Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
Extracellular RNA is becoming increasingly recognized as a signaling molecule. Virally derived double stranded (ds)RNA released into the extracellular space during virus induced cell lysis acts as a powerful inducer of classical type I interferon (IFN) responses; however, the receptor that mediates this response has not been identified. Class A scavenger receptors (SR-As) are likely candidates due to their cell surface expression and ability to bind nucleic acids. In this study, we investigated a possible role for SR-As in mediating type I IFN responses induced by extracellular dsRNA in fibroblasts, a predominant producer of IFNβ. Fibroblasts were found to express functional SR-As, even SR-A species thought to be macrophage specific. SR-A specific competitive ligands significantly blocked extracellular dsRNA binding, entry and subsequent interferon stimulated gene (ISG) induction. Candidate SR-As were systematically investigated using RNAi and the most dramatic inhibition in responses was observed when all candidate SR-As were knocked down in unison. Partial inhibition of dsRNA induced antiviral responses was observed in vivo in SR-AI/II-/- mice compared with WT controls. The role of SR-As in mediating extracellular dsRNA entry and subsequent induced antiviral responses was observed in both murine and human fibroblasts. SR-As appear to function as ‘carriers’, facilitating dsRNA entry and delivery to the established dsRNA sensing receptors, specifically TLR3, RIGI and MDA-5. Identifying SR-As as gatekeepers of the cell, mediating innate antiviral responses, represents a novel function for this receptor family and provides insight into how cells recognize danger signals associated with lytic virus infections. Furthermore, the implications of a cell surface receptor capable of recognizing extracellular RNA may exceed beyond viral immunity to mediating other important innate immune functions.
Nearly all viruses produce dsRNA during their replication cycle. This molecule is not normally found in a healthy host cell and thus functions as a flag, alerting the host to a viral infection. Cells can die by lysis during virus infections, and the intracellular dsRNA is then released into the extracellular space. This dsRNA is stable in the extracellular milieu, and is able to function as a signaling molecule, detected by neighboring cells. This has been observed experimentally, as extracellular dsRNA has been used for years to trigger host antiviral responses. It has also been suggested that extracellular dsRNA plays a role in causing pathological symptoms in virus infected patients. Our data suggests that class A scavenger receptors (SR-As) function as cell surface receptors for dsRNA. SR-As bind extracellular, viral dsRNA and mediate its entry into the cell, where it delivers the dsRNA to other known intracellular dsRNA sensors, activating intracellular antiviral responses. These findings shed new light on how the host detects and responds to virus infection.
The U.S. Tox21 collaborative program represents a paradigm shift in toxicity testing of chemical compounds from traditional in vivo tests to less expensive and higher throughput in vitro methods to prioritize compounds for further study, identify mechanisms of action, and ultimately develop predictive models for adverse health effects in humans. The NIH Chemical Genomics Center (NCGC) is an integral component of the Tox21 collaboration due to its quantitative high throughput screening (qHTS) paradigm, in which titration-based screening is used to profile hundreds of thousands of compounds per week. Here, we describe the Tox21 collaboration, qHTS-based compound testing, and the various Tox21 screening assays that have been validated and tested at the NCGC to date.
Tox21; National Research Council; National Toxicology Program; toxicity testing; in vitro assays; NIH Roadmap; NIH Chemical Genomics Center; quantitative high-throughput screening
Increased incidences of infectious and septic complications during post-burn courses represent the main contributor to burn injury mortality. Sustained increases in catecholamine levels, especially norepinephrine (NE), contribute to immune disturbances in severely burned patients. The precise mechanisms underlying NE-mediated immunoregulation are not fully understood. Here we hypothesize that persistently elevated NE levels are associated with immunodysfunctions. We examined the effects of NE on the phenotype and functions of bone marrow-derived macrophages (BMMs). Whole mouse bone marrow cells were treated in vitro with 40 ng/mL of M-CSF and with 1 x 10-6 M or 1 x 10-8 M of NE or without NE for 7 days; cells were collected and stained with antibodies for CD11b, F4/80, MHC II and the inflammatory CC chemokine receptor 2 (CCR2). We found 1 x 10-6 M of NE inhibited MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells. It also inhibited BMM proliferation by inhibiting CSF-1R expression. On the contrary, 1 x 10-8 M of NE slightly increased both MHC II and CCR2 expression on CD11b+/F4/80+ BMM cells but inhibited CD11b+/F4/80+ BMM proliferation. MCP-1 based migration assay showed that the migration of 1 x 10-6 M of NE-treated BMM toward MCP-1 was significantly decreased compared to BMM without NE treatment. Both 1 x 10-8 M and 1 x 10-6 M of NE enhanced TNF-α production and phagocytosis of FITC-Dextran. Intracellular staining of transcriptional factor MafB showed that 1 x 10-6 M of NE treatment enhanced its expression, whereas 1 x 10-8 M of NE decreased expression. Stimulation with LPS in the last 24-hours of BMM culture further decreased CCR2 and MHC II expression of these BMM, suggesting the synergistic effect of LPS and NE on macrophage. Our results demonstrate that NE regulates macrophage differentiation, proliferation and function, and may play a critical role in the dysfunctional immune response post-burn.
The authors provide an analysis of sex differences in National Institutes of Health (NIH) award programs to inform potential initiatives for promoting diversity in the research workforce.
In 2010, the authors retrieved data for NIH extramural grants in the electronic Research Administration Information for Management, Planning, and Coordination II database, and used statistical analysis to determine any sex differences in securing NIH funding, as well as subsequent success of researchers who had already received independent NIH support.
Success and funding rates for men and women were not significantly different in most award programs. Furthermore, in programs where participation was lower for women than men, the disparity was primarily related to a lower percentage of women applicants compared to men, rather than decreased success rates or funding rates. However, for subsequent grants, both application and funding rates were generally higher for men than for women.
Cross-sectional analysis showed that women and men were generally equally successful at all career stages, but longitudinal analysis showed that men with previous experience as NIH grantees had higher application and funding rates than women at similar career points. On average, although women received larger R01 awards than men, men had more R01 awards than women at all points in their careers. Therefore, while greater participation of women in NIH programs is underway, further action will be required to eradicate remaining sex differences.
The research assessed faculty awareness of the National Institutes of Health (NIH) public access policy and faculty experiences with the copyright terms in their author agreements with publishers.
During the fall of 2011, 198 faculty members receiving funding from NIH at a large urban academic institution were invited to participate in an anonymous online survey. A total of 94 faculty members responded to the survey, representing a response rate of 47%.
Thirty percent of the survey respondents were either unaware of or not familiar with the NIH policy. Further, a significant number of faculty members (97.8%) indicated that they usually signed their copyright forms “as is.” The findings show that time, confusing instructions, and unclear journal policies are challenges experienced by NIH-funded faculty in complying with the federal mandate.
There is a need to educate faculty with respect to the value of retaining their copyrights and self-archiving their publications to help advance public access and open access scholarship.
Nitrate and nitrite are precursors of N-nitroso compounds, which induce tumors of the pancreas in animals. The authors evaluated the relation of dietary nitrate and nitrite to pancreatic cancer risk in the NIH-AARP Diet and Health Study. Nitrate and nitrite intakes were assessed at baseline using a 124-item food frequency questionnaire. During approximately 10 years of follow-up between 1995 and 2006, 1,728 incident pancreatic cancer cases were identified. There was no association between total nitrate or nitrite intake and pancreatic cancer in men or women. However, men in the highest quintile of summed nitrate/nitrite intake from processed meat had a nonsignificantly elevated risk of pancreatic cancer (hazard ratio = 1.18, 95% confidence interval: 0.95, 1.47; P-trend = 0.11). The authors observed a stronger increase in risk among men for nitrate/nitrite intake from processed meat at ages 12–13 years (highest quintile vs. lowest: hazard ratio = 1.32, 95% confidence interval: 0.99, 1.76; P-trend = 0.11), though the relation did not achieve statistical significance. The authors found no associations between adult or adolescent nitrate or nitrite intake from processed meats and pancreatic cancer among women. These results provide modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men and provide no support for the hypothesis in women.
diet; nitrates; nitrites; nitroso compounds; pancreatic neoplasms
Experimental evidence suggests that estrogen and other steroid hormones may protect against glioma. Although epidemiologic studies provide only weak support for a role of exogenous or endogenous hormones in gliogenesis, few cohort studies have addressed this question. The authors therefore examined the association between menstrual and reproductive factors, exogenous hormone use, and glioma risk among 225,355 women aged 50 to 71 years who completed the baseline questionnaire in the NIH-AARP Diet and Health Study. During 7 years of follow-up 174 cases of incident, primary glioma were ascertained. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for exposures taking potential confounders into account. Older age at menarche was positively associated with risk: HR 1.67 (95% CI: 1.03, 2.69). Other reproductive factors, including age at first live birth, parity, age at menopause, type of menopause (natural vs. medical), and exogenous hormone use showed no association with glioma risk. The results were similar when the analysis was restricted to cases with glioblastoma (N = 130). The present study provides only limited support for the hypothesis that menstrual/reproductive factors or exogenous hormone use play a role in gliogenesis.
Adverse socioeconomic conditions, at both the individual and the neighborhood level, increase the risk of colorectal cancer (CRC) death, but little is known regarding whether CRC survival varies geographically and the extent to which area-level socioeconomic deprivation affects this geographic variation. Using data from the National Institutes of Health (NIH)-AARP Diet and Health Study, the authors examined geographic variation and the role of area-level socioeconomic deprivation in CRC survival. CRC cases (n = 7,024), identified during 1995–2003, were followed for their CRC-specific vital status through 2005 and overall vital status through 2006. Bayesian multilevel survival models showed that there was significant geographic variation in overall (variance = 0.2, 95% confidence interval (CI): 0.1, 0.2) and CRC-specific (variance = 0.3, 95% CI: 0.1, 0.4) risk of death. More socioeconomically deprived neighborhoods had a higher overall risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.4) and a higher CRC-specific risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.5). However, neighborhood socioeconomic deprivation did not account for the geographic variation in overall and CRC-specific risks of death. In future studies, investigators should evaluate other neighborhood characteristics to help explain geographic heterogeneity in CRC survival. Such research could facilitate interventions for reducing geographic disparity in CRC survival.
cohort studies; colorectal neoplasms; geography; multilevel analysis; residence characteristics; socioeconomic factors; survival
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50-71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks (RR) and 95% confidence intervals (CI) for lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (0.73, 0.91), 0.86 (0.78, 0.96), and 0.86 (0.78, 0.96), respectively; corresponding RRs in women were 0.97 (0,85, 1.12), 0.95 (0.83, 1.09), and 0.92 (0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruit and vegetables in lung cancer prevention in men, although these findings could also be due to residual confounding by smoking or chance.
cohort studies; fruit; lung neoplasms; vegetables
Increased fruit and vegetable consumption may protect against lung cancer, although epidemiologic findings are inconclusive. The authors prospectively examined associations between lung cancer risk and intakes of fruit, vegetables, and botanical subgroups in 472,081 participants aged 50–71 years in the National Institutes of Health (NIH)-AARP Diet and Health Study. Diet was assessed at baseline (1995–1996) with a 124-item dietary questionnaire. A total of 6,035 incident lung cancer cases were identified between 1995 and 2003. Total fruit and vegetable intake was unrelated to lung cancer risk in both men and women. Higher consumption of several botanical subgroups, however, was significantly inversely associated with risk, but only in men. For example, the relative risks of lung cancer among men in the highest versus lowest quintiles of intake of rosaceae, convolvulaceae, and umbelliferae were 0.82 (95% confidence interval (CI): 0.73, 0.91), 0.86 (95% CI: 0.75, 0.96), and 0.86 (95% CI: 0.78, 0.96), respectively; corresponding relative risks in women were 0.97 (95% CI: 0.85, 1.12), 0.95 (95% CI: 0.83, 1.09), and 0.92 (95% CI: 0.80, 1.06). These results provide support for a protective role of specific botanical subgroups of fruits and vegetables in lung cancer prevention in men, although the findings could also be due to residual confounding by smoking or chance.
cohort studies; fruit; lung neoplasms; vegetables
The growth of the Translating Unit of the National Institutes of Health Library, founded in 1938, was slow until 1950, when seventeen translators and clerical assistants comprised its staff. Today eleven staff members translate, type, and distribute translations from eighteen European languages. Contract service is arranged for those languages for which the Unit has little or no competency. Three recent innovations have improved the translating service: (1) production standards, (2) fee for service, and (3) microfilmed translations. A monthly bulletin, Recent Translations, a Selected List, includes those articles translated by the Translating Unit of the NIH Library. An author index to all translations cited in the Selected List is now available upon request.
The importance of gathering and monitoring aggregate demographic data on the annual population of study volunteers in FDA-regulated clinical trials is widely acknowledged. To date, no formal mechanism exists to capture this information. The Tufts Center for the Study of Drug Development identified and tested a publicly available source of information on clinical trial participant data, NDA Reviews stored in the FDA’s drugs@FDA database, to determine its accuracy, reliability, and feasibility. Thirty-seven new drug applications approved between 2006 and 2008 were evaluated and compared with published sources of demographic data. The authors conclude that the approach described here—NDA review extraction—provides reasonably reliable and conservative estimates of study volunteer demographics and can serve as a useful baseline until Clinicaltrials.gov or other, more complete, public sources become available.
Clinical trial; FDA; NDA; NIH; Demographic data
Two families of transcription factors that play a major role in the development of adipocytes are the CCAAT/enhancer-binding proteins (C/EBPs) and the peroxisome proliferator-activated receptors (PPARs), in particular PPARγ. Ectopic expression of either C/EBPα or PPARγ in NIH 3T3 fibroblasts results in the conversion of these cells to adipocyte-like cells replete with fat droplets. NIH 3T3 cells ectopically expressing C/EBPα (NIH-C/EBPα) differentiate into adipocytes and exhibit insulin-stimulated glucose uptake, whereas NIH 3T3 cells ectopically expressing PPARγ (NIH-PPARγ) differentiate but do not exhibit any insulin-stimulated glucose uptake, nor do they express any C/EBPα. The reason for the lack of insulin-responsive glucose uptake in the NIH-PPARγ cells is their virtual lack of the insulin-responsive glucose transporter, Glut4. The NIH-PPARγ cells express functionally active components of the insulin receptor-signaling pathway (the insulin receptor, IRS-1, phosphatidylinositol 3-kinase, and Akt2) at levels comparable to those in responsive cell lines. They also express components of the insulin-sensitive vesicular transport machinery, namely, VAMP2, syntaxin-4, and IRAP, the last of these being the other marker of insulin-regulated vesicular traffic along with Glut4. Interestingly, the NIH-PPARγ cells show normal insulin-dependent translocation of IRAP and form an insulin-responsive vesicular compartment as assessed by cell surface biotinylation and sucrose velocity gradient analysis, respectively. Moreover, expression of a Glut4-myc construct in the NIH-PPARγ cells results in its insulin-dependent translocation to the plasma membrane as assessed by immunofluorescence and Western blot analysis. Based on these data, we conclude that major role of C/EBPα in the context of the NIH-PPARγ cells is to regulate Glut4 expression. The differentiated cells possess a large insulin-sensitive vesicular compartment with negligible Glut4, and Glut4 translocation can be reconstituted on expression of this transporter.
Intense interest surrounds the recent expansion of US National Institutes of Health (NIH) budgets as part of economic stimulus legislation. However, the relationship between NIH funding and cardiovascular disease research is poorly understood, making the likely impact of this policy change unclear.
The National Library of Medicine's PubMed database was searched for articles published from 1996 to 2006, originating from U.S. institutions, and containing the phrases “cardiolog,” “cardiovascular,” or “cardiac,” in the first author's department. Research methodology, journal of publication, journal impact factor, and receipt of NIH funding were recorded. Differences in means and trends were tested with t-tests and linear regression, respectively, with P≤0.05 for significance.
Of 117,643 world cardiovascular articles, 36,684 (31.2%) originated from the U.S., of which 10,293 (28.1%) received NIH funding. The NIH funded 40.1% of U.S. basic science articles, 20.3% of overall clinical trials, 18.1% of randomized-controlled, and 12.2% of multicenter clinical trials. NIH-funded and total articles grew significantly (65 articles/year, P<0.001 and 218 articles/year, P<0.001, respectively). The proportion of articles receiving NIH funding was stable, but grew significantly for basic science and clinical trials (0.87%/year, P<0.001 and 0.67%/year, P = 0.029, respectively). NIH-funded articles had greater journal impact factors than non NIH-funded articles (5.76 vs. 3.71, P<0.001).
NIH influence on U.S. cardiovascular research expanded in the past decade, during the period of NIH budget doubling. A substantial fraction of research is now directly funded and thus likely sensitive to budget fluctuations, particularly in basic science research. NIH funding predicts greater journal impact.
In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2’-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50 = 1.9 (0.7 – 5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50 = 0.75 (0.26 – 2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.
Selective delta opioid; (-)-(1R,5R,9R)-5,9-Dimethyl-2’-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082); antinociception; antihyperalgesia; mouse; rat; rhesus monkey
This essay is written from my perspective as a program officer for research and training activities at the National Institute of General Medical Sciences (NIGMS) for almost 27 yr. It gives a bird's-eye view of the job of a program officer, which includes providing advice to applicants and grantees, making funding recommendations, overseeing grantees' progress, facilitating scientific opportunities in specific areas of program responsibility, and shaping NIGMS and National Institutes of Health (NIH) policy. I have highlighted the numerous rewards of serving as a program officer, as well as some of the difficulties. For those who may be considering a position as an NIH program officer now or in the future, I've also described the qualities and qualifications that are important for such a career choice. Finally, this essay addresses some of the challenges for the NIH and the research community in the years ahead as we simultaneously face exciting scientific opportunities and tighter budgets.
An understanding of the nature of the immune response to asexual erythrocytic stages of malaria parasites will facilitate vaccine development by identifying which responses the vaccine should preferentially induce. The present study examined and compared the immune responses of NIH mice in either single or mixed infections with avirulent (DK) or virulent (DS) strains of Plasmodium chabaudi adami using the ELISA test for detecting and measurement of cytokines and antibody production. In both single and mixed infections, the study showed that both cell- and antibody-mediated responses were activated. In all experiments, an early relatively high level of IFN-γ and IgG2a during the acute phase of the infection, and later elevation of IL-4 and IgG1, suggested that there was a sequential Th1/Th2 response. However, in the avirulent DK strain infection a stronger Th1 response was observed compared to the virulent DS strain-infection or in mixed infections. In the virulent DS infection, there was a stronger Th2 response compared to that in the DK and mixed infections. The faster proliferation rate of the virulent DS strain compared to the DK strain was also evident.
Plasmodium chabaudi adami; immune response; cytokine; single and mixed infection; NIH mouse; Th1/Th2
organochlorine; NIH3T3-L1; adipose tissue; fatty acid uptake; lipolysis; adipokine
For innovators at academic or industrial institutions to develop personalized medicine products at the accelerated pace required, rapid access to state-of-the-art research tools and reagents are needed. Unreasonable restrictions or delays in the use of such tools may undermine the development of these customized diagnostics and therapeutic products designed to provide significant treatment benefits to patients who frequently do not benefit from traditional therapeutic approaches. In its funding agreements and its own internal research programs, the National Institutes of Health is implementing policies to facilitate the exchanges of these research tools and related resources.
Bayh–Dole Act; NIH; personalized medicine; research tools
The present study examined the effects of NIH 11082 ((−)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride), a benzomorphan analogue, in the mouse tail suspension, an assay used to detect antidepressant agents. NIH 11082 significantly decreased immobility time during tail suspension, with a comparable magnitude as the tricyclic antidepressant desipramine. Importantly, NIH 11082 failed to elicit convulsions or other overt behavioral signs of toxicity. The delta-opioid receptor antagonist naltrindole (AD50=2.0 mg/kg), but not the nonselective mu-opioid receptor antagonist naltrexone or the kappa-opioid receptor antagonist nor-BNI, blocked the effects of NIH 11082 in the tail suspension test. These results reinforce the notion that delta opioid receptor agonists can produce significant effects in a behavioral model used to screen antidepressant drugs.
The Stories and Music for Adolescent/Young Adult Resilience during Transplant (SMART) study (R01NR008583; U10CA098543; U10CA095861) is an ongoing multi-site Children’s Oncology Group randomized clinical trial testing the efficacy of a therapeutic music video intervention for adolescents/young adults (11–24 years of age) with cancer undergoing stem cell transplant. Treatment fidelity strategies from our trial are consistent with the NIH Behavior Change Consortium Treatment Fidelity Workgroup (BCC) recommendations and provide a successful working model for treatment fidelity implementation in a large, multi-site behavioral intervention study. In this paper we summarize 20 specific treatment fidelity strategies used in the SMART trial and how these strategies correspond with NIH BCC recommendations in 5 specific areas: 1) study design, 2) training providers, 3) delivery of treatment, 4) receipt of treatment, and 5) enactment of treatment skills. Increased use and reporting of treatment fidelity procedures is essential in advancing the reliability and validity of behavioral intervention research. The SMART trial provides a strong model for the application of fidelity strategies to improve scientific findings and addresses the absence of published literature illustrating the application of BCC recommendations in behavioral intervention studies.
treatment fidelity; intervention integrity; quality assurance monitoring; behavioral intervention research; clinical trials
The present work was initiated to investigate regulation of the taurine transporter TauT by reactive oxygen species (ROS) and the tonicity-responsive enhancer binding protein (TonEBP) in NIH3T3 mouse fibroblasts during acute and long-term (4 h) exposure to low-sodium/hypo-osmotic stress. Taurine influx is reduced following reduction in osmolarity, keeping the extracellular Na+ concentration constant. TonEBP activity is unaltered, whereas TauT transcription as well as TauT activity are significantly reduced under hypo-osmotic conditions. In contrast, TonEBP activity and TauT transcription are significantly increased following hyperosmotic exposure. Swelling-induced ROS production in NIH3T3 fibroblasts is generated by NOX4 and by increasing total ROS, by either exogenous application of H2O2 or overexpressing NOX4, we demonstrate that TonEBP activity and taurine influx are regulated negatively by ROS under hypo-osmotic, low-sodium conditions, whereas the TauT mRNA level is unaffected. Acute exposure to ROS reduces taurine uptake as a result of modulated TauT transport kinetics. Thus, swelling-induced ROS production could account for the reduced taurine uptake under low-sodium/hypo-osmotic conditions by direct modulation of TauT.
Electronic supplementary material
The online version of this article (doi:10.1007/s00232-012-9416-8) contains supplementary material, which is available to authorized users.
NADPH oxidase; Hyponatremia; Osmolyte transport; Hypo-osmolal