Publications by authors named "Sneha Rao"

33 Publications

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

Cancer Med 2021 Nov 27. Epub 2021 Nov 27.

Department of Orthopaedics, Duke University, Durham, North Carolina, USA.

Introduction: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS.

Methods: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years.

Discussion And Conclusion: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.
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http://dx.doi.org/10.1002/cam4.4428DOI Listing
November 2021

Using GIS-based spatial analysis to determine urban greenspace accessibility for different racial groups in the backdrop of COVID-19: a case study of four US cities.

GeoJournal 2021 Nov 3:1-21. Epub 2021 Nov 3.

Department of Geography & Environmental Studies, University of Alaska Anchorage, Anchorage, AK 99508 USA.

As the United States leads COVID-19 cases on global charts, its spatial distribution pattern offers a unique opportunity for studying the social and ecological factors that contribute to the pandemic's scale and size. We use a GIS-data-based approach to evaluate four American cities-Anchorage (Alaska), Atlanta (Georgia), Phoenix (Arizona), and Portland (Oregon) characterized by the significant composition of different racial and ethnic group populations. Building upon previous studies that investigated urban spatial inequalities using the environmental justice framework, we examine: (1) the relative racial vulnerability of Census Block Groups (CBG) and ZIP Code Tabulation Areas (ZCTA) to COVID-19 (2) green space distribution at CBG and ZCTA scale. Using standard normalization methods, we ranked racial vulnerability against % available green space for each city. Our results highlight the legacy of past and present urban planning injustices. The project is useful from environmental justice, public health management, and urban planning perspectives.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10708-021-10538-8.
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http://dx.doi.org/10.1007/s10708-021-10538-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564283PMC
November 2021

Doxycycline Significantly Enhances Induction of Induced Pluripotent Stem Cells to Endoderm by Enhancing Survival Through Protein Kinase B Phosphorylation.

Hepatology 2021 Oct;74(4):2102-2117

Department of Pathology, University of California San Francisco, San Francisco, CA.

Background And Aims: Induced pluripotent stem cells (iPSCs) provide an important tool for the generation of patient-derived cells, including hepatocyte-like cells, by developmental cues through an endoderm intermediate. However, most iPSC lines fail to differentiate into endoderm, with induction resulting in apoptosis.

Approach And Results: To address this issue, we built upon published methods to develop an improved protocol. We discovered that doxycycline dramatically enhances the efficiency of iPSCs to endoderm differentiation by inhibiting apoptosis and promoting proliferation through the protein kinase B pathway. We tested this protocol in >70 iPSC lines, 90% of which consistently formed complete sheets of endoderm. Endoderm generated by our method achieves similar transcriptomic profiles, expression of endoderm protein markers, and the ability to be further differentiated to downstream lineages.

Conclusions: Furthermore, this method achieves a 4-fold increase in endoderm cell number and will accelerate studies of human diseases in vitro and facilitate the expansion of iPSC-derived cells for transplantation studies.
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http://dx.doi.org/10.1002/hep.31898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544023PMC
October 2021

Genome analysis of a halophilic bacterium Halomonas malpeensis YU-PRIM-29 reveals its exopolysaccharide and pigment producing capabilities.

Sci Rep 2021 01 18;11(1):1749. Epub 2021 Jan 18.

Yenepoya Research Centre, Yenepoya (Deemed to be University), University Road, Deralakatte, Mangalore, 575018, India.

Halomonas malpeensis strain YU-PRIM-29 is a yellow pigmented, exopolysaccharide (EPS) producing halophilic bacterium isolated from the coastal region. To understand the biosynthesis pathways involved in the EPS and pigment production, whole genome analysis was performed. The complete genome sequencing and the de novo assembly were carried out using Illumina sequencing and SPAdes genome assembler (ver 3.11.1) respectively followed by detailed genome annotation. The genome consists of 3,607,821 bp distributed in 18 contigs with 3337 protein coding genes and 53% of the annotated CDS are having putative functions. Gene annotation disclosed the presence of genes involved in ABC transporter-dependent pathway of EPS biosynthesis. As the ABC transporter-dependent pathway is also implicated in the capsular polysaccharide (CPS) biosynthesis, we employed extraction protocols for both EPS (from the culture supernatants) and CPS (from the cells) and found that the secreted polysaccharide i.e., EPS was predominant. The EPS showed good emulsifying activities against the petroleum hydrocarbons and its production was dependent on the carbon source supplied. The genome analysis also revealed genes involved in industrially important metabolites such as zeaxanthin pigment, ectoine and polyhydroxyalkanoate (PHA) biosynthesis. To confirm the genome data, we extracted these metabolites from the cultures and successfully identified them. The pigment extracted from the cells showed the distinct UV-Vis spectra having characteristic absorption peak of zeaxanthin (λ 448 nm) with potent antioxidant activities. The ability of H. malpeensis strain YU-PRIM-29 to produce important biomolecules makes it an industrially important bacterium.
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http://dx.doi.org/10.1038/s41598-021-81395-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814019PMC
January 2021

Intraoperative Type I Acute Myocardial Infarction During Liver Transplant Requiring Intra-Aortic Balloon Pump: A Case Report.

Exp Clin Transplant 2020 Nov 27. Epub 2020 Nov 27.

From the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.

We describe a complex case of liver transplant in a 70-year-old male patient with no known history of coronary artery disease, normal preoperative left ventricular function, and negative preoperative cardiac workup who developed progressive intra-operative left ventricular myocardial dysfunction secondary to class I acute myocardial infarction, ultimately requiring intraoperative intra-aortic balloon pump insertion to optimize myocardial perfusion. Management of myocardial ischemia was complicated by bleeding in the setting of coagulopathy necessitating correction. Once hemostasis was achieved, the patient immediately underwent coronary angiography and bare metal stent placement in the mid-left anterior descending coronary artery for an acute plaque rupture.
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http://dx.doi.org/10.6002/ect.2020.0205DOI Listing
November 2020

A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma.

Cancers (Basel) 2020 Nov 11;12(11). Epub 2020 Nov 11.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.

Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.

Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity.

Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
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http://dx.doi.org/10.3390/cancers12113335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696249PMC
November 2020

Potential synergistic activity of quercetin with antibiotics against multidrug-resistant clinical strains of Pseudomonas aeruginosa.

PLoS One 2020 6;15(11):e0241304. Epub 2020 Nov 6.

Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India.

Development of drug resistance in opportunistic pathogens is one of the major healthcare challenges associated with infection management. Combination therapy has many advantages due to the simultaneous action of two drugs on two separate cellular targets. However, selection of the drugs should offer safety and synergistic interaction against most of the strains. Here, the efficacy of antibiotics in combination with quercetin, a natural flavonoid capable of targeting quorum sensing was tested against biofilm-forming Pseudomonas aeruginosa strains previously isolated from catheter associated urinary tract infection. Based on the antibiotic susceptibility pattern, synergistic effect of quercetin with selected antibiotics (levofloxacin, ceftriaxone, gentamycin, tobramycin and amikacin) was tested at the fractional concentrations of MIC by the checkerboard method and the fractional inhibitory concentration index (FICi) was calculated to estimate the synergistic effect. Effect of the synergistic combinations were further tested using time-kill assay, and against biofilm formation and biofilm cell viability. Cytotoxicity assays were performed using Human Embryonic Kidney 293T cells (HEK-293T) using the effective drug combinations with respective controls. The biofilm formation and biofilm cell viability were drastically affected with quercetin and selected antibiotics combinations with ≥80% inhibition. In vitro infection studies showed that all the strains could exert significant cell killing (68 to 85%) and the drug combinations decreased the infection rate significantly by reducing the cell killing effect of P. aeruginosa (p<0.05). The synergistic effect of quercetin is attributed to its quorum sensing inhibitory properties. These findings indicate that quercetin along with existing antibiotics can potentiate the treatment against P. aeruginosa infection and may reduce the selection pressure due to antibiotic overuse.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241304PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647105PMC
December 2020

First Report of Pathogenic Bacterium Isolated from Urine of a Kidney Stone Patient: Draft Genome and Evidence for Role in Struvite Crystallization.

Pathogens 2020 Aug 29;9(9). Epub 2020 Aug 29.

Department of Soil and Environmental Sciences, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung 40227, Taiwan.

Uropathogenic bacteria are widely distributed in the environment and urinary tract infection is implicated in kidney stone disease. Here, we report on a urease negative bacterium (strain YU22) isolated from the urine of a struvite stone (MgNHPO·6HO) patient. The closest species, IIIF1SW-P2 was reported from International Space Station samples. However, there are no earlier reports on its human association. Using whole genome and experimental analysis, its involvement in urinary tract colonization and struvite crystallization was explored. The strain YU22 showed many virulence factors that are needed for host cell invasion and colonization including cell adhesion factors, swimming and swarming motilities, biofilm and siderophore among others. In vitro infection studies in HEK-293T cells demonstrated the host cell attachment and killing. It was able to utilize amino acids as sole carbon source and showed growth in synthetic and healthy urine establishing metabolic adaptation to urinary tract. Increased pH and availability of ammonium ions from amino acid breakdown promoted struvite crystallization. The results from this study support the involvement of urease negative uropathogen in the struvite lithogenesis. Further studies on other isolates of are warranted to assess its health risks.
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http://dx.doi.org/10.3390/pathogens9090711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558591PMC
August 2020

Microwave-assisted rapid synthesis of silver nanoparticles using fucoidan: Characterization with assessment of biocompatibility and antimicrobial activity.

Int J Biol Macromol 2020 Nov 26;163:745-755. Epub 2020 Jun 26.

Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka 575018, India. Electronic address:

Silver nanoparticles (AgNPs) have gained attention due to their exceptional physicochemical properties and biological activities, owing to which they are extensively used in biomedical field. We synthesized AgNPs by rapid microwave-assisted method using fucoidan as a reducing agent. The synthesized fucoidan-AgNPs (F-AgNPs) were characterized for the structural and functional properties. The bactericidal effect and mode of action of F-AgNPs on the pathogenic bacteria and biofilm formation were investigated along with the cytotoxicity studies. The UV-Visible spectra of the F-AgNPs showed the surface resonance peak at 419 nm. The nanoparticles were spherical in shape with particle size of 59.5 ± 1.46 nm and polydispersity index (PDI) of 0.3 ± 0.01. Capping of fucoidan on AgNPs was confirmed by FTIR with characteristic peaks of sulfate group. Silver content of F-AgNPs was 87% with 13% contribution from the fucoidan moieties. The F-AgNPs showed antimicrobial activity against common pathogenic bacteria and was able to inhibit biofilm formation in Pseudomonas aeruginosa at 20 μg/mL concentration. The oxidative stress and intracellular protein leakage were observed due to the F-AgNP interaction with the cell bringing about bactericidal effect. The results highlight the synthesis and bioactivity of AgNPs doped with organic moieties for applications as antimicrobials.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.06.230DOI Listing
November 2020

A Localized Scaffold for cGMP Increase Is Required for Apical Dendrite Development.

Cell Rep 2020 04;31(2):107519

Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794-5230, USA. Electronic address:

Studies in cultured neurons have established that axon specification instructs neuronal polarization and is necessary for dendrite development. However, dendrite formation in vivo occurs when axon formation is prevented. The mechanisms promoting dendrite development remain elusive. We find that apical dendrite development is directed by a localized cyclic guanosine monophosphate (cGMP)-synthesizing complex. We show that the scaffolding protein Scribble associates with cGMP-synthesizing enzymes soluble-guanylate-cyclase (sGC) and neuronal nitric oxide synthase (nNOS). The Scribble scaffold is preferentially localized to and mediates cGMP increase in dendrites. These events are regulated by kinesin KifC2. Knockdown of Scribble, sGC-β1, or KifC2 or disrupting their associations prevents cGMP increase in dendrites and causes severe defects in apical dendrite development. Local cGMP elevation or sGC expression rescues the effects of Scribble knockdown on dendrite development, indicating that Scribble is an upstream regulator of cGMP. During neuronal polarization, dendrite development is directed by the Scribble scaffold that might link extracellular cues to localized cGMP increase.
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http://dx.doi.org/10.1016/j.celrep.2020.03.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293895PMC
April 2020

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Front Oncol 2020 11;10:117. Epub 2020 Feb 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, United States.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
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http://dx.doi.org/10.3389/fonc.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026496PMC
February 2020

Left Lower Lung Collapse in a Patient Undergoing Endoscopic Procedure.

Case Rep Anesthesiol 2020 31;2020:8670102. Epub 2020 Jan 31.

Department of Anesthesiology, NYP-Brooklyn Methodist Hospital, New York City, NY, USA.

ASA closed claims from 2000 to 2009 have shown that adverse respiratory events are more common in nonoperating room locations like endoscopy suite than in the operating room (44% v/s 20%). Here, we report a case of lung atelectasis which resulted in hypoxemia in a malnourished patient undergoing endoscopic procedure. It is crucial to identify the high-risk patients and monitor them appropriately in the postoperative phase. Continuous capnometry may offer additional benefit by identifying hypercapnia, hypoventilation at the earliest in the recovery area, thus preventing serious complications.
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http://dx.doi.org/10.1155/2020/8670102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013292PMC
January 2020

Sulfated Polysaccharides from Macroalgae for Bone Tissue Regeneration.

Curr Pharm Des 2019 ;25(11):1200-1209

Department of Marine Life Sciences, Korean Maritime and Ocean University, 727 Taejong-ro, Yeongdo-Gu, Busan 49112, Korea.

Background: Utilization of macroalgae has gained much attention in the field of pharmaceuticals, nutraceuticals, food and bioenergy. Macroalgae has been widely consumed in Asian countries as food from ancient days and proved that it has potential bioactive compounds which are responsible for its nutritional properties. Macroalgae consists of a diverse range of bioactive compounds including proteins, lipids, pigments, polysaccharides, etc. Polysaccharides from macroalgae have been utilized in food industries as gelling agents and drug excipients in the pharmaceutical industries owing to their biocompatibility and gel forming properties. Exploration of macroalgae derived sulfated polysaccharides in biomedical applications is increasing recently.

Methods: In the current review, we have provided information of three different sulfated polysaccharides such as carrageenan, fucoidan and ulvan and their isolation procedure (enzymatic precipitation, microwave assisted method, and enzymatic hydrolysis method), structural details, and their biomedical applications exclusively for bone tissue repair and regeneration.

Results: From the scientific results on sulfated polysaccharides from macroalgae, we conclude that sulfated polysaccharides have exceptional properties in terms of hydrogel-forming ability, scaffold formation, and mimicking the extracellular matrix, increasing alkaline phosphatase activity, enhancement of biomineralization ability and stem cell differentiation for bone tissue regeneration.

Conclusion: Overall, sulfated polysaccharides from macroalgae may be promising biomaterials in bone tissue repair and regeneration.
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http://dx.doi.org/10.2174/1381612825666190425161630DOI Listing
February 2020

An Integrative Systems Biology and Experimental Approach Identifies Convergence of Epithelial Plasticity, Metabolism, and Autophagy to Promote Chemoresistance.

J Clin Med 2019 Feb 7;8(2). Epub 2019 Feb 7.

Duke Cancer Institute and the Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

The evolution of therapeutic resistance is a major cause of death for cancer patients. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure of the host immune system. These selective forces often lead to evolutionary convergence on pathways or hallmarks that drive progression. Thus, a deeper understanding of the evolutionary convergences that occur could reveal vulnerabilities to treat therapy-resistant cancer. To this end, we combined phylogenetic clustering, systems biology analyses, and molecular experimentation to identify convergences in gene expression data onto common signaling pathways. We applied these methods to derive new insights about the networks at play during transforming growth factor-β (TGF-β)-mediated epithelial⁻mesenchymal transition in lung cancer. Phylogenetic analyses of gene expression data from TGF-β-treated cells revealed convergence of cells toward amine metabolic pathways and autophagy during TGF-β treatment. Knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to cancer therapies following TGF-β-induced resistance, implicating autophagy as a TGF-β-mediated chemoresistance mechanism. In addition, high ATG16L expression was found to be a poor prognostic marker in multiple cancer types. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities for cancer.
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http://dx.doi.org/10.3390/jcm8020205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406733PMC
February 2019

Prevalence, clinical features, and diagnosis of among female STI clinic attendees in Trinidad.

J Family Med Prim Care 2018 Sep-Oct;7(5):1054-1057

Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad and Tobago.

Background: (TV) is one of the most common pathogens causing sexually transmitted infections (STIs) in both men and women. Since there are no accurate prevalence data available on TV infection among women for Trinidad and Tobago and in the Caribbean region, there is a great need for research to study the dynamics of the infection and its transmission.

Objectives: To determine the prevalence and diagnose TV infection in women attending the STI clinic and to provide recommendations for control and prevention of trichomoniasis in the community.

Study Design: A cross-sectional study was designed after obtaining the informed consent. Following a routine clinical examination, vaginal swabs were collected - one for wet mount preparation, one for InPouch culture, and other two for OSOM rapid test/and fluorescent antibody testing. Cotton swabs and Dacron swabs were used for testing.

Results: A prevalence of 16% of trichomoniasis out of 422 females was recorded. In all, 65 (65%) were in the age range of 15-29 years and peak of 30% in the age group of 20-24 years. Vaginal discharge was a common complaint (83%); 75.6% had foul odor and only 9.8% had typical fishy odor. The majority of them (87%) had whitish-yellow colored discharge.

Conclusion: Prevalence of trichomoniasis is significant in the female population attending STI clinic. Targeting high-risk age group between 15 and 29 years for control and prevention would be beneficial. Prompt and accurate diagnosis using appropriate laboratory test is recommended.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_102_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259553PMC
January 2019

Polymicrobial Infections in Hip Arthroplasty: Lower Treatment Success Rate, Increased Surgery, and Longer Hospitalization.

J Arthroplasty 2019 04 9;34(4):710-716.e3. Epub 2018 Oct 9.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC.

Background: Polymicrobial hip arthroplasty infections are a subset of periprosthetic joint infection (PJI) with distinct challenges representing 10%-47% of PJI.

Methods: Records were reviewed from all PJIs involving partial or total hip arthroplasty with positive hip cultures between 2005 and 2015 in order to determine baseline characteristics and outcomes including treatment success, surgeries for infection, and days in hospital for infection. Analysis was restricted to patients who had at least 2 years of follow-up after their final surgery or hospitalization for infection. Factors with P-value less than .05 in univariate outcomes analysis were included in multivariable models.

Results: After multivariable analysis, 28 of 95 hip arthroplasty PJIs which were polymicrobial were associated with significantly lower treatment success, more surgery, and longer hospitalizations compared to PJIs which were not polymicrobial. Patients diagnosed with polymicrobial infection later in treatment (4 of 28) had the lowest treatment success rate, underwent the most surgery, and spent the longest time in hospital.

Conclusion: Polymicrobial periprosthetic hip infection is a particularly devastating complication of hip arthroplasty associated with decreased likelihood of treatment success, increased surgery for infection, and greater time in hospital. Patients with late polymicrobial infection had the worst outcomes. This investigation further characterizes the natural history of periprosthetic hip infections with more than one infectious organism. Patients who present with a subsequent polymicrobial infection should be educated that they have a particularly difficult treatment course and treatment success may not be possible.
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http://dx.doi.org/10.1016/j.arth.2018.09.090DOI Listing
April 2019

Novel properties of recombinant Sso7d-Taq DNA polymerase purified using aqueous two-phase extraction: Utilities of the enzyme in viral diagnosis.

Biotechnol Rep (Amst) 2018 Sep 27;19:e00270. Epub 2018 Jun 27.

Cancyte Technologies Pvt. Ltd, Rangadore Memorial Hospital, 1st Cross, Shankarapuram, Bangalore 560004, India.

Using Sso7d from as the DNA binding protein fused to Taq DNA polymerase at its amino terminus, we report the hyper-expression and a novel purification methodology of Sso7d-Taq polymerase (S-Taq) using aqueous two-phase extraction system followed by Ni-affinity chromatography. The utility of such a fusion enzyme in carrying out PCR of human genes from whole blood directly and in detecting hepatitis B virus from clinical samples is demonstrated in this article. We present data on the enhanced thermo-stability of S-Taq DNA polymerase over Taq DNA polymerase and also provide evidence of its higher stability with detergents in comparison to Taq polymerase. The purified S-Taq protein showed acceptable limits of host genomic DNA levels without the use of DNases and other DNA precipitating agents and shows promising potential for use in PCR based diagnostics, in-situ PCR's and forensic science.
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http://dx.doi.org/10.1016/j.btre.2018.e00270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127375PMC
September 2018

Diabetic wound management.

Br J Community Nurs 2018 Sep;23(Sup9):S16-S22

Assistant Professor, Yenepoya Research Centre, Yenepoya University, India.

Diabetes is a global disease, and its prevalence has increased rapidly in the last century. Many complications are associated with diabetes, and diabetic foot ulcers (DFU) are common. There is a variety of different treatments for DFU, and the aim of this article is to discuss the factors responsible for delayed wound healing in patients with diabetes, and the treatment strategies that are available.
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http://dx.doi.org/10.12968/bjcn.2018.23.Sup9.S16DOI Listing
September 2018

Cloning and high-level expression of Thermus thermophilus RecA in E. coli: purification and novel use in HBV diagnostics.

Braz J Microbiol 2018 Oct - Dec;49(4):848-855. Epub 2018 Apr 12.

Cancyte Technologies Pvt. Ltd., Rangadore Memorial Hospital, Sri Shankara Research Center, Shankarapuram, Bangalore, India. Electronic address:

We studied the role of Thermus thermophilus Recombinase A (RecA) in enhancing the PCR signals of DNA viruses such as Hepatitis B virus (HBV). The RecA gene of a thermophilic eubacterial strain, T. thermophilus, was cloned and hyperexpressed in Escherichia coli. The recombinant RecA protein was purified using a single heat treatment step without the use of any chromatography steps, and the purified protein (>95%) was found to be active. The purified RecA could enhance the polymerase chain reaction (PCR) signals of HBV and improve the detection limit of the HBV diagnosis by real time PCR. The yield of recombinant RecA was ∼35mg/L, the highest yield reported for a recombinant RecA to date. RecA can be successfully employed to enhance detection sensitivity for the diagnosis of DNA viruses such as HBV, and this methodology could be particularly useful for clinical samples with HBV viral loads of less than 10IU/mL, which is interesting and novel.
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http://dx.doi.org/10.1016/j.bjm.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175717PMC
December 2018

Repositioning of Somatic Golgi Apparatus Is Essential for the Dendritic Establishment of Adult-Born Hippocampal Neurons.

J Neurosci 2018 01 7;38(3):631-647. Epub 2017 Dec 7.

Department of Neurobiology and Behavior, State University of New York-Stony Brook, Stony Brook, New York 11794

New dentate granule cells (DGCs) are continuously generated, and integrate into the preexisting hippocampal network in the adult brain. How an adult-born neuron with initially simple spindle-like morphology develops into a DGC, consisting of a single apical dendrite with further branches, remains largely unknown. Here, using retroviruses to birth date and manipulate newborn neurons, we examined initial dendritic formation and possible underlying mechanisms. We found that GFP-expressing newborn cells began to establish a DGC-like morphology at ∼7 d after birth, with a primary dendrite pointing to the molecular layer, but at this stage, with several neurites in the neurogenic zone. Interestingly, the Golgi apparatus, an essential organelle for neurite growth and maintenance, was dynamically repositioning in the soma of newborn cells during this initial integration stage. Two weeks after birth, by which time most neurites in the neurogenic zone were eliminated, a compact Golgi apparatus was positioned exclusively at the base of the primary dendrite. We analyzed the presence of Golgi-associated genes using single-cell transcriptomes of newborn DGCs, and among Golgi-related genes, found the presence of and , regulators of embryonic neuronal development. When we knocked down either of these two proteins, we found Golgi mislocalization and extensive aberrant dendrite formation. Furthermore, overexpression of a mutated form of STRAD, underlying the disorder polyhydramnios, megalencephaly, and symptomatic epilepsy, characterized by abnormal brain development and intractable epilepsy, caused similar defects in Golgi localization and dendrite formation in adult-born neurons. Together, our findings reveal a role for Golgi repositioning in regulating the initial integration of adult-born DGCs. Since the discovery of the continuous generation of new neurons in the adult hippocampus, extensive effort was directed toward understanding the functional contribution of these newborn neurons to the existing hippocampal circuit and associated behaviors, while the molecular mechanisms controlling their early morphological integration are less well understood. Dentate granule cells (DGCs) have a single, complex, apical dendrite. The events leading adult-born DGCs' to transition from simple spindle-like morphology to mature dendrite morphology are largely unknown. We studied establishment of newborn DGCs dendritic pattern and found it was mediated by a signaling pathway regulating precise localization of the Golgi apparatus. Furthermore, this Golgi-associated mechanism for dendrite establishment might be impaired in a human genetic epilepsy syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy.
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http://dx.doi.org/10.1523/JNEUROSCI.1217-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777113PMC
January 2018

Micellar nanocomplexes for biomagnetic delivery of intracellular proteins to dictate axon formation during neuronal development.

Biomaterials 2017 01 8;112:176-191. Epub 2016 Oct 8.

Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA. Electronic address:

During mammalian embryonic development, neurons polarize to create distinct cellular compartments of axon and dendrite that inherently differ in form and function, providing the foundation for directional signaling in the nervous system. Polarization results from spatio-temporal segregation of specific proteins' activities to discrete regions of the neuron to dictate axonal vs. dendritic fate. We aim to manipulate axon formation by directed subcellular localization of crucial intracellular protein function. Here we report critical steps toward the development of a nanotechnology for localized subcellular introduction and retention of an intracellular kinase, LKB1, crucial regulator of axon formation. This nanotechnology will spatially manipulate LKB1-linked biomagnetic nanocomplexes (LKB1-NCs) in developing rodent neurons in culture and in vivo. We created a supramolecular assembly for LKB1 rapid neuronal uptake and prolonged cytoplasmic stability. LKB1-NCs retained kinase activity and phosphorylated downstream targets. NCs were successfully delivered to cultured embryonic hippocampal neurons, and were stable in the cytoplasm for 2 days, sufficient time for axon formation. Importantly, LKB1-NCs promoted axon formation in these neurons, representing unique proof of concept for the sufficiency of intracellular protein function in dictating a central developmental event. Lastly, we established NC delivery into cortical progenitors in live rat embryonic brain in utero. Our nanotechnology provides a viable platform for spatial manipulation of intracellular protein-activity, to dictate central events during neuronal development.
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http://dx.doi.org/10.1016/j.biomaterials.2016.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121005PMC
January 2017

The "Fingerprint" of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach.

IEEE Trans Biomed Eng 2016 05 18;63(5):1082-6. Epub 2015 Sep 18.

Goal: Abnormalities of microvascular morphology have been associated with tumor angiogenesis for more than a decade, and are believed to be intimately related to both tumor malignancy and response to treatment. However, the study of these vascular changes in-vivo has been challenged due to the lack of imaging approaches which can assess the microvasculature in 3-D volumes noninvasively. Here, we use contrast-enhanced "acoustic angiography" ultrasound imaging to observe and quantify heterogeneity in vascular morphology around solid tumors.

Methods: Acoustic angiography, a recent advance in contrast-enhanced ultrasound imaging, generates high-resolution microvascular images unlike anything possible with standard ultrasound imaging techniques. Acoustic angiography images of a genetically engineered mouse breast cancer model were acquired to develop an image acquisition and processing routine that isolated radially expanding regions of a 3-D image from the tumor boundary to the edge of the imaging field for assessment of vascular morphology of tumor and surrounding vessels.

Results: Quantitative analysis of vessel tortuosity for the tissue surrounding tumors 3 to 7 mm in diameter revealed that tortuosity decreased in a region 6 to 10 mm from the tumor boundary, but was still significantly elevated when compared to control vasculature.

Conclusion: Our analysis of angiogenesis-induced changes in the vasculature outside the tumor margin reveals that the extent of abnormal tortuosity extends significantly beyond the primary tumor mass.

Significance: Visualization of abnormal vascular tortuosity may make acoustic angiography an invaluable tool for early tumor detection based on quantifying the vascular footprint of small tumors and a sensitive method for understanding changes in the vascular microenvironment during tumor progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070672PMC
http://dx.doi.org/10.1109/TBME.2015.2479590DOI Listing
May 2016

The effect of dietary counseling on nutrient intakes in gastric banding surgery patients.

J Investig Med 2013 Dec;61(8):1165-72

From the *Division of Nutrition and Metabolic Diseases, †Department of Internal Medicine, and ‡Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas; §Department of Kinesiology, Texas Christian University, Fort Worth, TX; and ∥Department of Clinical Sciences, University of Texas Southwestern Medical Center at Dallas.

Background: There is some evidence that bariatric surgery patients who undergo the purely restrictive procedures, such as the gastric banding (GB) or the vertical banded gastroplasty surgery, do not meet the dietary reference intakes for several nutrients. Whether dietary counseling improves micronutrient and macronutrient intakes was examined in GB surgery patients.

Methods: Twenty-three GB surgery patients received dietary and behavioral counseling for 12 weeks to limit energy intake and improve nutrient intakes. Food intake was assessed by 3-day food record at baseline and 6 and 12 weeks. Postintervention data were available in 21 patients.

Results: At baseline, more than 50% of the subjects reported inadequate dietary intakes of 13 nutrients but overconsumption of sodium and percent energy from saturated and trans-fatty acids. Mixed-effects model for repeated measures revealed a significant reduction in energy (P = 0.0007), absolute protein (P = 0.04), cholesterol (P = 0.045), and potassium (P = 0.01) intake and an increase in vitamin K (P = 0.03) intake and percent energy from protein (P = 0.005) during the 12 weeks. The McNemar test showed a reduction in the proportion of the subjects with an inadequate intake of vitamin K (P = 0.008) but an increase in the proportion of the subjects with an inadequate intake of thiamin (P = 0.03) at 12 weeks. The proportion of the subjects who did not meet the nutrient requirements for the remaining 27 nutrients was generally high and remained unchanged.

Conclusions: Dietary intervention improved the intake of some nutrients in the GB surgery patients. However, most nutrient intake requirements remained unmet by many subjects. These results indicate that nutritional counseling beyond 12 weeks is warranted in GB surgery patients to improve their dietary nutrient intakes.
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http://dx.doi.org/10.2310/JIM.0000000000000002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931008PMC
December 2013

Quality of life and parental adjustment in pediatric pulmonary hypertension.

Chest 2014 Feb;145(2):237-244

Department of Cardiology, Boston Children's Hospital; Department of Psychiatry, Boston Children's Hospital; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Psychiatry, Harvard Medical School, Boston, MA.

Background: This study examines the impact of pulmonary hypertension (PH) on the quality of life (QoL) of affected youth, as well as the relationships among PH disease severity, parental adjustment variables, and family relational functioning.

Methods: Subjects were 47 eligible parents of children with PH aged 2 to 18 years who were evaluated at Boston Children's Hospital. Measures of patient QoL and of parental stress, coping, and adjustment were administered to the caregivers. Clinicians rated illness severity and family relational functioning.

Results: Youth with PH scored significantly lower than healthy norms on a measure of parent-reported QoL (total, psychosocial, and physical QoL, each P < .0001). The parents reported encountering stressful events more frequently than published norms of parents of children with cancer (P < .0001). Thirty-four percent of parents of children with PH met criteria for presumed psychiatric diagnosis, and they reported using psychologic coping strategies significantly more often than a normative sample. A summary parental stress measure correlated inversely with child QoL, an effect that held true even after controlling for disease severity (P = .03).

Conclusions: PH takes a major toll on children and their families. Decreased QoL among youth with PH was significantly associated with high levels of parental stress, over and above the effect of illness severity. These findings suggest that interventions to better support the caretakers of affected children and adolescents should accompany medical treatment advances so as to improve QoL for patients facing pediatric PH.
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http://dx.doi.org/10.1378/chest.13-0636DOI Listing
February 2014

Elevated rates of ADHD in mothers of children with comorbid ADHD and epilepsy.

Neuropsychiatry (London) 2012 Oct;2(5):385-391

Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

OBJECTIVES: To describe the prevalence of ADHD in mothers of children with comorbid ADHD and epilepsy (ADHD+E) and to compare ADHD symptoms in mothers with (Fam(+)) and without (Fam(-)) additional relative(s) with epilepsy. PATIENTS & METHODS: Mothers (n = 16) of children with ADHD+E were assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children ADHD module and the ADHD Rating Scale IV. Information was collected on the presence (Fam(+)) or absence (Fam(-)) of first- or second-degree relatives with epilepsy in the sample. RESULTS: A total of 50% of mothers met the DSM-IV criteria for ADHD. ADHD was more prevalent in Fam(+) mothers (80%) compared with Fam(-) mothers (36%; p = 0.14). Fam(+) mothers had more current hyperactivity symptoms than Fam(-) mothers (p = 0.002), higher current ADHD severity (p = 0.02) and higher ADHD Rating Scale IV hyperactivity scores (p = 0.008). CONCLUSION: The prevalence of ADHD in mothers of children with ADHD+E is elevated in this pilot study, suggesting that ADHD symptoms in children with epilepsy and their mothers reflects shared familial genetic or environmental risks, potentially resulting in a higher prevalence of both disorders among family members. This is a pilot study and larger controlled studies are warranted.
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http://dx.doi.org/10.2217/npy.12.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565178PMC
October 2012

High-volume exercise program in obese bariatric surgery patients: a randomized, controlled trial.

Obesity (Silver Spring) 2011 Sep 16;19(9):1826-34. Epub 2011 Jun 16.

Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.

Weight regain is a problem among many bariatric surgery patients. Whether a high-volume exercise program (HVEP), a strategy to limit weight regain, is feasible in these patients is unknown. The feasibility of an HVEP in obese post-bariatric-surgery patients was determined by randomizing 33 Roux-en-Y gastric bypass (RYGB) and gastric banding (GB) surgery patients with a mean BMI of 41 ± 6 kg/m2 to an HVEP or control group for 12 weeks. The HVEP group was instructed to expend ≥ 2,000 kcal/week in moderate-intensity exercise. All patients were counseled to limit energy intake. Treatment effect was assessed by repeated measures analysis. During the last 4 weeks of the study, 53% of the HVEP group expended ≥ 2,000 kcal/week and 82% expended ≥ 1,500 kcal/week. Step count, reported time spent and energy expended during moderate physical activity, maximal oxygen consumption relative to weight, and incremental area under the postprandial blood glucose curve were significantly improved over 12 weeks in the HVEP group compared to controls (group-by-week effect: P = 0.009-0.03). Both groups reported significant improvement in some quality-of-life scales. Changes in weight, energy and macronutrient intake, resting energy expenditure (REE), fasting lipids and glucose, and fasting and postprandial insulin concentrations were not different between the two groups. HVEP is feasible in about 50% of the patients and enhances physical fitness and reduces postprandial blood glucose in bariatric surgery patients.
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http://dx.doi.org/10.1038/oby.2011.172DOI Listing
September 2011

Large quantities of Abeta peptide are constitutively released during amyloid precursor protein metabolism in vivo and in vitro.

J Biol Chem 2011 May 22;286(18):15989-97. Epub 2011 Mar 22.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

The metabolism of the amyloid precursor protein (APP) has been extensively investigated because its processing generates the amyloid-β-peptide (Aβ), which is a likely cause of Alzheimer disease. Much prior research has focused on APP processing using transgenic constructs and heterologous cell lines. Work to date in native neuronal cultures suggests that Aβ is produced in very large amounts. We sought to investigate APP metabolism and Aβ production simultaneously under more physiological conditions in vivo and in vitro using cultured rat cortical neurons and live pigs. We found in cultured neurons that both APP and Aβ are secreted rapidly and at extremely high rates into the extracellular space (2-4 molecules/neuron/s for Aβ). Little APP is degraded outside of the pathway that leads to extracellular release. Two metabolic pools of APP are identified, one that is metabolized extremely rapidly (t1/2;) = 2.2 h), and another, surface pool, composed of both synaptic and extrasynaptic elements, that turns over very slowly. Aβ release and accumulation in the extracellular medium can be accounted for stoichiometrically by the extracellular release of β-cleaved forms of the APP ectodomain. Two α-cleavages of APP occur for every β-cleavage. Consistent with the results seen in cultured neurons, an extremely high rate of Aβ production and secretion from the brain was seen in juvenile pigs. In summary, our experiments show an enormous and rapid production and extracellular release of Aβ and the soluble APP ectodomain. A small, slowly metabolized, surface pool of full-length APP is also identified.
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http://dx.doi.org/10.1074/jbc.M110.191262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3091208PMC
May 2011

Total reversal of weight loss from adjustable gastric banding surgery associated with excessive intake of energy dense liquid and solid foods: A case report.

Obes Res Clin Pract 2011 Jan-Mar;5(1):e1-e78

Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States. Electronic

Summary: We report excessive binging and total reversal of weight loss in a patient after adjustable gastric banding surgery (AGBS). A 42-year-old female who underwent AGBS 4 years earlier was randomized to a diet group in a study on exercise training. The patient was on therapy for pre-diabetes and depression. She weighed 115 kg pre-surgery, lost 27.3 kg post-surgery, and weighed 117.3 kg at the start of the study. Her energy intake, assessed by 3-day food record, was 14,096 kcal/d at the beginning of the study of which 3086 kcal/d was from liquid and 7273 kcal/d from solid energy dense foods. The patient reported that the liquid foods facilitated binging on solid foods despite gastric band adjustments. Following intensive dietary counseling for 5 weeks, her reported energy intake decreased to <3000 kcal/d and body weight by 1 kg. Evaluating and actively addressing any dietary behavioral issues before and after AGBS are recommended.:
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http://dx.doi.org/10.1016/j.orcp.2010.09.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875385PMC
December 2013

Tolerability of atomoxetine for treatment of pediatric attention-deficit/hyperactivity disorder in the context of epilepsy.

Epilepsy Behav 2011 Jan 13;20(1):95-102. Epub 2010 Dec 13.

Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.

To examine atomoxetine's tolerability in patients with epilepsy, we reviewed medical records of all patients with epilepsy who were treated with atomoxetine in a tertiary care pediatric psychopharmacology practice. Twenty-seven patients (10.1 ± 4.2 years, 63% male) with an average seizure frequency at baseline of 7 ± 24 per month (median: 0, range: 0-90) were found. Symptoms of attention-deficit/hyperactivity disorder in twenty-five patients (92.5%) had previously not responded to stimulants. Atomoxetine, average dose 35.2 ± 24.4 mg, was given for a median of 26 weeks (range: 4-141). Seventeen patients (63%) discontinued atomoxetine due to: inadequate response (n=7, 26%), worsening behavior such as increased irritability/activation (n = 7, 26%), nonadherence (n=1, 4%), emerging psychotic-like symptoms (n=1, 4%), and appetite decrease and tremor (n=1, 4%). There were no discontinuations because of seizure exacerbation. Atomoxetine dose, epilepsy etiology, seizure type, and comorbid psychiatric disorders did not predict discontinuation. No safety problems of sufficient magnitude to preclude prospective studies of atomoxetine in children with epilepsy were found.
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http://dx.doi.org/10.1016/j.yebeh.2010.11.002DOI Listing
January 2011

Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy.

Epilepsy Behav 2010 Jul 21;18(3):229-37. Epub 2010 May 21.

Department of Psychiatry, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

Objective: The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy.

Methods: Thirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial.

Results: There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study.

Conclusion: A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.
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http://dx.doi.org/10.1016/j.yebeh.2010.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902631PMC
July 2010
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