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Galactomannan Downregulates the Inflammation Responses in Human Macrophages via NFÎºB2/p100. - Mediators of inflammation
We show that galactomannan, a polysaccharide consisting of a mannose backbone with galactose side groups present on the cell wall of several fungi, induces a reprogramming of the inflammatory response in human macrophages through dectin-1 receptor. The nuclear factor kappa-light-chain-enhancer of activated B cells 2 (NFÎºB2)/p100 was overexpressed after galactomannan challenge. Knocking down NFÎºB2/p100 using small interfering RNA (siRNA) indicated that NFÎºB2/p100 expression is a crucial factor in the progression of the galactomannan-induced refractoriness. The data presented in this study could be used as a modulator of inflammatory response in clinical situations where refractory state is required.
Modeling the longitudinal latent effect of pregabalin on self-reported changes in sleep disturbances in outpatients with generalized anxiety disorder managed in routine clinical practice. - Drug design, development and therapy
Anxiety disorders are among the most common psychiatric illnesses, with generalized anxiety disorder (GAD) being one of the most common. Sleep disturbances are highly prevalent in GAD patients. While treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across many controlled clinical trials, mediational analysis has suggested that a substantial portion of this effect could be the result of a direct effect of pregabalin. Thus, the objective of this study was to model the longitudinal latent effect of pregabalin or usual care (UC) therapies on changes in sleep in outpatients with GAD under routine clinical practice.Male and female GAD outpatients, aged 18 years or above, from a 6-month prospective noninterventional trial were analyzed. Direct and indirect effects of either pregabalin or UC changes in anxiety symptoms (assessed with Hamilton Anxiety Scale) and sleep disturbances (assessed with Medical Outcomes Study-Sleep Scale [MOS-S]) were estimated by a conditional latent curve model applying structural equation modeling.A total of 1,546 pregabalin-naÃ¯ve patients were analyzed, 984 receiving pregabalin and 562 UC. Both symptoms of anxiety and sleep disturbances were significantly improved in both groups, with higher mean (95% confidence interval) score reductions in subjects receiving pregabalin: -15.9 (-15.2; -16.6) vs -14.5 (-13.5; -15.5), P=0.027, in Hamilton Anxiety Scale; and -29.7 (-28.1; -31.3) vs -24.0 (-21.6; -26.4), P<0.001, in MOS-S. The conditional latent curve model showed that the pregabalin effect on sleep disturbances was significant (Î³ =-3.99, P<0.001), after discounting the effect on reduction in anxiety symptoms. A mediation model showed that 70% of the direct effect of pregabalin on sleep remained after discounting the mediated effect of anxiety improvement.A substantial proportion of the incremental improvements in anxiety-related sleep disturbances with pregabalin vs UC were explained by its direct effect, not mediated by improvements in anxiety symptoms.
A G-quadruplex-binding macrodomain within the "SARS-unique domain" is essential for the activity of the SARS-coronavirus replication-transcription complex. - Virology
The multi-domain non-structural protein 3 of SARS-coronavirus is a component of the viral replication/transcription complex (RTC). Among other domains, it contains three sequentially arranged macrodomains: the X domain and subdomains SUD-N as well as SUD-M within the "SARS-unique domain". The X domain was proposed to be an ADP-ribose-1"-phosphatase or a poly(ADP-ribose)-binding protein, whereas SUD-NM binds oligo(G)-nucleotides capable of forming G-quadruplexes. Here, we describe the application of a reverse genetic approach to assess the importance of these macrodomains for the activity of the SARS-CoV RTC. To this end, Renilla luciferase-encoding SARS-CoV replicons with selectively deleted macrodomains were constructed and their ability to modulate the RTC activity was examined. While the SUD-N and the X domains were found to be dispensable, the SUD-M domain was crucial for viral genome replication/transcription. Moreover, alanine replacement of charged amino-acid residues of the SUD-M domain, which are likely involved in G-quadruplex-binding, caused abrogation of RTC activity.Copyright Â© 2015 Elsevier Inc. All rights reserved.
Pregabalin for the treatment of patients with generalized anxiety disorder with inadequate treatment response to antidepressants and severe depressive symptoms. - International clinical psychopharmacology
To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222â€‰mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms.
Impact of Vesicular Stomatitis Virus M Proteins on Different Cellular Functions. - PloS one
Three different matrix (M) proteins termed M1, M2 and M3 have been described in cells infected with vesicular stomatitis virus (VSV). Individual expression of VSV M proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. Analogous to viroporins, M1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membrane permeability. In contrast to M1, M2 and M3 neither interact with the cellular membrane nor promote the budding of double membrane vesicles at the cell surface. Nonetheless, all three species of M protein interfere with the transport of cellular mRNAs from the nucleus to the cytoplasm and also modulate the redistribution of the splicing factor. The present findings indicate that all three VSV M proteins share some activities that interfere with host cell functions.
Clinical and economic outcomes of adjunctive therapy with pregabalin or usual care in generalized anxiety disorder patients with partial response to selective serotonin reuptake inhibitors. - Annals of general psychiatry
This study is done to compare the effect of adjunctive therapy with pregabalin versus usual care (UC) on health-care costs and clinical and patients consequences in generalized anxiety disorder (GAD) subjects with partial response (PR) to a previous selective serotonin reuptake inhibitor (SSRI) course in medical practice in Spain.Post hoc analysis of patients with PR to SSRI monotherapy enrolled in a prospective 6-month naturalistic study was done. PR was defined as a Clinical Global Impression (CGI) scale score â‰¥3 and insufficient response with persistence of anxiety symptoms â‰¥16 in the Hamilton Anxiety Rating Scale (HAM-A). Two groups were analyzed: 1) adjunctive therapy (AT) with pregabalin (150-600Â mg/day) to existing therapy and 2) UC (switching to a different SSRI or adding another anxiolytic different than pregabalin). Costs included GAD-related health-care resources utilization. Consequences were a combination of psychiatrist-based measurements [HAM-A, CGI, and Montgomery-Asberg Depression Rating Scale (MADRS)] and patient-reported outcomes [Medical Outcomes Study Sleep (MOS-sleep) scale, disability (World Health Organization Disability Assessment Schedule II (WHO-DAS II) and quality-of-life (Euro Qol-5D (EQ-5D)]. Changes in both health-care costs and scale scores were compared separately at end-of-trial visit by a general linear model with covariates.Four hundred eighty-six newly prescribed pregabalin and 239 UC GAD patients [mean (SD) HAM-A 26.7 (6.9) and CGI 4.1 (0.5)] were analyzed. Adding pregabalin was associated with significantly higher mean (95% CI) score reductions vs. UC in HAM-A [-14.9 (-15.6; -14.2) vs. -11.2 (-12.2; -10.2), pâ€‰<â€‰0.001] and MADRS [-11.6 (-12.2; -10.9) vs. -7.8 (-8.7; -6.8), pâ€‰<â€‰0.001]. Changes in all patient-reported outcomes favored significantly patients receiving pregabalin, including quality-of-life gain; 26.4 (24.7; 28.1) vs. 19.4 (17.1; 21.6) in the EQ-VAS, pâ€‰<â€‰0.001. Health-care costs were significantly reduced in both cohorts yielding similar 6-month costs; â‚¬1,565 (1,426; 1,703) pregabalin and â‚¬1,406 (1,200; 1,611) UC, pâ€‰=â€‰0.777. The effect of sex on costs and consequences were negligible.In medical practice, GAD patients with PR to SSRI experienced greater consequence improvements with adjunctive therapy with pregabalin versus UC, without increasing health-care cost. The effect of pregabalin was independent of patient gender.
L protease from foot and mouth disease virus confers eIF2-independent translation for mRNAs bearing picornavirus IRES. - FEBS letters
The leader protease (L(pro)) from foot-and-mouth disease virus (FMDV) has the ability to cleave eIF4G, leading to a blockade of cellular protein synthesis. In contrast to previous reports, our present findings demonstrate that FMDV L(pro) is able to increase translation driven by FMDV IRES. Additionally, inactivation of eIF2 subsequent to phosphorylation induced by arsenite or thapsigargin in BHK cells blocks protein synthesis directed by FMDV IRES, whereas in the presence of L(pro), significant translation is found under these conditions. This phenomenon was also observed in cell-free systems after induction of eIF2 phosphorylation by addition of poly(I:C).Copyright Â© 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Pharmacoeconomic outcomes for pregabalin: a systematic review in neuropathic pain, generalized anxiety disorder, and epilepsy from a Spanish perspective. - Advances in therapy
Pregabalin is an anticonvulsant approved in Europe for the treatment of neuropathic pain, as an adjunct therapy for epileptic seizures, and recently for generalized anxiety disorder. The aim of this study was to conduct a systematic review to evaluate the cost-effectiveness of pregabalin associated with the treatment of its labeled indications from a societal perspective in Spain.Data from the MEDLINE database were searched using algorithms to identify relevant economic evaluations published in English or Spanish on pregabalin for the management of neuropathic pain, generalized anxiety disorder (GAD), and epilepsy in Spanish patients over the last 10Â years.In total, 52 potentially relevant abstracts were identified from the MEDLINE database. Twenty manuscripts met the inclusion criteria. The majority of the selected papers (14/20) evaluated pregabalin for neuropathic pain from a societal perspective in Spain (5 economic models of pregabalin vs. gabapentin, 4 economic analyses of pregabalin in comparison with usual care, 4 economic evaluations comparing pregabalin monotherapy with add-on strategies, and one that evaluated different times of initiating pregabalin therapy). Five studies analyzed the use of pregabalin in Spain for the management of GAD (one cost-effectiveness model that compared pregabalin with venlafaxine, 2 secondary analyses in benzodiazepine-refractory patients, and 2 studies evaluating pregabalin vs. usual care in patients refractory to standard regimens). The last manuscript described a cost-effectiveness model that compared pregabalin versus levetiracetam use for the treatment of refractory partial epilepsy.The majority of published evidence supports the possibility that pregabalin could be a cost-effective and/or cost-saving alternative for the treatment of refractory epilepsy, GAD, and neuropathic pain, in both treatment-naÃ¯ve patients and in those who have demonstrated inadequate response or intolerance to previous therapy.
Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis. - Multiple sclerosis (Houndmills, Basingstoke, England)
Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients (p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS (p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers.
Exploring the interaction between childhood maltreatment and temperamental traits on the severity of borderline personality disorder. - Comprehensive psychiatry
Childhood maltreatment and temperamental traits play a role in the development of Borderline Personality Disorder (BPD). The aim of the present study was to assess the involvement and the interrelationship of both factors in the clinical severity of BPD.The self-reported history of childhood trauma, psychobiological temperamental traits, and severity of BPD symptoms were evaluated in 130 subjects with BPD.Approximately 70% of the sample reported some form of abuse or neglect. Childhood maltreatment inversely correlated with sociability, but no correlation was observed with the other temperamental traits. The regression model showed that neuroticism-anxiety and aggression-hostility traits, as well as emotional abuse, were risk factors independently associated with the severity of BPD. Sexual abuse was not associated with the severity of the disorder. Finally, the interaction between high neuroticism-anxiety traits and the presence of severe emotional abuse was associated with BPD severity.These results suggest that the interaction between temperamental traits and childhood emotional abuse has an influence not only on the development but also on the severity of BPD. Further studies are needed to identify more biological and environmental factors associated with the severity of the disorder.Â© 2014.
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