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1.  Treatment Goals of Depressed Outpatients: A Qualitative Investigation of Goals Identified by Participants in a Depression Treatment Trial 
Journal of psychiatric practice  2010;16(6):425-430.
Treatment goals and preferences of depressed patients are important, but they are rarely empirically studied. Although clinicians are likely to discuss goals with individual patients, research that clarifies overall patterns in the treatment goals of depressed patients could be useful in informing new interventions for depression. Such research could also potentially help address problems such as poor adherence and psychotherapy drop-out. In this preliminary qualitative investigation, we examined treatment goals established by depressed outpatients in the context of a trial of behaviorally oriented psychotherapy. The treatment goals that were most commonly articulated included improving social and family relationships, increasing physical health behaviors, finding a job, and organizing one’s home. These results underscore the fact that, in addition to improvement in the symptoms of depression, functional improvements are viewed as key treatment goals by depressed individuals.
PMCID: PMC4070877  PMID: 21107149
depression; treatment; goals; psychotherapy
2.  Therapeutic Potential of Thiazolidinedione-8 as an Antibiofilm Agent against Candida albicans 
PLoS ONE  2014;9(5):e93225.
Candida albicans is known as a commensal microorganism but it is also the most common fungal pathogen in humans, causing both mucosal and systemic infections. Biofilm-associated C. albicans infections present clinically important features due to their high levels of resistance to traditional antifungal agents. Quorum sensing is closely associated with biofilm formation and increasing fungal pathogenicity. We investigated the ability of the novel bacterial quorum sensing quencher thiazolidinedione-8 (S-8) to inhibit the formation of, and eradication of mature C. albicans biofilms. In addition, the capability of S-8 to alter fungal adhesion to mammalian cells was checked. S-8 exhibited specific antibiofilm and antiadhesion activities against C. albicans, at four- to eightfold lower concentrations than the minimum inhibitory concentration (MIC). Using fluorescence microscopy, we observed that S-8 dose-dependently reduces C. albicans–GFP binding to RAW macrophages. S-8 at sub-MICs also interfered with fungal morphogenesis by inhibiting the yeast-to-hyphal form transition. In addition, the tested agent strongly affected fungal cell wall characteristics by modulating its hydrophobicity. We evaluated the molecular mode of S-8 antibiofilm and antiadhesion activities using real-time RT-PCR. The expression levels of genes associated with biofilm formation, adhesion and filamentation, HWP1, ALS3 and EAP1, respectively, were dose-dependently downregulated by S-8. Transcript levels of UME6, responsible for long-term hyphal maintenance, were also significantly decreased by the tested agent. Both signaling pathways of hyphal formation-cAMP-PKA and MAPK-were interrupted by S-8. Their upstream general regulator RAS1 was markedly suppressed by S-8. In addition, the expression levels of MAPK cascade components CST20, HST7 and CPH1 were downregulated by S-8. Finally, transcriptional repressors of filament formation, TUP1 and NRG1, were dramatically upregulated by our compound. Our results indicate that S-8 holds a novel antibiofilm therapeutic mean in the treatment and prevention of biofilm-associated C. albicans infections.
PMCID: PMC4010395  PMID: 24796422
3.  Kenya’s emergency-hire nursing programme: a pilot evaluation of health service delivery in two districts 
To assess the feasibility of utilizing a small-scale, low-cost, pilot evaluation in assessing the short-term impact of Kenya’s emergency-hire nursing programme (EHP) on the delivery of health services (outpatient visits and maternal-child health indicators) in two underserved health districts with high HIV/AIDS prevalence.
Six primary outcomes were assessed through the collection of data from facility-level health management forms—total general outpatient visits, vaginal deliveries, caesarean sections, antenatal care (ANC) attendance, ANC clients tested for HIV, and deliveries to HIV-positive women. Data on outcome measures were assessed both pre-and post-emergency-hire nurse placement. Informal discussions were also conducted to obtain supporting qualitative data.
The majority of EHP nurses were placed in Suba (15.5%) and Siaya (13%) districts. At the time of the intervention, we describe an increase in total general outpatient visits, vaginal deliveries and caesarean sections within both districts. Similar significant increases were seen with ANC attendance and deliveries to HIV-positive women. Despite increases in the quantity of health services immediately following nurse placement, these levels were often not sustained. We identify several factors that challenge the long-term sustainability of these staffing enhancements.
There are multiple factors beyond increasing the supply of nurses that affect the delivery of health services. We believe this pilot evaluation sets the foundation for future, larger and more comprehensive studies further elaborating on the interface between interventions to alleviate nursing shortages and promote enhanced health service delivery. We also stress the importance of strong national and local relationships in conducting future studies.
PMCID: PMC4003900  PMID: 24636052
Emergency-hire programme; Human resources for health; Human resource information systems; Health management information systems; Kenya; Nursing; Primary care
Journal of Cellular Physiology  2012;227(6):2677-2685.
The transcription factor Osterix (Sp7) is essential for osteoblastogenesis and bone formation in mice. Genome wide association studies have demonstrated that Osterix is associated with bone mineral density in humans; however, the molecular significance of Osterix in human osteoblast differentiation is poorly described. In this study we have characterized the role of Osterix in human mesenchymal progenitor cell (hMSC) differentiation. We first analyzed temporal microarray data of primary hMSC treated with bone morphogenetic protein-6 (BMP6) using clustering to identify genes that are associated with Osterix expression. Osterix clusters with a set of osteoblast-associated extracellular matrix (ECM) genes, including bone sialoprotein (BSP) and a novel set of proteoglycans, osteomodulin (OMD), osteoglycin, and asporin. Maximum expression of these genes is dependent upon both the concentration and duration of BMP6 exposure. Next we overexpressed and repressed Osterix in primary hMSC using retrovirus. The enforced expression of Osterix had relatively minor effects on osteoblastic gene expression independent of exogenous BMP6. However, in the presence of BMP6, Osterix overexpression enhanced expression of the aforementioned ECM genes. Additionally, Osterix overexpression enhanced BMP6 induced osteoblast mineralization, while inhibiting hMSC proliferation. Conversely, Osterix knockdown maintained hMSC in an immature state by decreasing expression of these ECM genes and decreasing mineralization and hMSC proliferation. Overexpression of the Osterix regulated gene OMD with retrovirus promoted mineralization of hMSC. These results suggest that Osterix is necessary, but not sufficient for hMSC osteoblast differentiation. Osterix regulates the expression of a set of ECM proteins which are involved in terminal osteoblast differentiation.
PMCID: PMC3241898  PMID: 21898406
bone morphogenetic protein-6; osteoblast; human; Osterix; osteomodulin
5.  Information systems on human resources for health: a global review 
Although attainment of the health-related Millennium Development Goals relies on countries having adequate numbers of human resources for health (HRH) and their appropriate distribution, global understanding of the systems used to generate information for monitoring HRH stock and flows, known as human resources information systems (HRIS), is minimal. While HRIS are increasingly recognized as integral to health system performance assessment, baseline information regarding their scope and capability around the world has been limited. We conducted a review of the available literature on HRIS implementation processes in order to draw this baseline.
Our systematic search initially retrieved 11 923 articles in four languages published in peer-reviewed and grey literature. Following the selection of those articles which detailed HRIS implementation processes, reviews of their contents were conducted using two-person teams, each assigned to a national system. A data abstraction tool was developed and used to facilitate objective assessment.
Ninety-five articles with relevant HRIS information were reviewed, mostly from the grey literature, which comprised 84 % of all documents. The articles represented 63 national HRIS and two regionally integrated systems. Whereas a high percentage of countries reported the capability to generate workforce supply and deployment data, few systems were documented as being used for HRH planning and decision-making. Of the systems examined, only 23 % explicitly stated they collect data on workforce attrition. The majority of countries experiencing crisis levels of HRH shortages (56 %) did not report data on health worker qualifications or professional credentialing as part of their HRIS.
Although HRIS are critical for evidence-based human resource policy and practice, there is a dearth of information about these systems, including their current capabilities. The absence of standardized HRIS profiles (including documented processes for data collection, management, and use) limits understanding of the availability and quality of information that can be used to support effective and efficient HRH strategies and investments at the national, regional, and global levels.
PMCID: PMC3433380  PMID: 22546089
Human resources information system; HRIS; Human resources for health; Literature review; Workforce surveillance; Workforce science; Global health
6.  Effects of Cholinesterase Inhibitors on Visual Attention in Drivers with Alzheimer’s Disease 
We conducted a combined observational cohort and case-control study in patients with Alzheimer’s disease (AD) to assess the effects of acetylcholinesterase inhibitor (ChEI) treatment on cognitive functions important for driving.
Performance of twenty-four outpatients with newly diagnosed (untreated) early stage AD was compared prior to beginning ChEI (Pre-ChEI) and after 3 months of therapy (Post-ChEI) on a set of computerized tests of visual attention and executive function administered under both single-task and dual-task conditions. In order to address the limitation of a lack of an untreated control group in this observational cohort study, performance of thirty-five outpatients with newly diagnosed (untreated) early stage AD (ChEI Non-Users) were also compared to a demographically-matched group of AD patients treated with stable doses of a ChEI (ChEI Users) on these tasks.
Performance was consistently worse under dual-task than single-task conditions regardless of ChEI treatment status. However, ChEI treatment consistently affected specific components of attention within each test across both sets of comparisons: ChEI treatment enhanced simulated driving accuracy, and was associated with significantly better visual search target detection accuracy and response time in both Pre/Post ChEI and Users/Non-Users treatment comparisons. ChEI treatment also improved overall time to complete a set of mazes while not affecting accuracy of completion.
ChEI treatment was associated with improvements in tests of executive function and visual attention. These findings could have important implications for patients who continue to drive in the early stages of AD.
PMCID: PMC3289132  PMID: 20473058
All cognitive disorders/dementia; Alzheimer’s disease; Cholinesterase inhibitors; Attention; Driving
7.  Disruption of cell-matrix interactions by heparin enhances mesenchymal progenitor adipocyte differentiation 
Experimental cell research  2008;314(18):3382-3391.
Differentiation of marrow-derived mesenchymal progenitors to either the osteoblast or adipocyte lineage is reciprocally regulated. Factors that promote osteoblastogenesis inhibit adipogenesis, while adipogenic factors are inhibitory to osteoblast differentiation. Heparin, a soluble glycosaminoglycan, inhibits bone formation in vivo and osteoblast cell differentiation and function in vitro, and has been shown to promote adipocyte differentiation. To elucidate the role that heparin plays in the adipogenic induction of murine mesenchymal progenitors, we studied immortalized marrow stromal cells (IM-MSC), the MSC cell line, ST2, and 3T3L1 pre-adipocytes. Heparin alone was not sufficient to induce adipogenesis, but enhanced the induction under a variety of adipogenic cocktails. This effect was both dose- and time-dependent. Heparin showed a positive effect at concentrations > 0.1 μg/ml when applied before day 3 during the induction course. Heparin’s effect on adipogenesis was independent of cell proliferation, cell density, and extracellular lipid. This effect is likely related to the unique structure of heparin because another polyanionic glycosaminoglycan, dextran sulfate, did not promote adipogenic differentiation. Heparin treatment altered morphology and adhesion characteristics of progenitor cells, resulting in cell rounding and aggregation. As well, heparin counteracted the known inhibitory effect of fibronectin on adipogenesis and decreased basal focal adhesion kinase and paxillin phosphorylation. We conclude that heparin-mediated disruption of cell-matrix adhesion enhances adipogenic potential.
PMCID: PMC3179914  PMID: 18674534
8.  Time series gene expression profiling and temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization 
BMC Systems Biology  2011;5:82.
BMP6 mediated osteoblast differentiation plays a key role in skeletal development and bone disease. Unfortunately, the signaling pathways regulated by BMP6 are largely uncharacterized due to both a lack of data and the complexity of the response.
To better characterize the signaling pathways responsive to BMP6, we conducted a time series microarray study to track BMP6 induced osteoblast differentiation and mineralization. These temporal data were analyzed using a customized gene set analysis approach to identify temporally coherent sets of genes that act downstream of BMP6. Our analysis identified BMP6 regulation of previously reported pathways, such as the TGF-beta pathway. We also identified previously unknown connections between BMP6 and pathways such as Notch signaling and the MYB and BAF57 regulatory modules. In addition, we identify a super-network of pathways that are sequentially activated following BMP6 induction.
In this work, we carried out a microarray-based temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization using GAGE method. This novel temporal analysis is more informative and powerful than the classical static pathway analysis in that: (1) it captures the interconnections between signaling pathways or functional modules and demonstrates the even higher level organization of molecular biological systems; (2) it describes the temporal perturbation patterns of each pathway or module and their dynamic roles in osteoblast differentiation. The same set of experimental and computational strategies employed in our work could be useful for studying other complex biological processes.
PMCID: PMC3126716  PMID: 21605425
9.  High Occurrence of Mood and Anxiety Disorders among Older Adults: The National Comorbidity Survey Replication 
Archives of general psychiatry  2010;67(5):489-496.
Little is known about prevalence rates of DSM-IV disorders across age strata of older adults, including common conditions such as individual and coexisting mood and anxiety disorders.
To determine nationally representative estimates of 12-month prevalence rates of mood, anxiety, and comorbid mood-anxiety disorder across young-old, mid-old, old-old, and oldest old community-dwelling adults.
Design and Setting
The National Comorbidity Survey Replication (NCS-R) is a population-based probability sample of 9282 participants 18 years and older, conducted between February 2001 and April 2003. The NCS-R survey used the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview.
We studied the 2575 participants 55 years and older who were part of NCS-R (43% 55-64; 32% 65-74; 20% 75-84; 5% ≥85 years). This included only non-institutionalized adults, as all NCS-R participants resided in households within the community.
Main Outcome Measures
Twelve-month prevalence of mood disorders (MDD, dysthymia, bipolar disorder), anxiety disorders (panic disorder, agoraphobia, specific phobia, social phobia, generalized anxiety disorder, posttraumatic stress disorder), and coexisting mood-anxiety disorder were assessed using DSM-IV criteria. Prevalence rates were weighted to adjust for the complex design in order to infer generalizability to the U.S. population.
The likelihood of having a mood, anxiety, or combined mood-anxiety disorder generally showed a pattern of decline with age (P < .05). Twelve-month disorders showed higher rates in women compared to men; a statistically significant trend with age. In addition, anxiety disorders were as high if not higher than mood disorders across age groups (overall 12-month rates: mood=5% and anxiety=12%). No differences were found between race/ethnicity groups.
Prevalence rates of DSM-IV mood and anxiety disorders in late life tend to decline with age, but remain very common; especially in women. These results highlight the need for intervention and prevention strategies.
PMCID: PMC2933177  PMID: 20439830
10.  Perceived Interpersonal Mistreatment Among Obese Americans: Do Race, Class, and Gender Matter? 
Obesity (Silver Spring, Md.)  2008;16(Suppl 2):S60-S68.
We examine the extent to which body weight affects three types of perceived interpersonal mistreatment, and evaluate whether these patterns vary by race, social class, and gender in a large sample of American men and women.
Methods and Procedures:
We use data from the first wave (1995) of the Midlife Development in the United States (N = 3,511), a survey of persons aged 25–74, to contrast underweight, normal weight, overweight, obese I, and obese II/III persons' reports of three types of perceived interpersonal mistreatment: disrespectful treatment; harassment/teasing; and being treated as if one has a character flaw. We assess whether these relationships are contingent upon one's gender, race, and occupational status. We control for possible confounding influences, including physical and mental health.
In the total sample, obese I and obese II/III persons report significantly higher levels of all three types of perceived mistreatment (compared to normal weight persons), even when demographic, socioeconomic status, and health characteristics are controlled. Among black men, however, obese II/III persons report significantly lower levels of all three types of perceived mistreatment, compared to their normal weight peers. Among both men and women, obese professional workers report significantly more perceived interpersonal mistreatment, compared to obese persons of lower socioeconomic status.
These findings reveal the ways that intersecting social identities may shape obese Americans' perceptions of stigmatizing interpersonal encounters.
PMCID: PMC2852250  PMID: 18978765
11.  Integrating Co-Morbid Depression and Chronic Physical Disease Management: Identifying and Resolving Failures in Self-Regulation 
Clinical psychology review  2008;28(8):1426-1446.
Research suggests that treatments for depression among individuals with chronic physical disease do not improve disease outcomes significantly, and chronic disease management programs do not necessarily improve mood. For individuals experiencing co-morbid depression and chronic physical disease, demands on the self-regulation system are compounded, leading to a rapid depletion of self-regulatory resources. Because disease and depression management are not integrated, patients lack the understanding needed to prioritize self-regulatory goals in a way that makes disease and depression management synergistic. A framework in which the management of co-morbidity is considered alongside the management of either condition alone offers benefits to researchers and practitioners and may help improve clinical outcomes.
PMCID: PMC2669084  PMID: 18848740
12.  GAGE: generally applicable gene set enrichment for pathway analysis 
BMC Bioinformatics  2009;10:161.
Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs.
To address these limitations, we present a new GSA method called Generally Applicable Gene-set Enrichment (GAGE). We successfully apply GAGE to multiple microarray datasets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better results when compared to two other commonly used GSA methods of GSEA and PAGE. We demonstrate this improvement in the following three aspects: (1) consistency across repeated studies/experiments; (2) sensitivity and specificity; (3) biological relevance of the regulatory mechanisms inferred.
GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies. From two published lung cancer data sets, GAGE derived a more cohesive and predictive mechanistic scheme underlying lung cancer progress and metastasis. For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT signaling, Wnt signaling, and estrogen signaling pathways–all of which are supported by the experimental literature.
GAGE is generally applicable to gene expression datasets with different sample sizes and experimental designs. GAGE consistently outperformed two most frequently used GSA methods and inferred statistically and biologically more relevant regulatory pathways. The GAGE method is implemented in R in the "gage" package, available under the GNU GPL from .
PMCID: PMC2696452  PMID: 19473525
13.  Resistance of Porphyromonas gingivalis ATCC 33277 to Direct Killing by Antimicrobial Peptides Is Protease Independent▿  
Antimicrobial peptides are short, positively charged, amphipathic peptides that possess a wide spectrum of antimicrobial activity and have an important role in the host's innate immunity. Lack of, or dysfunctions in, antimicrobial peptides have been correlated with infectious diseases, including periodontitis. Porphyromonas gingivalis, a gram-negative anaerobe and a major pathogen associated with periodontal diseases, is resistant to antimicrobial peptides of human and nonhuman origin, a feature that likely contributes to its virulence. Expressing a robust proteolytic activity, P. gingivalis hydrolyzes antimicrobial peptides. In this study, P. gingivalis inactivated three antimicrobial peptides, while a d-enantiomer was resistant to degradation. P. gingivalis was resistant to the protease-resistant d-enantiomer peptide, and importantly, a protease-deficient P. gingivalis mutant was also resistant to the antimicrobial peptide. Finally, the binding of a fluorescently labeled antimicrobial peptide to protease-deficient P. gingivalis was much weaker than the binding of susceptible Escherichia coli. Our results suggest that the resistance of P. gingivalis ATCC 33277 to direct killing by antimicrobial peptides is protease independent and results (at least partially) from the low affinity of antimicrobial peptides to P. gingivalis.
PMCID: PMC2224744  PMID: 18086848
14.  Empirical Comparison of Tests for Differential Expression on Simulated Time Series Microarray Experiments 
Methods for identifying differential expression were compared on time series microarray data from artificial gene networks. Identifying differential expression was dependent on normalization and whether the background was removed. Loess after background correction improved results for most methods. On data without background correction median centering improved performance. We recommend Cui and Churchill’s ANOVA variants on background subtracted data and Efron and Tibshirani’s Empirical Bayes Wilcoxon Rank Sum test when the background cannot be removed.
PMCID: PMC1839752  PMID: 17238540
15.  Highly efficient genetic transduction of primary human synoviocytes with concentrated retroviral supernatant 
Arthritis Research  2002;4(3):215-219.
We are developing retroviral-mediated gene transfer to human fibroblast-like synovial cells (FLS) as one approach to characterizing genetic pathways involved in synoviocyte pathophysiology. Prior work has suggested that FLS are relatively refractory to infection by Moloney murine leukemia virus based vectors. To determine if viral titer influenced the transduction efficiency of FLS, we optimized a rapid, efficient, and inexpensive centrifugation method to concentrate recombinant retroviral supernatant. The technique was evaluated by measurement of the expression of a viral enhanced green fluorescent protein transgene in transduced cells, and by analysis of viral RNA in retroviral supernatant. Concentration (100-fold) was achieved by centrifugation of viral supernatant for four hours, with 100% recovery of viral particles. The transduction of FLS increased from approximately 15% with unconcentrated supernatant, to nearly 50% using concentrated supernatant. This protocol will be useful for investigators with applications that require efficient, stable, high level transgene expression in primary FLS.
PMCID: PMC111025  PMID: 12010573
enhanced green fluorescent protein; fibroblast-like synovial cell; gene therapy; retrovirus; titer
16.  Biochemical Consequences of Type 2 Adenovirus and Simian Virus 40 Double Infections of African Green Monkey Kidney Cells 
Journal of Virology  1970;5(5):586-597.
African green monkey kidney (AGMK) cells were nonpermissive hosts for type 2 adenovirus although the restriction was not complete; when only 3 plaque-forming units/cell was employed as the inoculum, the viral yield was about 0.1% of the maximum virus produced when simian virus 40 (SV40) enhanced adenovirus multiplication. The viral yield of cells infected only with type 2 adenovirus increased as the multiplicity of infection was increased. Type 2 adenovirus could infect almost all AGMK cells in culture; adenovirus-specific early proteins and DNA were synthesized in most cells, but small amounts of late proteins were made in relatively few cells. Even when cells were infected with both SV40 and adenovirus, only about 50% were permissive for synthesis of adenovirus capsid proteins. Approximately the same quantity of adenovirus deoxyribonucleic acid (DNA) was synthesized in the restricted as in the SV40-enhanced infection. However, in cells infected with SV40 and type 2 adenovirus, replication of SV40 DNA was blocked, multiplication of SV40 was accordingly inhibited, and synthesis of host DNA was not stimulated. To enhance propagation of type 2 adenovirus, synthesis of an early SV40 protein was essential; 50 μg of cycloheximide per ml prevented the SV40-induced enhancement of adenovirus multiplication, whereas 5 × 10−6m 5-fluoro-2-deoxyuridine did not abrogate the enhancing phenomenon.
PMCID: PMC376044  PMID: 4315958

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