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1.  Checking In: A Pilot of a Physician-Delivered Intervention to Increase Parent-Adolescent Communication about Blood Glucose Monitoring 
Clinical pediatrics  2015;54(14):1346-1353.
Low-cost, translatable interventions to promote adherence in adolescents with type 1 diabetes are needed. This study evaluated a brief physician-delivered intervention designed to increase parent-adolescent communication about blood glucose (BG) monitoring. Thirty adolescent/parent dyads completed baseline questionnaires and received the physician-delivered intervention. Participants completed follow-up questionnaires at 12 weeks; HbA1c and glucometer data were abstracted from medical charts. Parent-reported conflict surrounding diabetes management decreased from pre- to post-intervention. Participants who reported adhering to the intervention plan (n=15) demonstrated an increase in BG monitoring frequency and trends in improved HbA1c and parental diabetes collaboration from pre- to post-intervention. Participants and physicians reported overall satisfaction with the program. Results demonstrate initial feasibility as well as a trend towards improvement in diabetes-specific health indicators for parent/adolescent dyads who adhered to program components. Frequent joint review of glucometer data can be a useful strategy to improve T1D-related health outcomes and parent-adolescent communication.
PMCID: PMC4615374  PMID: 25896723
adolescence; blood glucose self-monitoring; communication; patient adherence
2.  Clinical and Hematological Profile of Acute Megakaryoblastic Leukemia: A 2 Year Study 
Acute megakaryoblastic leukemia is a rare subtype of acute myeloid leukemia with a characteristic morphologic and immunophenotypic profile. It has to be distinguished from other subtypes of acute myeloid leukemia as well as acute myeloid leukemia with t (1; 22) (p13;q13) and acute megakaryoblastic leukemia in Down Syndrome because of its poor prognosis. We studied ten cases diagnosed over a period of 2 years (from July 2011 to June 2013). All the ten cases were in the pediatric age group ranging from 4 months to 2 years. On morphology, pointers to the diagnosis were clustering of blasts, presence of cytoplasmic blebs and platelet budding. An additional interesting morphological feature observed in our study was nuclear blebs which were seen in nine cases. Diagnosis was confirmed in all cases by positive immunostaining for CD61. Two of the cases had an extremely rare clinical presentation as granulocytic sarcoma. Although rare, acute megakaryoblastic leukemia should be kept in mind especially in leukemia in infants.
PMCID: PMC4375136  PMID: 25825554
Acute megakaryoblastic leukemia; Granulocytic sarcoma ; Infants ; Flowcytometry
3.  The importance of cardiovascular pathology contributing to maternal death: Confidential Enquiry into Maternal Deaths in South Africa, 2011–2013 
Cardiac disease is emerging as an important contributor to maternal deaths in both lower-to-middle and higher-income countries. There has been a steady increase in the overall institutional maternal mortality rate in South Africa over the last decade. The objectives of this study were to determine the cardiovascular causes and contributing factors of maternal death in South Africa, and identify avoidable factors, and thus improve the quality of care provided.
Data collected via the South African National Confidential Enquiry into Maternal Deaths (NCCEMD) for the period 2011–2013 for cardiovascular disease (CVD) reported as the primary pathology was analysed. Only data for maternal deaths within 42 days post-delivery were recorded, as per statutory requirement. One hundred and sixty-nine cases were reported for this period, with 118 complete hospital case files available for assessment and data analysis.
Peripartum cardiomyopathy (PPCM) (34%) and complications of rheumatic heart disease (RHD) (25.3%) were the most important causes of maternal death. Hypertensive disorders of pregnancy, HIV disease infection and anaemia were important contributing factors identified in women who died of peripartum cardiomyopathy. Mitral stenosis was the most important contributor to death in RHD cases. Of children born alive, 71.8% were born preterm and 64.5% had low birth weight. Seventy-eight per cent of patients received antenatal care, however only 33.7% had a specialist as an antenatal care provider. Avoidable factors contributing to death included delay in patients seeking help (41.5%), lack of expertise of medical staff managing the case (29.7%), delay in referral to the appropriate level of care (26.3%), and delay in appropriate action (36.4%).
The pattern of CVD contributing to maternal death in South Africa was dominated by PPCM and complications of RHD, which could, to a large extent, have been avoided. It is likely that there were many CVD deaths that were not reported, such as late maternal mortality (up to one year postpartum). Infrastructural changes, use of appropriate referral algorithm and training of primary, secondary and tertiary staff in CVD complicating pregnancy is likely to improve the outcome. The use of simple screening equipment and point-of-care testing for early-onset heart failure should be explored via research projects.
PMCID: PMC4928161  PMID: 26895406
cardiac disease in pregnancy; valve disease; valve thrombosis; rheumatic heart disease; cardiomyopathy; peripartum cardiomyopathy
4.  A case of papillary microcarcinoma of the thyroid with abundant colloid (masquerading as colloid goiter with papillary hyperplasia): Cytological evaluation with histopathological correlation 
Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid. On fine-needle aspiration (FNA) cytology smears of conventional PTC, the background usually shows scanty, bubble gum-like colloid. But the macrofollicular variant and papillary microcarcinoma reveals abundant thin colloid in the background. We report a case of papillary carcinoma of thyroid in a 37-year-old female with abundant thin colloid, obscuring the nuclear morphology in many clusters, along with the presence of typical nuclear features within occasional clusters in FNA cytology and hence, masquerading as colloid goiter with papillary hyperplasia. Histopathological examination of the total thyroidectomy specimen revealed papillary microcarcinomatous focus in a background of nodular hyperplasia. The differential diagnosis of PTC should be entertained even in colloid-rich FNA smears if the typical nuclear features are present. Hence, a meticulous search for any fragment with nuclear features of PTC is mandatory before labeling the smears as benign nodular hyperplasia.
PMCID: PMC4707794  PMID: 26811580
Abundant thin colloid; fine-needle aspiration (FNA) cytology; nuclear features; thyroid papillary microcarcinoma
5.  Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica 
Pharmacognosy Magazine  2015;11(Suppl 3):S414-S422.
Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness.
For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety.
Materials and Methods:
In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease).
The docking results were evaluated based on free energies of binding (ΔG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations.
The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery.
In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug likeness score of the standard anti HIV drug zidovudine. Results from simulation analysis revealed that toddanol RT complex is more stable than toddanone RT complex inferring toddanol as a potential anti HIV drug molecule.
Abbreviations used: HIV: Human immunodeficiency virus, HIV 1 RT: HIV 1 reverse transcriptase, RNase H: Ribonuclease H, MD: Molecular dynamics, PDB: Protein databank, RMSD: Root mean square deviation, RMSF: Root mean square fluctuation.
PMCID: PMC4745211  PMID: 26929575
Alkaloids; Autodock v4.0; drug-likeness; human immunodeficiency virus-1 reverse transcriptase; molecular dynamics simulation; molecular properties; toddanol; toddanone
6.  Apoptosis Induction of Centella Asiatica on Human Breast Cancer Cells 
The present study evaluated the ability of methanolic extract of Centella asiatica (Linn) Urban (Umbelliferae) to induce apoptosis in different cancer cell lines. MCF-7 cells emerged as the most sensitive cell line for in vitro growth inhibitory activity. C. asiatica extract induced apoptosis in MCF-7 cells as indicated by nuclear condensation, increased annexin staining, loss of mitochondrial membrane potential and induction of DNA breaks identified by TUNEL reactivity. It is possible that the use of C. asiatica extract as a component in herbal medicines could be justifiable.
PMCID: PMC2816528  PMID: 20162036
Apoptosis; Cancer; Centella asiatica
7.  Limiting influenza virus, HIV and dengue virus infection by targeting viral proteostasis 
Immunity  2016;44(1):46-58.
Viruses are obligate parasites as they require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy to suppress viral replication and a potential pan antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling, genetic, and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses, and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication we have identified targetable host factors for broad-spectrum antiviral therapies.
PMCID: PMC4878455  PMID: 26789921
8.  A newly emerged swine origin A(H3N2)v influenza virus dampens host antiviral immunity but induces potent inflammasome activation 
The Journal of infectious diseases  2015;212(12):1923-1929.
We compared the innate immune response to newly emerged swine origin H3N2 influenza A variant virus containing the M gene from A(H1N1)pdm09 virus (A(H3N2)vpm), with 2010 swine-origin A(H3N2)v and seasonal A(H3N2) viruses. Our results demonstrated that A(H3N2)vpM virus-induced myeloid dendritic cells secreted significantly lower levels of type I interferon (IFN) but produced significantly higher levels of pro-inflammatory cytokines and induced potent inflammasome activation. The reduction in antiviral immunity with increased inflammatory responses upon A(H3N2)vpM virus infection suggest that these viruses have the potential for increased disease severity in susceptible hosts.
PMCID: PMC5240150  PMID: 26068782
A(H3N2)vpM; myeloid dendritic cell; pro-inflammatory cytokines; type I IFN; ROS; inflammasome activation
9.  Cryptochromes interact directly with PIFs to control plant growth in limiting blue light 
Cell  2015;164(0):233-245.
Sun-loving plants have the ability to detect and avoid shading through sensing of both blue and red light wavelengths. Higher plant cryptochromes (CRYs) control how plants modulate growth in response to changes in blue light. For growth under a canopy, where blue light is diminished, CRY1 and CRY2 perceive this change and respond by directly contacting two bHLH transcription factors, PIF4 and PIF5. These factors are also known to be controlled by phytochromes, the red/far-red photoreceptors; however, transcriptome analyses indicate that the gene regulatory programs induced by the different light wavelengths are distinct. Our results indicate that CRYs signal by modulating PIF activity genome-wide, and that these factors integrate binding of different plant photoreceptors to facilitate growth changes under different light conditions.
PMCID: PMC4721562  PMID: 26724867
10.  Methylation-dependent and independent regulatory regions in the Na,K-ATPase alpha4 gene (Atp1a4) may impact its testis-specific expression 
Gene  2015;575(0):339-352.
The α4 Na,K-ATPase is a sperm-specific protein essential for sperm motility and fertility yet little is known about the mechanisms that regulate its expression in germ cells. Here, the potential involvement of DNA methylation in regulating the expression of this sperm-specific protein is explored. A single, intragenic CpG island (Mα4-CGI) was identified in the gene encoding the mouse α4 Na,K-ATPase (Atp1a4), which displayed reduced methylation in mouse sperm (cells that contain α4) compared to mouse kidney (tissue that lacks α4 expression). Unlike the intragenic CGI, the putative promoter (the −700 to +200 region relative to the transcriptional start site) of Atp1a4 did not show differential methylation between kidney and sperm nevertheless it did drive methylation-dependent reporter gene expression in the male germ cell line GC-1spg. Furthermore, treatment of GC-1spg cells with 5-Aza2-Deoxycytidine led to upregulation of the α4 transcript and decreased methylation of both the Atp1a4 promoter and the Mα4-CGI. In addition, Atp1a4 expression in mouse embryonic stem cells deficient in DNA methytransferases suggests that both maintenance and de novo methylation are involved in regulating its expression. In an attempt to define the regulatory function of the Mα4-CGI, possible roles of the Mα4-CGI in regulating Atp1a4 expression via methylation-dependent transcriptional elongation inhibition in somatic cells and via its ability to repress promoter activity in germ cells were uncovered. In all, our data suggests that both the promoter and the intragenic CGI could combine to provide multiple modes of regulation for optimizing the Atp1a4 expression level in a cell type-specific manner.
PMCID: PMC4662617  PMID: 26343794
Epigenetics; Dnmts; transcriptional elongation; spermatozoa; motility
11.  Influenza virus exploits tunneling nanotubes for cell-to-cell spread 
Scientific Reports  2017;7:40360.
Tunneling nanotubes (TNTs) represent a novel route of intercellular communication. While previous work has shown that TNTs facilitate the exchange of viral or prion proteins from infected to naïve cells, it is not clear whether the viral genome is also transferred via this mechanism and further, whether transfer via this route can result in productive replication of the infectious agents in the recipient cell. Here we present evidence that lung epithelial cells are connected by TNTs, and in spite of the presence of neutralizing antibodies and an antiviral agent, Oseltamivir, influenza virus can exploit these networks to transfer viral proteins and genome from the infected to naïve cell, resulting in productive viral replication in the naïve cells. These observations indicate that influenza viruses can spread using these intercellular networks that connect epithelial cells, evading immune and antiviral defenses and provide an explanation for the incidence of influenza infections even in influenza-immune individuals and vaccine failures.
PMCID: PMC5216422  PMID: 28059146
13.  Do Radiologists Have Stage Fright? Tumor Staging and How We Can Add Value to the Care of Patients with Cancer 
Radiology  2015;278(1):11-12.
With current shifts in our health care system and a growing national discussion around the concept of the value of imaging, it is time for radiologists and nuclear medicine physicians to recognize and accept our role in the multidisciplinary oncology team.
PMCID: PMC4699490  PMID: 26690989
14.  Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: effect of radiation dose and conditioning regimen 
Background and Purpose
Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow (BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function.
Materials and Methods
We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n=42) and reduced intensity (RIC, n=56) doses of TBI from 2003-2013, including BM cellularity, histologic features of injury and repair, hematologic and immunologic recovery.
Following MA conditioning, a 30% decrease in the marrow cellularity persisted at 1 year post-transplant (p=0.03). RIC HCT marrow cellularity transiently decreased but returned to baseline by 6 months even though the RIC group received mostly umbilical cord blood (UCB) grafts (82%, vs. 17% in the MA cohort, p<0.01). There was no evidence of persistent marrow vascular damage or inflammation. Recipients of more intensive conditioning did not show more persistent cytopenias with the exception of a tendency for minimal thrombocytopenia. Immune recovery was similar between MA and RIC.
These findings suggest that TBI associated with MA conditioning leads to prolonged reductions in marrow cellularity, but does not show additional histological evidence of long-term injury, which is further supported by similar peripheral counts and immunologic recovery.
PMCID: PMC4764403  PMID: 26653357
Bone marrow transplantation; total body irradiation; marrow cellularity
15.  The Global Alzheimer’s Association Interactive Network 
The Global Alzheimer’s Association Interactive Network (GAAIN) is consolidating the efforts of independent Alzheimer’s disease data repositories around the world with the goals of revealing more insights into the causes of Alzheimer’s disease, improving treatments, and designing preventative measures that delay the onset of physical symptoms.
We developed a system for federating these repositories that is reliant upon the tenets that (a) its participants require incentives to join, (b) joining the network is not disruptive to existing repository systems, and (c) the data ownership rights of its members are protected.
We are currently in various phases of recruitment with over 55 data repositories in North America, Europe, Asia and Australia and can presently query 250,000+ subjects using GAAIN’s search interfaces.
GAAIN’s data sharing philosophy, which guided our architectural choices, is conducive to motivating membership in a voluntary data sharing network.
PMCID: PMC4817494  PMID: 26318022
GAAIN; data sharing; federated data repositories; Alzheimer’s disease
16.  MRI-based brain atrophy rates in ADNI phase 2: acceleration and enrichment considerations for clinical trials 
Neurobiology of aging  2015;37:26-37.
The goal of this work was to assess statistical power to detect treatment effects in Alzheimer’s disease (AD) clinical trials using magnetic resonance imaging (MRI)–derived brain biomarkers. We used unbiased tensor-based morphometry (TBM) to analyze n = 5,738 scans, from Alzheimer’s Disease Neuroimaging Initiative 2 participants scanned with both accelerated and nonaccelerated T1-weighted MRI at 3T. The study cohort included 198 healthy controls, 111 participants with significant memory complaint, 182 with early mild cognitive impairment (EMCI) and 177 late mild cognitive impairment (LMCI), and 155 AD patients, scanned at screening and 3, 6, 12, and 24 months. The statistical power to track brain change in TBM-based imaging biomarkers depends on the interscan interval, disease stage, and methods used to extract numerical summaries. To achieve reasonable sample size estimates for potential clinical trials, the minimal scan interval was 6 months for LMCI and AD and 12 months for EMCI. TBM-based imaging biomarkers were not sensitive to MRI scan acceleration, which gave results comparable with nonaccelerated sequences. ApoE status and baseline amyloid-beta positron emission tomography data improved statistical power. Among healthy, EMCI, and LMCI participants, sample size requirements were significantly lower in the amyloid+/ApoE4+ group than for the amyloid−/ApoE4− group. ApoE4 strongly predicted atrophy rates across brain regions most affected by AD, but the remaining 9 of the top 10 AD risk genes offered no added predictive value in this cohort.
PMCID: PMC4827255  PMID: 26545631
Alzheimer’s disease; Mild cognitive impairment; Imaging biomarker; Longitudinal; Enrichment; ApoE; Amyloid
17.  Adapting Telemonitoring Technology Use for Older Adults: A Pilot Study 
Telehealth technologies are increasing health care access for patients in the home, community, and rural and underserved areas. Older adults may be challenged to use new technologies due to aging related changes, lack of experience, and different attitudes toward its use. This pilot study evaluated potential issues in training/instructions and use of a telemonitoring application. The feedback from this study will be used to adapt the application and training to support dementia caregivers.
Seven cognitively intact older adults attended a one-on-one training session for using a telemonitoring application on an iPad Mini or iPod Touch device. They returned one week after training to demonstrate actual use of the telemonitoring application. The demonstration session was video-recorded. Behavioral coding of the videos was used to determine which steps were problematic, and to identify modifications needed in the application and training. Use of telemonitoring application involved ten steps: turn on device, get to the App screen, open the App, position/reposition the device to record, change front-back camera setting, record, view recording, upload, delete, and return to start screen. The following challenges (errors) were coded; ask question, refer to manual, pause, ineffective tap, express frustration, cueing by the research assistant, and mistake. Participants also completed an ease of use questionnaire.
Descriptive analysis of the video recordings and the questionnaire identified usability challenges.
The actual use return demonstration session took an average of 50 minutes. All participants referred to the instruction manual. Participants varied in the number of challenges to completing the task but had an average of 19 coded errors or challenges to complete the process. This information was used to revise training materials and to work with the developer to improve the application.
Older adults may benefit from specific adaptations and training to use new health care technologies. Behavioral coding is an effective way to evaluate the user interface for new technologies with older adults.
PMCID: PMC4839531  PMID: 26020575
Telehealth; technology; older adults
18.  Bioengineering novel floating nanoparticles for protein and drug delivery 
Materials Today : proceedings  2016;3(2):206-210.
Gas vesicle nanoparticles (GVNPs) are hollow protein nanoparticles produced by Halobacterium sp. NRC-1 which are being engineered for protein delivery. To advance the bioengineering potential of GVNPs, a strain of NRC-1 deleted for the gvpC gene (ΔgvpC) was constructed and a synthetic gene coding for Gaussia princeps luciferase was fused to an abbreviated gvpC gene on an expression plasmid. When introduced into theΔgvpC strain, an active GvpC-luciferase fusion protein bound to GVNPs resulted. These results represent both a technical improvement in the GVNP display system and its expansion for the display of active enzymes.
PMCID: PMC4856160  PMID: 27158595
Gas vesicle naoparticles (GVNPs); vaccine; luciferase; Gaussia princeps; enzyme display
19.  Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis 
For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) μg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) μg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 μg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.
PMCID: PMC4914618  PMID: 27139475
20.  Can social media be used as a hospital quality improvement tool? 
Journal of hospital medicine  2015;11(1):52-55.
Many hospitals wish to improve their patients’ experience of care. In order to learn whether social media could be used as a tool to engage patients and to identify opportunities for hospital quality improvement (QI), we solicited patients’ narrative feedback on the Baystate Medical Center (BMC) Facebook page during a three-week period in 2014. Two investigators used directed qualitative content analysis to code comments and descriptive statistics to assess the frequency of selected codes and themes. We identified common themes, including: 1.) comments about staff (17/37 respondents, 45.9%); 2.) comments about specific departments (22/37, 59.5%); 3.) comments on technical aspects of care, including perceived errors and inattention to pain control (9/37, 24.3%); and 4.) comments describing the hospital physical plant, parking, and amenities (9/37, 24.3%). A small number (n=3) of patients repeatedly responded, accounting for 30% (45/148) of narratives. While patient feedback on social media could help to drive hospital QI efforts, any potential benefits must be weighed against the reputational risks, the lack of representativeness among respondents, and the volume of responses needed to identify areas of improvement.
PMCID: PMC4926770  PMID: 26390277
Social media; quality improvement; patient experience; qualitative research
21.  Specificity protein 4 (Sp4) transcriptionally regulates inhibitory GABAergic receptors in neurons 
Biochimica et biophysica acta  2015;1863(1):1-9.
Previous studies in our laboratory have shown that the neuron-specific specificity protein 4 (Sp4) transcriptionally regulates many excitatory neurotransmitter receptor subunit genes, such as those for GluN1, GluN2A, and GluN2B of N-methyl-D-aspartate (NMDA) receptors and Gria2 of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. It also regulates Atp1a1 and Atp1b1 subunit genes of Na+/K+-ATPase, a major energy-consuming enzyme, as well as all 13 subunits of cytochrome c oxidase (COX), an important energy-generating enzyme. Thus, there is a tight coupling between energy consumption, energy production, and excitatory neuronal activity at the transcriptional level in neurons. The question is whether inhibitory neurotransmitter receptors are also regulated by Sp4. In the present study, we tested our hypothesis that Sp4 regulates receptor subunit genes of a major inhibitory neurotransmitter, GABA, specifically GABAA receptors. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, real-time quantitative PCR, chromatin immunoprecipitation, promoter mutational analysis, over-expression and shRNA of Sp4, functional assays, and western blots, we found that Sp4 functionally regulates the transcription of Gabra1 (GABAA-α1) and Gabra2 (GABAA-α2), but not Gabra3 (GABAA-α3) subunit genes. The binding sites of Sp4 are conserved among rats, humans, and mice. Thus, our results substantiate our hypothesis that Sp4 plays a key role in regulating the transcription of GABAA receptor subunit genes. They also indicate that Sp4 is in a position to transcriptionally regulate the balance between excitatory and inhibitory neurochemical expressions in neurons.
PMCID: PMC4658289  PMID: 26469128
Gene regulation; Sp4; GABAA receptors; Gabra1; Gabra2; Gabra3
22.  History and Genomic Sequence Analysis of the Herpes Simplex Virus 1 KOS and KOS1.1 Sub-Strains 
Virology  2015;487:215-221.
A collection of genomic DNA sequences of herpes simplex virus (HSV) strains has been defined and analyzed, and some information is available about genomic stability upon limited passage of viruses in culture. The nature of genomic change upon extensive laboratory passage remains to be determined. In this report we review the history of the HSV-1 KOS laboratory strain and the related KOS1.1 laboratory sub-strain, also called KOS (M), and determine the complete genomic sequence of an early passage stock of the KOS laboratory sub-strain and a laboratory stock of the KOS1.1 sub-strain. The genomes of the two sub-strains are highly similar with only five coding changes, 20 non-coding changes, and about twenty non-ORF sequence changes. The coding changes could potentially explain the KOS1.1 phenotypic properties of increased replication at high temperature and reduced neuroinvasiveness. The study also provides sequence markers to define the provenance of specific laboratory KOS virus stocks.
PMCID: PMC4679709  PMID: 26547038
23.  Correlates of Segmental Pulse Wave Velocity in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study 
American Journal of Hypertension  2015;29(1):114-122.
Carotid-femoral PWV (cfPWV) is a well-established measure of central arterial stiffness, while brachial-ankle PWV (baPWV) is being used more frequently in East Asian countries. Few studies have simultaneously characterized the distributions and correlates of segment-specific PWV measures and their associations with cardiovascular risk factors.
We evaluated segment-specific PWV (cfPWV, baPWV, and femoral-ankle (faPWV)) in 4,974 older-aged African American and Caucasian adults in the community-based Atherosclerosis Risk in Communities (ARIC) Study using a standardized protocol and the OMRON VP-1000 Plus system. We examined the distribution and multivariable-adjusted correlates of PWV measures by race and sex.
Mean age ranged from 74±5 to 76±5 years across race–sex groups. In all race–sex groups, cfPWV correlated with baPWV but not with faPWV, and cfPWV and baPWV were higher with age, whereas faPWV was not. Heart rate and systolic blood pressure (SBP) were positively associated and weight was negatively associated with all PWV measures; however, the associations with age, glycated hemoglobin, triglycerides, and high-density lipoprotein (HDL) cholesterol varied by segment and race–sex group.
Our findings indicate that cfPWV and faPWV reflect distinct aspects of segment-specific vascular stiffness and their associated profile of cardiovascular risk factors. Even among older adults, age is associated with higher cfPWV and baPWV, but not with faPWV. Understanding factors that ostensibly play a role in increasing arterial stiffness in different arterial territories can inform opportunities for cardiovascular disease (CVD) prevention and risk management.
PMCID: PMC4692984  PMID: 26045531
arterial stiffness; arteriosclerosis; atherosclerosis; blood pressure; cardiovascular disease risk factors; elastic artery; epidemiology; hypertension; muscular artery; subclinical cardiovascular disease; vascular stiffness.
24.  Dialysis-Requiring Acute Kidney Injury among Hospitalized Adults with Documented Hepatitis C Virus Infection: A Nationwide Inpatient Sample Analysis 
Journal of viral hepatitis  2015;23(1):32-38.
Chronic Hepatitis C virus (HCV) infection may cause kidney injury, particularly in the setting of cryoglobulinemia or cirrhosis; however, few studies have evaluated the epidemiology of acute kidney injury in patients with HCV. We aimed to describe national temporal trends of incidence and impact of severe AKI requiring renal replacement (“dialysis-requiring AKI”) in hospitalized adults with HCV. We extracted our study cohort from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using data from 2004–2012. We defined HCV and dialysis-requiring acute kidney injury based on previously validated ICD-9-CM codes. We analyzed temporal changes in the proportion of hospitalizations complicated by dialysis-requiring AKI and utilized survey multivariable logistic regression models to estimate its impact on in-hospital mortality. We identified a total of 4,603,718 adult hospitalizations with an associated diagnosis of HCV from 2004–2012, of which 51,434 (1.12%) were complicated by dialysis-requiring acute kidney injury. The proportion of hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly from 0.86% in 2004 to 1.28% in 2012. In-hospital mortality was significantly higher in hospitalizations complicated by dialysis-requiring acute kidney injury vs. those without (27.38% vs. 2.95%; adjusted odds ratio 2.09, 95% Confidence Interval 1.74–2.51). The proportion of HCV hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly between 2004–2012. Similar to observations in the general population, dialysis-requiring acute kidney injury was associated with a two-fold increase in odds of in-hospital mortality in adults with HCV. These results highlight the burden of acute kidney injury in hospitalized adults with HCV infection.
PMCID: PMC4695275  PMID: 26189719
acute kidney injury; dialysis; mortality; hepatitis C
25.  Multivariate statistical analysis and optimization of ultrasound-assisted extraction of natural pigments from waste red beet stalks 
In this study, ultrasound-assisted extraction (UAE) of natural pigment extraction from waste red beet stalks were optimized under four factors (extraction temperature, ultrasonic power, extraction time and solid–liquid ratio) by using three level Box-Behnken response surface design. Extraction temperature, ultrasonic power and solid–liquid ratio were significantly influenced the extraction yield of pigments. Extraction temperature of 53 °C, ultrasonic power of 89 w, extraction time of 35 min and SL ratio of 1:19 g/ml was identified as the optimal condition. Under this condition, the actual yield of (betacyanin of 1.28 ± 0.02 and betaxanthin of 5.31 ± 0.09 mg/g) pigments was well correlated with predicted values (betacyanin was 1.29 mg/g and betaxanthin was 5.32 mg/g).
PMCID: PMC4711424  PMID: 26788000
Natural pigment; Extraction; Box-Behnken design; Optimization

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