UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.... more UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.8; 95% CI, 0.7-0.9), history of vaginal discharge (LR, 0.3; 95% CI, 0.1- 0.9), history of vaginal irritation (LR, 0.2; 95% CI, 0.1-0.9), and vaginal discharge on examination (LR, 0.7; 95% CI, 0.5-0.9). Of all individual diagnostic signs and symp- toms, the 2 most
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010
Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse ... more Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted ...
The use of dietary supplements for treating a wide range of health conditions has grown rapidly i... more The use of dietary supplements for treating a wide range of health conditions has grown rapidly in the United States. In the field of men's health, the most common dietary supplement used is an extract of the berry of the saw palmetto plant, with which men commonly self-medicate in order to treat lower urinary tract symptoms. Throughout the past two decades, substantial literature has emerged examining the biologic and clinical effects of saw palmetto extracts. Several lines of evidence suggest that saw palmetto may exert physiologic effects consistent with a beneficial clinical effect on the mechanisms of benign prostatic hyperplasia. Although most clinical studies tend to suggest a modest efficacy benefit of saw palmetto, more recent studies are less consistent and the precise clinical value of saw palmetto for treating lower urinary tract symptoms remains undefined. Overall, there appear to be few safety concerns with short-term use of this herbal medicine, although large-sca...
Systematic review is a type of research that attempts to identify and summarize all of the eviden... more Systematic review is a type of research that attempts to identify and summarize all of the evidence related to a specific research question. It can be thought of as a "pause" in the process of conducting research in a particular area, in which the following questions are asked: Based on all of the available evidence, what do we know about this specific question so far, and what future studies should be conducted to clarify areas of uncertainty? The systematic review arose as an alternative to the traditional narrative review-which allows authors to pick and choose the studies they discuss and the depth at which they discuss them-a process prone to bias. By adhering to a prospectively defined protocol that specifies how studies should be identified, evaluated, and statistically combined (the statistical process is a component of systematic review and is called "meta-analysis"), systematic reviews reduce the bias inherent to traditional narrative reviews. Systemati...
Proceedings. IEEE Computer Society Bioinformatics Conference, 2002
Analyses of microbial community structure based on terminal restriction fragment length polymorph... more Analyses of microbial community structure based on terminal restriction fragment length polymorphisms (T-RFLP) of 16S rRNA genes are hindered by the lack of computational tools needed to aid experimental design, and to archive and analyze large data sets. The aim of this research was to develop a suite of Web-based tools that would enable researchers to perform several tasks, including:
The herbal extracts kava and valerian are the leading dietary supplements used in the self-manage... more The herbal extracts kava and valerian are the leading dietary supplements used in the self-management of anxiety and insomnia, respectively. There is limited evidence to support their effectiveness for these common symptoms. The Internet has been used to a limited extent for research, but it is not known whether randomized controlled trials can be conducted entirely using Internet technology. We performed a randomized, double-blind, placebo-controlled trial using a novel Internet-based design to determine if kava is effective for reducing anxiety and if valerian is effective for improving sleep quality. E-mail recruitment letters and banner advertisements on websites were used to recruit a large pool of interested participants (1551) from 45 states over an 8-week period. Participants were first asked to read study information, complete an online informed consent process, and undergo electronic identity verification. In order to be eligible for the study, participants were required to have 1) anxiety as documented by scores of at least 0.5 standard deviations above the mean on the State-Trait Anxiety Inventory State subtest (STAI-State) on 2 separate occasions, and 2) insomnia, defined as a "problem getting to sleep or staying asleep over the past 2 weeks." We randomly assigned 391 eligible participants to 1 of the following 3 groups, and mailed 28 days' supply: kava with valerian placebo (n = 121), valerian with kava placebo (n = 135), or double placebo (n = 135). The primary outcome measures were changes from baseline in anxiety (STAI-State questionnaire) and insomnia (Insomnia Severity Index [ISI]) compared with placebo. Participants receiving placebo had a 14.4 point decrease in anxiety symptoms on the STAI-State score and an 8.3 point decrease in insomnia symptoms on the ISI. Those receiving kava had similar reductions in STAI-State score (2.7 point greater reduction in placebo compared with kava; 95% confidence interval [CI], -0.8 to +6.2). Those receiving valerian and placebo had similar improvements in sleep (0.4 point greater reduction in the placebo than the valerian group; 95% CI, -1.3 to +2.1). Results were similar when limited to the 83% of participants who adhered to study compounds for all 4 weeks. Neither kava nor valerian relieved anxiety or insomnia more than placebo. This trial demonstrates the feasibility of conducting randomized, blinded trials entirely via the Internet.
Journal of the American Academy of Child & Adolescent Psychiatry, 2014
Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with ... more Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.
This study evaluated chondrogenesis of mesenchymal progenitor stem cells (MSCs) cultured initiall... more This study evaluated chondrogenesis of mesenchymal progenitor stem cells (MSCs) cultured initially under pre-confluent monolayer conditions exposed to transforming growth factor-beta1 (TGF-beta1), and subsequently in three-dimensional cultures containing insulin-like growth factor I (IGF-I). Bone marrow aspirates and chondrocytes were obtained from horses and cultured in monolayer with 0 or 5 ng of TGF-beta 1 per ml of medium for 6 days. TGF-beta 1 treated and untreated cultures were distributed to three-dimensional fibrin disks containing 0 or 100 ng of IGF-I per ml of medium to establish four treatment groups. After 13 days, cultures were assessed by toluidine blue staining, collagen types I and II in situ hybridization and immunohistochemistry, proteoglycan production by [35S]-sulfate incorporation, and disk DNA content by fluorometry. Mesenchymal cells in monolayer cultures treated with TGF-beta1 actively proliferated for the first 4 days, developed cellular rounding, and formed cell clusters. Treated MSC cultures had a two-fold increase in medium proteoglycan content. Pretreatment of MSCs with TGF-beta1 followed by exposure of cells to IGF-I in three-dimensional culture significantly increased the formation of markers of chondrocytic function including disk proteoglycan content and procollagen type II mRNA production. However, proteoglycan and procollagen type II production by MSC's remained lower than parallel chondrocyte cultures. MSC pretreatment with TGF-beta1 without sequential IGF-I was less effective in initiating expression of markers of chondrogenesis. This study indicates that although MSC differentiation was less than complete when compared to mature chondrocytes, chondrogenesis was observed in IGF-I supplemented cultures, particularly when used in concert with TGF-beta1 pretreatment.
The feasibility of articular gene therapy using insulin-like growth factor-I transgene expression... more The feasibility of articular gene therapy using insulin-like growth factor-I transgene expression in synovial tissues was assessed in vitro by transfection of synovial explant and monolayer cultures. Synovial membrane was harvested from horses and distributed for explant culture in multiwell plates or digested for monolayer culture in multiwell plates and chamber slides. Synovial monolayers were cultured for 48 h after infection with 0, 100, 200, or 500 moi adenovirus-IGF-I (AdeIGF-I) to establish an optimum dose. Explants were then either infected with AdeIGF-I or adenoviral LacZ and cultured for 8 days, treated with 100 ng/ml recombinant IGF-I as a positive control, or remained as uninfected untreated culture controls. Expression of IGF-I in explants and monolayers was assessed by in situ hybridization and quantitative polymerase chain reaction (PCR), and translation confirmed by IGF-I radioimmunoassay (RIA) and tissue immunoreaction. Effects of IGF-I on synovial function was assessed by proteoglycan and hyaluronan assay, and northern blot assessment of decorin and collagen type I expression. Significant transgene expression in synovial cells was present for all AdeIGF-I concentrations. Similarly, medium IGF-I concentrations were significantly elevated in AdeIGF-I infected synovial monolayer and explant cultures at all time points. Peak IGF-I concentration of 246 +/- 43 ng/ml developed in explant cultures on day 4; IGF-I levels in control explant groups were unchanged over baseline values. In situ hybridization and immunolocalization for IGF-I indicated focal IGF-I expression in intimal and subintimal layers of infected explants, with diffuse immunoreaction throughout infected subintimal and fibrous layers. For monolayer cultures, intracellular immunoreaction to IGF-I was markedly higher in infected cells, and was most prominent at 100 moi. Effects of IGF-I on synoviocyte cultures were evident on northern blots, which showed decreased decorin expression and elevated type I collagen production in AdeIGF-I infected monolayers. Proteoglycan concentration in the medium from explant cultures rose over the initial 4 days but was similar between treatment groups. The concentration of hyaluronan in medium from explant cultures did not differ significantly within or between treated and control groups during the 8-day study period. These data indicate that IGF-I can be successfully introduced to synovial structures by adenoviral vectors and results in effective IGF-I ligand synthesis without untoward synovial morphologic effects.
UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.... more UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.8; 95% CI, 0.7-0.9), history of vaginal discharge (LR, 0.3; 95% CI, 0.1- 0.9), history of vaginal irritation (LR, 0.2; 95% CI, 0.1-0.9), and vaginal discharge on examination (LR, 0.7; 95% CI, 0.5-0.9). Of all individual diagnostic signs and symp- toms, the 2 most
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010
Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse ... more Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted ...
The use of dietary supplements for treating a wide range of health conditions has grown rapidly i... more The use of dietary supplements for treating a wide range of health conditions has grown rapidly in the United States. In the field of men's health, the most common dietary supplement used is an extract of the berry of the saw palmetto plant, with which men commonly self-medicate in order to treat lower urinary tract symptoms. Throughout the past two decades, substantial literature has emerged examining the biologic and clinical effects of saw palmetto extracts. Several lines of evidence suggest that saw palmetto may exert physiologic effects consistent with a beneficial clinical effect on the mechanisms of benign prostatic hyperplasia. Although most clinical studies tend to suggest a modest efficacy benefit of saw palmetto, more recent studies are less consistent and the precise clinical value of saw palmetto for treating lower urinary tract symptoms remains undefined. Overall, there appear to be few safety concerns with short-term use of this herbal medicine, although large-sca...
Systematic review is a type of research that attempts to identify and summarize all of the eviden... more Systematic review is a type of research that attempts to identify and summarize all of the evidence related to a specific research question. It can be thought of as a "pause" in the process of conducting research in a particular area, in which the following questions are asked: Based on all of the available evidence, what do we know about this specific question so far, and what future studies should be conducted to clarify areas of uncertainty? The systematic review arose as an alternative to the traditional narrative review-which allows authors to pick and choose the studies they discuss and the depth at which they discuss them-a process prone to bias. By adhering to a prospectively defined protocol that specifies how studies should be identified, evaluated, and statistically combined (the statistical process is a component of systematic review and is called "meta-analysis"), systematic reviews reduce the bias inherent to traditional narrative reviews. Systemati...
Proceedings. IEEE Computer Society Bioinformatics Conference, 2002
Analyses of microbial community structure based on terminal restriction fragment length polymorph... more Analyses of microbial community structure based on terminal restriction fragment length polymorphisms (T-RFLP) of 16S rRNA genes are hindered by the lack of computational tools needed to aid experimental design, and to archive and analyze large data sets. The aim of this research was to develop a suite of Web-based tools that would enable researchers to perform several tasks, including:
The herbal extracts kava and valerian are the leading dietary supplements used in the self-manage... more The herbal extracts kava and valerian are the leading dietary supplements used in the self-management of anxiety and insomnia, respectively. There is limited evidence to support their effectiveness for these common symptoms. The Internet has been used to a limited extent for research, but it is not known whether randomized controlled trials can be conducted entirely using Internet technology. We performed a randomized, double-blind, placebo-controlled trial using a novel Internet-based design to determine if kava is effective for reducing anxiety and if valerian is effective for improving sleep quality. E-mail recruitment letters and banner advertisements on websites were used to recruit a large pool of interested participants (1551) from 45 states over an 8-week period. Participants were first asked to read study information, complete an online informed consent process, and undergo electronic identity verification. In order to be eligible for the study, participants were required to have 1) anxiety as documented by scores of at least 0.5 standard deviations above the mean on the State-Trait Anxiety Inventory State subtest (STAI-State) on 2 separate occasions, and 2) insomnia, defined as a "problem getting to sleep or staying asleep over the past 2 weeks." We randomly assigned 391 eligible participants to 1 of the following 3 groups, and mailed 28 days' supply: kava with valerian placebo (n = 121), valerian with kava placebo (n = 135), or double placebo (n = 135). The primary outcome measures were changes from baseline in anxiety (STAI-State questionnaire) and insomnia (Insomnia Severity Index [ISI]) compared with placebo. Participants receiving placebo had a 14.4 point decrease in anxiety symptoms on the STAI-State score and an 8.3 point decrease in insomnia symptoms on the ISI. Those receiving kava had similar reductions in STAI-State score (2.7 point greater reduction in placebo compared with kava; 95% confidence interval [CI], -0.8 to +6.2). Those receiving valerian and placebo had similar improvements in sleep (0.4 point greater reduction in the placebo than the valerian group; 95% CI, -1.3 to +2.1). Results were similar when limited to the 83% of participants who adhered to study compounds for all 4 weeks. Neither kava nor valerian relieved anxiety or insomnia more than placebo. This trial demonstrates the feasibility of conducting randomized, blinded trials entirely via the Internet.
Journal of the American Academy of Child & Adolescent Psychiatry, 2014
Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with ... more Preliminary evidence suggests that omega-3 fatty acids may reduce hyperactivity in children with autism spectrum disorder (ASD). We sought to examine the feasibility of a novel, Internet-based clinical trial design to evaluate the efficacy of this supplement. E-mail invitations were sent to parents of children aged 5 to 8 years enrolled in the Interactive Autism Network. All study procedures, including screening, informed consent, and collection of outcome measures took place over the Internet. The primary outcome measures were parent- and teacher-rated changes in hyperactivity on the Aberrant Behavior Checklist (ABC-H). During the 6-week recruitment period, 57 children from 28 states satisfied all eligibility criteria and were randomly assigned to 1.3 grams of omega-3 fatty acids or an identical placebo daily for 6 weeks. Outcome assessments were obtained from all 57 participants and 57 teachers, and the study was completed in 3 months. Children in the omega-3 fatty acid group had a greater reduction in hyperactivity (-5.3 points) compared to the placebo group (-2.6 points), but the difference was not statistically significant (1.9-point greater improvement in the omega-3 group, 95% CI = -2.2 to 5.2). Adverse events were rare and not associated with omega-3 fatty acids. Participant feedback was positive. Internet-based, randomized controlled trials of therapies in children with ASD are feasible and may lead to marked reductions in the time and cost of completing trials. A larger sample size is required to definitively determine the efficacy of omega-3 fatty acids. Clinical trial registration information-Omega-3 Fatty Acids for Hyperactivity Treatment in Autism Spectrum Disorder; http://clinicaltrials.gov; NCT01694667.
This study evaluated chondrogenesis of mesenchymal progenitor stem cells (MSCs) cultured initiall... more This study evaluated chondrogenesis of mesenchymal progenitor stem cells (MSCs) cultured initially under pre-confluent monolayer conditions exposed to transforming growth factor-beta1 (TGF-beta1), and subsequently in three-dimensional cultures containing insulin-like growth factor I (IGF-I). Bone marrow aspirates and chondrocytes were obtained from horses and cultured in monolayer with 0 or 5 ng of TGF-beta 1 per ml of medium for 6 days. TGF-beta 1 treated and untreated cultures were distributed to three-dimensional fibrin disks containing 0 or 100 ng of IGF-I per ml of medium to establish four treatment groups. After 13 days, cultures were assessed by toluidine blue staining, collagen types I and II in situ hybridization and immunohistochemistry, proteoglycan production by [35S]-sulfate incorporation, and disk DNA content by fluorometry. Mesenchymal cells in monolayer cultures treated with TGF-beta1 actively proliferated for the first 4 days, developed cellular rounding, and formed cell clusters. Treated MSC cultures had a two-fold increase in medium proteoglycan content. Pretreatment of MSCs with TGF-beta1 followed by exposure of cells to IGF-I in three-dimensional culture significantly increased the formation of markers of chondrocytic function including disk proteoglycan content and procollagen type II mRNA production. However, proteoglycan and procollagen type II production by MSC's remained lower than parallel chondrocyte cultures. MSC pretreatment with TGF-beta1 without sequential IGF-I was less effective in initiating expression of markers of chondrogenesis. This study indicates that although MSC differentiation was less than complete when compared to mature chondrocytes, chondrogenesis was observed in IGF-I supplemented cultures, particularly when used in concert with TGF-beta1 pretreatment.
The feasibility of articular gene therapy using insulin-like growth factor-I transgene expression... more The feasibility of articular gene therapy using insulin-like growth factor-I transgene expression in synovial tissues was assessed in vitro by transfection of synovial explant and monolayer cultures. Synovial membrane was harvested from horses and distributed for explant culture in multiwell plates or digested for monolayer culture in multiwell plates and chamber slides. Synovial monolayers were cultured for 48 h after infection with 0, 100, 200, or 500 moi adenovirus-IGF-I (AdeIGF-I) to establish an optimum dose. Explants were then either infected with AdeIGF-I or adenoviral LacZ and cultured for 8 days, treated with 100 ng/ml recombinant IGF-I as a positive control, or remained as uninfected untreated culture controls. Expression of IGF-I in explants and monolayers was assessed by in situ hybridization and quantitative polymerase chain reaction (PCR), and translation confirmed by IGF-I radioimmunoassay (RIA) and tissue immunoreaction. Effects of IGF-I on synovial function was assessed by proteoglycan and hyaluronan assay, and northern blot assessment of decorin and collagen type I expression. Significant transgene expression in synovial cells was present for all AdeIGF-I concentrations. Similarly, medium IGF-I concentrations were significantly elevated in AdeIGF-I infected synovial monolayer and explant cultures at all time points. Peak IGF-I concentration of 246 +/- 43 ng/ml developed in explant cultures on day 4; IGF-I levels in control explant groups were unchanged over baseline values. In situ hybridization and immunolocalization for IGF-I indicated focal IGF-I expression in intimal and subintimal layers of infected explants, with diffuse immunoreaction throughout infected subintimal and fibrous layers. For monolayer cultures, intracellular immunoreaction to IGF-I was markedly higher in infected cells, and was most prominent at 100 moi. Effects of IGF-I on synoviocyte cultures were evident on northern blots, which showed decreased decorin expression and elevated type I collagen production in AdeIGF-I infected monolayers. Proteoglycan concentration in the medium from explant cultures rose over the initial 4 days but was similar between treatment groups. The concentration of hyaluronan in medium from explant cultures did not differ significantly within or between treated and control groups during the 8-day study period. These data indicate that IGF-I can be successfully introduced to synovial structures by adenoviral vectors and results in effective IGF-I ligand synthesis without untoward synovial morphologic effects.
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Papers by Stephen Bent