Reversal of carotid dissection-induced ocular and cerebral ischemia by stenting.

PURPOSE: To present an example of how close clinical monitoring of a patient with acute Horner syndrome from carotid artery dissection may be critical in reversing neurologic dysfunction. OBSERVATIONS: A patient whose initial neuro-ophthalmic manifestation was Horner syndrome, but who evolved over 14 days to display transient monocular vision loss, ipsilateral ocular ischemic syndrome, and episodic contralateral hemiparesis. Digital subtraction angiography demonstrated progressive ipsilateral carotid occlusion with lack of collateral flow. The patient underwent stenting with rapid reversal of transient monocular visual loss and hemiparesis. Follow-up examination several months later confirmed complete resolution of all clinical abnormalities. CONCLUSIONS AND IMPORTANCE: This case displayed protracted evolution of ischemic manifestations following carotid artery dissection and their prompt reversal with stenting. This case emphasizes the value of close clinical attention to a patient with acute Horner syndrome because manifestations may appear more than 10 days after event onset that impel intervention for the dissection.

Injury patterns at Isle Royale National Park: an epidemiologic review of injuries and illnesses sustained in a remote environment.

OBJECTIVE: Isle Royale National Park is a remote island in northern Lake Superior that attracts 16,000 visitors annually. The epidemiology of injuries and illnesses sustained by Isle Royale׳s visitors has not been previously studied. The purpose of this study is to examine these data and evaluate them for injury patterns. METHODS: This is a retrospective observational study examining the epidemiology of injuries and illnesses sustained during the period from 2008 to 2012. Incident reports completed by park rangers were reviewed and the data sorted according to time of year, time of day, type of medical encounter, and whether the patient was stable, unstable, or required transport. RESULTS: Two hundred and seventy patient care reports were obtained from the National Park Service. Sixty-four percent of encounters occurred in July and August, and most patients sought care in the afternoon. Care was provided by park rangers, the majority of whom were trained to the level of emergency medical technician. Fifty-eight percent of cases were trauma related, and 20% of all cases were evacuated. CONCLUSIONS: The majority of incidents were trauma related. The majority of the rangers on the island are trained to the level of emergency medical technician-B and appear to offer appropriate care to the island's many visitors, utilizing the National Park Service treatment protocols and comprehensive medical kits. In addition, access to advanced medical care is readily available by air and water evacuation.

Autofluorescence quantification of benign and malignant choroidal nevomelanocytic tumors.

IMPORTANCE: Accurate diagnosis of choroidal melanoma is challenging and has important implications for both physicians and patients. We assessed the utility of quantification of fundus autofluorescence in the evaluation and follow-up of choroidal nevomelanocytic tumors. OBJECTIVE: To assess the utility of autofluorescence quantification in distinguishing clinically diagnosed choroidal nevi, melanoma, and indeterminate nevomelanocytic lesions. DESIGN, SETTING, AND PARTICIPANTS: A retrospective observational study from 2006 to 2012 of patients with choroidal nevomelanocytic lesions who had digital autofluorescence and color fundus imaging performed at the University of Michigan Kellogg Eye Center. INTERVENTION: ImageJ software was used to output autofluorescence gray-scale values for each pixel of a 500 × 50-pixel region within each lesion and a corresponding adjacent control region. MAIN OUTCOME AND MEASURE: A single value was generated, termed the Index of Retinal Autofluorescence (IRA), to represent the total difference in gray-scale values between the 2 regions in each affected eye. RESULTS: Thirteen of the 14 clinically diagnosed nevi exhibited an IRA less than 150 gray-scale intensity squared (gsi2). Eight of 9 clinically diagnosed melanomas exhibited an IRA more than 150 gsi2. An IRA of 150 gsi2 distinguished nevi from melanomas with a sensitivity of 0.89 and specificity of 0.93. Fifteen of 19 patients with indeterminate nevomelanocytic lesions underwent clinical assessment and initial imaging with clinical follow-up at a median of 10 months. All 3 patients with an IRA less than 150 gsi2 showed no evidence of clinical progression and 6 of 12 lesions with an IRA more than 150 gsi2 showed clinical progression to melanoma. An IRA of 150 gsi2 identifies indeterminate lesions that progressed to melanoma with a sensitivity of 1.00 and specificity of 0.33. CONCLUSIONS AND RELEVANCE: Quantification of digital autofluorescence images can differentiate between clinically benign and malignant choroidal nevomelanocytic lesions and may be predictive for clinical progression of indeterminate lesions.

Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study.

Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

AZGP1 autoantibody predicts survival and histone deacetylase inhibitors increase expression in lung adenocarcinoma.

INTRODUCTION: The importance of alpha-2-glycoprotein 1, zinc (AZGP1) in lung adenocarcinoma (AD) remains largely unknown. Analysis of serum autoantibodies to tumor antigens combined with gene expression profiling of primary tumors may provide insight into the mechanisms underlying lung carcinogenesis and identify new AD biomarkers. METHODS: T7 phage cDNA libraries were used to identify AZGP1 autoantibodies in the serum of 473 patients (192 ADs, 192 matched controls, and 89 additional ADs for confirmation of findings). AZGP1 mRNA expression was examined in 86 ADs and 10 control lung tissue samples using oligonucleotide microarrays. AZGP1 protein expression was studied in 230 tissue samples (222 ADs; 8 controls) with immunohistochemistry. Kaplan-Meier analyses were used to correlate circulating autoantibody and tissue mRNA production with survival. AD cell lines A549 and SKLU1 were treated with 5-aza-2;-deoxycytidine (5-AZA) and trichostatin A (TSA) to examine the role of promoter methylation and histone deacetylation in the expression of AZGP1. Real-time polymerase chain reaction was used to quantify the effects of treatment. RESULTS: In patients with AD, AZGP1 autoantibodies were observed in 40% of serum samples. Autoantibody production correlated with improved overall 5-year survival (p = 0.002) and improved survival in those with stage I to II disease (p = 0.008). A verification analysis was performed for the survival benefit and found similar results with p values of 0.02 and 0.036, respectively. Although abundant mRNA expression was found in a subset of tumors, mRNA expression did not correlate with prognosis. In normal lung, AZGP1 mRNA and protein expression were low or absent, whereas in AD they were highly expressed in 31.3% and 42.8% of samples, respectively. To determine whether AZGP1 expression in this subset of tumors might be affected by epigenetic mechanisms, low AZGP1-expressing A549 and SKLU1 AD cell lines were treated with TSA and 5-AZA. A 713-fold and 169-fold increase in mRNA expression were noted on treatment with TSA, respectively. Treatment with 5-AZA had minimal effect on AZGP1 mRNA expression. CONCLUSIONS: The presence of AZGP1 serum autoantibody may be used as a prognostic marker in patients with AD. Furthermore, up-regulation of AZGP1 mRNA in AD may be affected by chromatin remodeling by means of histone acetylation.