Citations

SummaryObjectiveSeizures are currently defined by their electrographic features. However, neuronal networks are intrinsically dependent on neurotransmitters of which little is known regarding their periictal dynamics. Evidence supports adenosine as having a prominent role in seizure termination, as its administration can terminate and reduce seizures in animal models. Furthermore, microdialysis studies in humans suggest that adenosine is elevated periictally, but the relationship to the seizure is obscured by its temporal measurement limitations. Because electrochemical techniques can provide vastly superior temporal resolution, we test the hypothesis that extracellular adenosine concentrations rise during seizure termination in an animal model and humans using electrochemistry.MethodsWhite farm swine (n = 45) were used in an acute cortical model of epilepsy, and 10 human epilepsy patients were studied during intraoperative electrocorticography (ECoG). Wireless Instantaneous Neurotransmitter Concentration Sensor (WINCS)–based fast scan cyclic voltammetry (FSCV) and fixed potential amperometry were obtained utilizing an adenosine‐specific triangular waveform or biosensors, respectively.ResultsSimultaneousECoG and electrochemistry demonstrated an average adenosine increase of 260% compared to baseline, at 7.5 ± 16.9 s with amperometry (n = 75 events) and 2.6 ± 11.2 s withFSCV(n = 15 events) prior to electrographic seizure termination. In agreement with these animal data, adenosine elevation prior to seizure termination in a human patient utilizingFSCVwas also seen.SignificanceSimultaneousECoG and electrochemical recording supports the hypothesis that adenosine rises prior to seizure termination, suggesting that adenosine itself may be responsible for seizure termination. Future work using intraoperativeWINCS–basedFSCVrecording may help to elucidate the precise relationship between adenosine and seizure termination.

Abstract Purpose Intra‐articular (IA) hip cortisone injection is commonly performed as a therapeutic modality in patients with femoral acetabular impingement (FAI). To our knowledge, there is no published data evaluating the clinical benefit of these injections. The purpose of this study was to assess the efficacy of therapeutic IA cortisone injection in these patients. Methods At our institution, patients with FAI and labral tear prospectively recorded their numerical rating scale (NRS) pain scores pre‐injection, during post‐injection anaesthetic phase, and at 14 days post‐injection. From this cohort, all patients treated with guided IA cortisone injection, no radiographic evidence of arthritis (Tönnis grade 0 or 1) and pain relief during the anaesthetic phase of the IA injection were included. An absolute change of two points on the NRS score was considered the minimal amount of clinically significant pain relief. Pain scores were compared between the different types of steroid injected. Results Fifty‐four patients (35 females, 19 males) with a mean age of 32 ± 12 years were included. Average median pre‐injection NRS score was 7.0 (range 2.5–10.0), post‐injection anaesthetic phase was 1.0 (range 0.0–5.0), and 14 day post‐injection was 5.0 (range 0.0–10.0). As a group, NRS scores significantly diminished from post‐injection anaesthetic phase to 14 days post‐injection ( p < 0.001). At 14 days post‐injection, only 20 patients (37 %) and at 6 weeks, only 3 patients (6 %) reported a clinically significant decrease in pain. Average duration of pain relief was 9.8 days. There was no difference in pain reduction between steroid preparations. Conclusion In patients with symptomatic FAI and labral tear, intra‐articular cortisone injection has limited clinical benefit as a therapeutic modality. However, anaesthetic‐only IA injections for patients who may be candidates for hip arthroscopy can be a useful diagnostic tool. Level of evidence Therapeutic case series, Level IV.

The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. The frequent deletions and other alterations in these regions in multiple cancers has led to the discovery of a number of extremely large genes contained within these regions and several of the large CFS genes have already been demonstrated to function as tumor suppressors involved in the formation of many different cancers. To study the large CFS genes in oropharyngeal squamous cell carcinoma (OPSCC), we did RNA seq analysis from 11 head and neck cancer patients. This revealed that there are six large CFS genes which consistently had decreased expression in the tumor samples compared to their matched normal tissues. These six genes are PARK2, DLG2, NBEA, CTNNA3, DMD, and FHIT. PARK2 and FHIT are located within the two most frequently expressed CFSs and both have been demonstrated to function as tumor suppressors, while the other large genes are found to have frequent alterations in multiple cancers. Validation experiments using real time PCR indicated that over 60% of OPSCC tumors showed decreased expression for all six genes. Both HPV‐positive and HPV‐negative OPSCCs had similar proportions with loss of expression of these genes. Our results suggest that this selected group of large genes might serve as potential tumor suppressors involved in the development of OPSCCs. Further studies are needed to investigate whether the decreased expression observed is due to genomic instability within the CFS regions or the selection for alterations of specific large CFS genes. © 2014 Wiley Periodicals, Inc.

AbstractChronic cutaneous varicella zoster virus (VZV) infection has not been previously reported or characterized as a complication of dermatomyositis. Two patients with non‐malignancy‐associated dermatomyositis, treated with long‐term prednisone and methotrexate, developed persistent, painless ulcers ultimately established to be secondary to chronic VZV. The absence of pain or a history suggestive of acute VZV, and the lack of characteristic histopathology, resulted in a lengthy delay in diagnosis. Polymerase chain reaction and tissue immunohistochemistry were positive for VZV, and treatment with valacyclovir resulted in complete clearance. Diagnostic testing for VZV should thus be considered in the evaluation of ulcerative lesions in patients with dermatomyositis. The increased incidence of acute VZV in combination with the nature and duration of immunosuppressive treatment in this patient population may be contributory.

Abstract Atypical hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that atypical ductal hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas atypical lobular hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with atypical hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints. Cancer Prev Res; 7(2); 211–7. ©2014 AACR.

Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca 2+ oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca 2+ -activated Cl − channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca 2+ entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl − current in ICC and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca 2+ channel but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca 2+ current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl − equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl − dynamics in ICC.

Abstract Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion–induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference–mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. Cancer Res; 74(6); 1870–80. ©2014 AACR.