Research Spotlight

Posted March 15th 2017

Characteristics of new depression diagnoses in patients with and without prior chronic opioid use.

Laurel A. Copeland Ph.D.

Laurel A. Copeland Ph.D.

Scherrer, J. F., J. Salas, F. D. Schneider, K. K. Bucholz, M. D. Sullivan, L. A. Copeland, B. K. Ahmedani, T. Burroughs and P. J. Lustman (2017). “Characteristics of new depression diagnoses in patients with and without prior chronic opioid use.” J Affect Disord 210: 125-129.

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Chronic use (>90 Days) of opioid analgesics significantly increases the risk of development of new depression episodes (NDE). It is unclear whether depression that develops in this manner is similar to or different from NDE in persons not exposed to opioid analgesic use (OAU). METHODS: VA patients were classified into two groups, those who did not receive an opioid and developed depression (non-OAU+NDE, n=4314) and those that had >90 days OAU and developed NDE (OAU+NDE, n=444). OAU+NDE patients were compared to non-OAU+NDE in terms of depression severity (PHQ-9 scores), incidence of PTSD, other anxiety disorders and substance use disorders after NDE, receipt of acute phase antidepressant treatment, dual antidepressant treatment, mood stabilizers and atypical antipsychotics. Prior to computing bivariate analysis, the prevalence of pain conditions and average maximum pain scores were equalized between the two groups using propensity scores and inverse probability of treatment weighting. RESULTS: Controlling for pain, OAU+NDE patients had more depression symptoms (p=.012), more incident PTSD (p=.04) and opioid abuse/dependence and were more likely to receive 12 weeks of antidepressant treatment (p<.0001). Last, non-OAU+NDE were more likely to have incident diagnoses for any other anxiety disorder (p=.014). CONCLUSIONS: Within the limitations of electronic medical record data, results indicate OAU+NDE patients have more depression symptoms, greater treatment adherence and different comorbid psychiatric conditions compared to non-OAU+NDE, independent of pain. Overall OAU related depression is as severe as non-OAU related depression and repeated depression screening in chronic opioid therapy may be warranted for pain patients, regardless of pain severity.


Posted March 15th 2017

Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Shigeyasu, K., Y. Okugawa, S. Toden, C. R. Boland and A. Goel (2017). “Exportin-5 functions as an oncogene and a potential therapeutic target in colorectal cancer.” Clin Cancer Res 23(5): 1312-1322.

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Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. Although XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer remains unclear…Results: XPO5 is upregulated, both at mRNA and protein levels, in colorectal cancers compared with normal tissues. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1-S cell-cycle arrest, and downregulation of key oncogenic miRNAs in colorectal cancer cells. These findings were confirmed in a xenograft animal model, wherein silencing of XPO5 resulted in the attenuation of tumor growth…


Posted March 15th 2017

Effect of Obesity on Bone Healing After Foot and Ankle Long Bone Fractures.

Naohiro Shibuya D.P.M.

Naohiro Shibuya D.P.M.

Thorud, J. C., S. Mortensen, J. L. Thorud, N. Shibuya, Y. M. Maldonado and D. C. Jupiter (2017). “Effect of obesity on bone healing after foot and ankle long bone fractures.” J Foot Ankle Surg 56(2): 258-262.

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As obesity has become more common, fractures in the obese population have become more frequent. Concern exists regarding alterations in bone health and healing in obese patients. A matched case-control study was performed at 1 institution to evaluate whether an association exists between nonunion and a high body mass index in metatarsal and ankle fractures. A total of 48 patients with nonunion were identified, and control patients matched 2 to 1 (n = 96) were selected. The control patients were matched for age, sex, and fracture type. No association was identified between nonunion and the continuous body mass index (p = .23) or morbid obesity, with a body mass index of >/=40 kg/m2 (p = .51). However, the results from both univariate and multivariate analysis suggested that patients with a current alcohol problem or a history of an alcohol problem might have a greater risk of nonunion. The odds ratio of a patient with a history of alcohol use experiencing nonunion was 2.7 (95% confidence interval 1.2 to 6.2). Further studies are warranted to confirm these findings.


Posted March 15th 2017

Renal Function and Scaled Troponin in Patients Presenting to the Emergency Department with Symptoms of Myocardial Infarction.

Peter McCullough M.D.

Peter McCullough M.D.

Vasudevan, A., A. J. Singer, C. DeFilippi, G. Headden, J. M. Schussler, L. B. Daniels, M. Reed, M. P. Than, R. Birkhahn, S. W. Smith, T. W. Barrett, W. Arnold, W. F. Peacock and P. A. McCullough (2017). “Renal function and scaled troponin in patients presenting to the emergency department with symptoms of myocardial infarction.” Am J Nephrol 45(4): 304-309.

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BACKGROUND: Cardiac troponins are often found to be elevated in patients with renal dysfunction, even in the absence of acute myocardial injury. The objective of this report was to characterize the scaled troponin values and proportion of adjudicated acute myocardial infarction (AMI) among patients with and without renal dysfunction. METHODS: The data was from a multicenter prospective study including patients presenting to the emergency department with symptoms of AMI. Troponin measurements were standardized across various assays by calculating the observed results as multiples of the assay-specific 99th percentile upper limit of normal. Patients with an estimated glomerular filtration rate (eGFR; calculated by the Chronic Kidney Disease Epidemiology Collaboration formula) <60 mL/min/1.73 m2 were considered to have renal dysfunction. RESULTS: Of 430 included patients, 249 (58%) were male and 181 (42%) were female, with a mean age of 55.9 +/- 12.3 and 57.3 +/- 12.8 years, respectively. Eighty-seven (20.2%) had renal dysfunction. The proportions of patients with at least one scaled troponin value above the 99th percentile cut-off point among patients with and without renal dysfunction were 40 (45.9%) and 81 (23.6%) respectively (p < 0.001). The proportions of patients with an adjudicated diagnosis of AMI among those with and without renal dysfunction were 20.7 and 18.7%, respectively (p = 0.67). Using scaled troponins, by the second test there was >5X and by the third test >15X separation in the excursion of troponin among those with AMI compared to those without. CONCLUSIONS: One or more elevated troponin values are common in those with renal dysfunction. Scaled troponins for eGFR groups were similar, indicating that the use of this interpretative technique is applicable in discerning AMI for those with and without renal dysfunction.


Posted March 15th 2017

Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Vogel, K. R., E. Arning, T. Bottiglieri and K. M. Gibson (2017). “Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain.” J Inherit Metab Dis 40(2): 227-235.

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BACKGROUND: The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein-restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits. METHOD: Phenylalanine hydroxylase-deficient (PKU) mice and parallel controls (both wild-type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling. RESULTS: Phenylalanine (phe) was increased in all tissues (p < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine (p < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake. CONCLUSION: Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU.