structured multidisciplinary QOL components delivered over 4 weeks, with 10 follow‐up phone calls within 20 weeks. Caregivers attended four of the six sessions attended by patients. Sessions included physical therapy, coping and communication strategies, mental health education, spirituality, and social needs. Caregiver QOL (Caregiver Quality of Life Index‐Cancer Scale [CQOLC] and Linear Analogue Self‐Assessment [LASA]) and mood (Profile of Mood States‐Brief [POMS‐B]) were measured at baseline and 4, 27, and 52 weeks. Wilcoxon tests and effect sizes were used to compare the caregiver groups.ResultsOf the 131 caregivers (65 intervention and 66 usual care), 116 completed the study. Caregivers post‐intervention (at 4 weeks) had improved scores on LASA Spiritual Well‐being; POMS‐B total score, Vigor/Activity, and Fatigue/Inertia; and CQOLC Adaptation. At long term (at 27 weeks), caregivers retained improvement in POMS‐B Fatigue/Inertia and gained improvements in CQOLC Disruptiveness and Financial Concerns.ConclusionsCaregivers who received the intervention had higher QOL ratings for specific QOL domains but not for overall QOL. Although a comprehensive intervention was helpful, more specific, targeted interventions tailored for individual needs are recommended. Copyright © 2015 John Wiley & Sons, Ltd.