Citations

The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA‐binding protein 43 (TDP‐43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD–ALS cases and the understanding that repeat‐containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP‐43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.

Abstract Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment (TME), are a key source of the extracellular matrix (ECM) that constitutes the desmoplastic stroma. Through remodeling of the reactive tumor stroma and paracrine actions, CAFs regulate cancer initiation, progression, and metastasis, as well as tumor resistance to therapies. The CAFs found in stroma-rich primary hepatocellular carcinomas (HCC) and liver metastases of primary cancers of other organs predominantly originate from hepatic stellate cells (HSTC), which are pericytes associated with hepatic sinusoids. During tumor invasion, HSTCs transdifferentiate into myofibroblasts in response to paracrine signals emanating from either tumor cells or a heterogeneous cell population within the hepatic tumor microenvironment. Mechanistically, HSTC-to-myofibroblast transdifferentiation, also known as, HSTC activation, requires cell surface receptor activation, intracellular signal transduction, gene transcription, and epigenetic signals, which combined ultimately modulate distinct gene expression profiles that give rise to and maintain a new phenotype. The current review defines a paradigm that explains how HSTCs are activated into CAFs to promote liver metastasis. Furthermore, a focus on the most relevant intracellular signaling networks and epigenetic mechanisms that control HSTC activation is provided. Finally, we discuss the feasibility of targeting CAF/activated HSTCs, in isolation or in conjunction with targeting cancer cells, which constitutes a promising and viable therapeutic approach for the treatment of primary stroma-rich liver cancers and liver metastasis. Mol Cancer Res; 13(4); 604–12. ©2014 AACR.

Abstract KRAS mutations are frequently detected in human colorectal cancer and contribute to de novo apoptosis resistance and ultimately therapeutic failure. To overcome KRAS-mediated apoptosis resistance, the irreversible proteasome inhibitor, carfilzomib, was evaluated and found to potently induce Noxa, which was dependent upon c-Myc, and Bik. Isogenic mutant versus wild-type KRAS carcinoma cells showed elevated Bcl-xL, confirmed by KRAS siRNA or ectopic expression. Upregulated Bcl-xL by mutant KRAS was mediated by ERK as indicated by ERK knockdown. Bcl-xL expression was regulated at the level of mRNA and protein as shown using actinomycin D and cyclohexamide, respectively. Suppression of Bcl-xL by shRNA sensitized mutant KRAS cells to carfilzomib. Concurrent Bcl-xL antagonism by the BH3 mimetic ABT-263 combined with carfilzomib synergistically enhanced apoptosis that was dependent on Bax or p53, and was attenuated by Noxa or Bik shRNA. In support of this strategy, ectopically expressed Noxa enhanced apoptosis by ABT-263. Carfilzomib-induced Noxa and Bik sequestered Mcl-1 and ABT-263 released Bik and Bak from Bcl-xL, suggesting a mechanism for drug synergy. These preclinical findings establish mutant KRAS-mediated Bcl-xL upregulation as a key mechanism of apoptosis resistance in KRAS-mutant colorectal cancer. Furthermore, antagonizing Bcl-xL enabled carfilzomib-induced Noxa and Bik to induce synergistic apoptosis that reversed KRAS-mediated resistance. Implications: This novel study reveals a promising treatment strategy to overcome apoptosis resistance in KRAS-mutant colorectal cancer by concurrent upregulation of Noxa/Bik and antagonism of Bcl-xL. Mol Cancer Res; 13(4); 659–69. ©2014 AACR.

Abducens palsy (ie, sixth nerve palsy) is the most common single extraocular muscle palsy. The primary symptom is double vision. The treatment goal is to correct the underlying cause. If no cause is identified or the palsy is related to a well-managed chronic disease, treatment consists of patching one eye or applying a temporary prism. We report a patient whose abducens palsy resolved with four acupuncture treatments. The patient, a 58-year-old Vietnamese man with diabetes mellitus, presented to our institution's ophthalmology department with sudden onset of double vision. Ophthalmologic examination resulted in diagnosis of isolated left abducens palsy. The patient received a temporary prism for symptomatic relief. With no improvement after 2 months, he presented to our integrative medicine program inquiring about acupuncture. He received four acupuncture treatments over 11 weeks with complete resolution of his diplopia. This case is suggestive that acupuncture may be helpful treatment of patients with abducens palsy.

Processed nerve allografts have become an alternative to repair segmental nerve defects, with results comparable with autografts regarding sensory recovery; however, they have failed to reproduce comparable motor recovery. The purpose of this study was to determine how revascularizaton of processed nerve allograft would affect motor recovery. Eighty‐eight rats were divided in four groups of 22 animals each. A unilateral 10‐mm sciatic nerve defect was repaired with allograft (group I), allograft wrapped with silicone conduit (group II), allograft augmented with vascular endothelial growth factor (group III), or autograft (group IV). Eight animals from each group were sacrificed at 3 days, and the remaining animals at 16 weeks. Revascularization was evaluated by measuring the graft capillary density at 3 days and 16 weeks. Measurements of ankle contracture, compound muscle action potential, tibialis anterior muscle weight and force, and nerve histomorphometry were performed at 16 weeks. All results were normalized to the contralateral side. The results of capillary density at 3 days were 0.99% ± 1.3% for group I, 0.33% ± 0.6% for group II, 0.05% ± 0.1% for group III, and 75.6% ± 45.7% for group IV. At 16 weeks, the results were 69.9% ± 22.4% for group I, 37.0% ± 16.6% for group II, 84.6% ± 46.6% for group III, and 108.3% ± 46.8% for group IV. The results of muscle force were 47.5% ± 14.4% for group I, 21.7% ± 13.5% for group II, 47.1% ± 7.9% for group III, and 54.4% ± 10.6% for group IV. The use of vascular endothelial growth factor in the fashion used in this study improved neither the nerve allograft short‐term revascularization nor the functional motor recovery after 16 weeks. Blocking allograft vascularization from surrounding tissues was detrimental for motor recovery. The processed nerve allografts used in this study showed similar functional motor recovery compared with that of the autograft. © 2014 Wiley Periodicals, Inc. Microsurgery 36:134–143, 2016.

Abstract Aims Aldosterone activation is central to the sodium–fluid retention that marks the progression of heart failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. Methods and results Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Conclusions Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression.

AbstractPhakomatous choristoma (PC) is a rare benign congenital lesion of lenticular anlage. It presents in young patients as a firm subcutaneous mass in the medial eyelid or orbit and may raise clinical concern for neoplasms such as rhabdomyosarcoma, but its histopathology is distinct, consisting of dense collagenous stroma and eosinophilic cuboidal epithelial cells forming nests, tubules, cords, or pseudoglands. We present a case of PC in a 10‐week‐old boy to illustrate the unique clinical, histopathologic, and immunophenotypic features of this condition and to reaffirm that familiarity with this rare entity aids accurate diagnosis.

Pre‐surgical measurement of supraspinatus muscle extensibility is important for rotator cuff repair. The purpose of the present study was to explore the potential feasibility of a shear wave ultrasound elastography (SWE)‐based method, combined with B‐mode ultrasound, to measure the in vivo stiffness of the supraspinatus muscle non‐invasively and thus obtain key information about supraspinatus muscle extensibility. Our investigation comprised two steps. First, we determined the orientation of the supraspinatus muscle fibers in cadaveric shoulders without rotator cuff tear in order to optimize the ultrasound probe positions for SWE imaging. Second, we investigated the feasibility of quantifying the stiffness of the normal supraspinatus muscle by SWE in vivo. The supraspinatus muscle was divided into four anatomical regions: anterior superficial (AS), posterior superficial (PS), anterior deep (AD), and posterior deep (PD). Each region was examined by SWE. The SWE stiffnesses of AD, AS, PD, and PS were 40.0 ± 12.4, 34.0 ± 9.9, 32.7 ± 12.7, 39.1 ± 15.7 kPa, respectively. SWE combined with B‐Mode ultrasound imaging could be a feasible method for quantifying the local stiffness of the rotator cuff muscles. Clin. Anat. 28:213–218, 2015. © 2014 Wiley Periodicals, Inc.

A point-of-care workflow checklist in the form of an iOS (iPhone Operating System) app for use by stroke providers was introduced with the objective of standardizing acute stroke evaluation and documentation at 2 affiliated academic medical centers. Providers used the app in unselected, consecutive patients undergoing acute stroke evaluation in an emergency department or hospital setting between August 2012 and January 2013 and August 2013 and February 2014. Satisfaction surveys were prospectively collected pre- and postintervention from residents, staff neurologists, and clinical data specialists. Residents (20 preintervention and 16 postintervention), staff neurologists (6 pre and 5 post), and clinical data specialists (4 pre and 4 post) participated in this study. All 16 (100%) residents had increased satisfaction with their ability to perform an acute stroke evaluation postintervention but only 9 (56%) of 16 felt the app was more help than hindrance. Historical controls aligned with preintervention results. Staff neurologists conveyed increased satisfaction with resident presentations and decision making when compared to preintervention surveys. Stroke clinical data specialists estimated a 50% decrease in data abstraction when the app data were used in the clinical note. Concomitant effect on door-to-needle (DTN) time at 1 site, although not a primary study measure, was also evaluated. At that 1 center, the mean DTN time decreased by 16 minutes when compared to the corresponding months from the year prior. The point-of-care acute stroke workflow checklist app may assist trainees in presenting findings in a standardized manner and reduce data abstraction time. The app may help reduce DTN time, but this requires further study.