Research Spotlight

Posted October 15th 2016

Hyperlipidemia is associated with lower risk of poststroke mortality independent of statin use: A population-based study.

Samrat Yeramaneni, Ph.D.

Samrat Yeramaneni, Ph.D.

Yeramaneni, S., D. O. Kleindorfer, H. Sucharew, K. Alwell, C. J. Moomaw, M. L. Flaherty, D. Woo, O. Adeoye, S. Ferioli, F. de Los Rios La Rosa, S. Martini, J. Mackey, P. Khatri, B. M. Kissela and J. C. Khoury (2016). “Hyperlipidemia is associated with lower risk of poststroke mortality independent of statin use: A population-based study.” Int J Stroke: 2016 Sep [Epub ahead of print].

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BACKGROUND: Although statin therapy is associated with reduced stroke and mortality risk, some studies report that higher lipid levels are associated with improved outcomes following ischemic stroke. AIMS: We examined the association of hyperlipidemia (HLD) combined with statin therapy on all-cause mortality in stroke patients. METHODS: All stroke patients in the Greater Cincinnati Northern Kentucky region of approximately 1.3 million were identified using ICD-9 discharge codes in 2005 and 2010. Stroke patients with and without HLD were categorized based on their reported statin use at baseline or discharge into three groups: no-HLD/no-statins, HLD/no-statins, and HLD/on-statins. Cox proportional hazards model was used to estimate the risk of mortality at 30 days, 1 year, and 3 years poststroke. RESULTS: Overall, 77% (2953) of the 3813 ischemic stroke patients were diagnosed with HLD and 72% (n = 2123) of those patients were on statin medications. The mean age was 70.0 +/- 14.6 years, 56% were women, and 21% were black. In adjusted analyses, the HLD/no-statins group showed 35% (adjusted hazard ratio (aHR) = 0.65, 95% CI: 0.46-0.92), 27% (aHR = 0.73, 95% CI: 0.59-0.90), and 17% (aHR = 0.83, 95% CI: 0.70-0.97) reduced risk of mortality at 30 days, 1 year, and 3 years, respectively, poststroke, compared with no-HLD/no-statins group. The HLD/on-statins group showed an additional 17% significant survival benefit at 3 years poststroke compared with HLD/no-statins group. CONCLUSIONS: A diagnosis of HLD in ischemic stroke patients is associated with reduced short- and long-term mortality, irrespective of statin use. Statin therapy is associated with significant, additional long-term survival benefit.


Posted October 15th 2016

BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Zhong, X. Z., X. Sun, Q. Cao, G. Dong, R. Schiffmann and X. P. Dong (2016). “Bk channel agonist represents a potential therapeutic approach for lysosomal storage diseases.” Sci Rep 16(1): 503.

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Efficient lysosomal Ca2+ release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca2+-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca2+ release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca2+ release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs. In this study, we assessed the effect of BK agonist, NS1619 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-F408), Niemann-Pick type A (NPA) and Fabry disease. We found that TRPML1-mediated Ca2+ release was compromised in these LSDs. BK activation corrected the impaired Ca2+ release in these LSDs and successfully rescued the abnormal lysosomal storage of these diseases by promoting TRPML1-mediated lysosomal exocytosis. Our study suggests that BK channel activation stimulates the TRPML1-BK positive reinforcing loop to correct abnormal lysosomal storage in LSDs. Drugs targeting BK channel represent a potential therapeutic approach for LSDs.


Posted October 15th 2016

The validation of pharmacogenetics for the identification of fabry patients to be treated with migalastat.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Benjamin, E. R., M. C. Della Valle, X. Wu, E. Katz, F. Pruthi, S. Bond, B. Bronfin, H. Williams, J. Yu, D. G. Bichet, D. P. Germain, R. Giugliani, D. Hughes, R. Schiffmann, W. R. Wilcox, R. J. Desnick, J. Kirk, J. Barth, C. Barlow, K. J. Valenzano, J. Castelli and D. J. Lockhart (2016). “The validation of pharmacogenetics for the identification of fabry patients to be treated with migalastat.” Genet Med: 2016 Sep [Epub ahead of print].

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PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of alpha-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the alpha-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in alpha-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell alpha-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (>/=0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.


Posted October 15th 2016

Abnormalities of gait caused by ankle arthritis are improved by ankle arthrodesis.

James W. Brodsky, M.D.

James W. Brodsky, M.D.

Brodsky, J. W., J. M. Kane, S. Coleman, J. Bariteau and S. Tenenbaum (2016). “Abnormalities of gait caused by ankle arthritis are improved by ankle arthrodesis.” Bone Joint J 98-b(10): 1369-1375.

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AIMS: The surgical management of ankle arthritis with tibiotalar arthrodesis is known to alter gait, as compared with normal ankles. The purpose of this study was to assess post-operative gait function with gait before arthrodesis. PATIENTS AND METHODS: We prospectively studied 20 patients who underwent three-dimensional gait analysis before and after tibiotalar arthrodesis. Cadence, step length, walking velocity and total support time were assessed. Kinetic parameters, including the moment and power of the ankle in the sagittal plane and hip power were also recorded. RESULTS: Significant improvement was recorded across numerous parameters compared with pre-operative measurements. Temporal-spatial data demonstrated a significant increase in step length (p = 0.003) and velocity (p = < 0.001). Total support time decreased for the unaffected limb (p = 0.01). Kinematic results demonstrated that in the affected limb, total sagittal range of movement did not change significantly (p = 0.1259). However, the arc of movement had a near congruent shift with mean maximal dorsiflexion increasing from 5 degrees (-17 degrees to 16 degrees ) to 12 degrees (5 degrees to 18 degrees ) (p < 0.001) and mean maximal plantarflexion decreasing from 6.8 degrees (6 degrees to 21 degrees ) to 0.9 degrees (-9 degrees to 8 degrees ) (p = 0.003). Mean hip joint range of movement increased by 6 degrees (-7 degrees to 24 degrees ; p = 0.003). Kinetic results demonstrated no statistically significant change in ankle power (p = 0.1292). However, there was an increase in ankle moment (p = 0.04) and hip power (p = 0.01) in the surgically treated extremity. Sagittal plane range of movement was not reduced after tibiotalar fusion. CONCLUSION: Although following tibiotalar arthrodesis the gait demonstrated never matched the gait shown in unaffected ankles, compared with the pre-operative analysis there was improvement in numerous temporal-spatial, kinematic, and kinetic measures.


Posted October 15th 2016

A review of emerging il-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase ii studies.

Alan M. Menter M.D.

Alan M. Menter M.D.

Campa, M. and A. Menter (2016). “A review of emerging il-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase ii studies.” Expert Opin Investig Drugs: 2016 Sep [Epub ahead of print].

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INTRODUCTION: Interleukin-17 has recently been identified as a key player in the pathogenesis of psoriasis. As such, several drugs targeting IL-17 are in various stages of clinical development. AREAS COVERED: In this review, the authors describe several emerging therapies and drug candidates targeting IL-17. The authors detail many biologic injectable drug candidates as well as numerous potential oral and topical small molecule drug candidates. EXPERT OPINION: Approval of IL-17 inhibitors has significantly improved the treatment options for psoriasis patients. Secukinumab and ixekizumab are approved in both Europe and the USA, and brodalumab is likely facing approval by the end of 2016. Numerous additional biologic and small molecule drug candidates are in the pipeline, and once deemed safe and effective will likely offer significant benefit to our psoriasis population.