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1.  Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy 
Circulation  2014;130(15):1262-1273.
Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear.
Methods and Results
We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling.
We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
PMCID: PMC4316667  PMID: 25124496
calcineurin; CaMKII; cardiac hypertrophy; heart failure; signal transduction
2.  E-Learning Module on Chronic Low Back Pain in Older Adults: Evidence of Effect on Medical Student Objective Structured Clinical Examination Performance 
The Institute of Medicine has highlighted the urgent need to close undergraduate and graduate educational gaps in treating pain. Chronic low back pain (CLBP) is one of the most common pain conditions, and older adults are particularly vulnerable to potential morbidities associated with misinformed treatment. An e-learning case-based interactive module was developed at the University of Pittsburgh Center of Excellence in Pain Education, one of 12 National Institutes of Health–designated centers, to teach students important principles for evaluating and managing CLBP in older adults. A team of six experts in education, information technology, pain management, and geriatrics developed the module. Teaching focused on common errors, interactivity, and expert modeling and feedback. The module mimicked a patient encounter using a standardized patient (the older adult with CLBP) and a pain expert (the patient provider). Twenty-eight medical students were not exposed to the module (Group 1) and 27 were exposed (Group 2). Their clinical skills in evaluating CLBP were assessed using an objective structured clinical examination (OSCE). Mean scores were 62.0 ± 8.6 for Group 1 and 79.5 ± 10.4 for Group 2 (P < .001). Using an OSCE pass–fail cutoff score of 60%, 17 of 28 Group 1 students (60.7%) and 26 of 27 Group 2 students (96.3%) passed. The CLBP OSCE was one of 10 OSCE stations in which students were tested at the end of a Combined Ambulatory Medicine and Pediatrics Clerkship. There were no between-group differences in performance on eight of the other nine OSCE stations. This module significantly improved medical student clinical skills in evaluating CLBP. Additional research is needed to ascertain the effect of e-learning modules on more-advanced learners and on improving the care of older adults with CLBP.
PMCID: PMC4288568  PMID: 24833496
medical student education; older adults; low back pain; objective structured clinical examination
3.  Changes in Body Mass Index Following HAART Initiation among HIV-Infected Women in the Women's Interagency HIV Study 
Examine changes in, and factors associated with changing body mass index (BMI) in women following highly active antiretroviral therapy (HAART) initiation.
1177 HIV-infected Women's Interagency HIV Study participants who contributed 10,754 years of follow-up following HAART initiation were studied. Changes in median BMI up to 15 years following HAART initiation, and the highest and lowest BMI reached following HAART initiation were summarized by pre-HAART BMI category (<18.5 [underweight], 18.5–<25.0 [normal weight], 25.0–<30.0 [overweight], 30.0–<40.0 [obese], and ≥ 40.0 [morbidly obese]). Multivariate mixed effects ordinal logistic regression estimated the degree of association of each exposure of interest with post-HAART BMI.
Before HAART, 39% percent of women had normal BMI, 31% were overweight, 23% were obese, and 5% were morbidly obese. Following HAART initiation, median BMI change (per 5 years) was 0.21 kg/m2 (90% confidence interval [CI]: −1.33, 0.42) for those with normal pre-HAART BMI, 0.39 kg/m2 (90% CI: 0.15,0.66) for overweight, 0.31 kg/m2 (90% CI: −1.18,0.67) for obese, and −0.36kg/m2 for morbidly obese women. After initiating HAART, 40% with normal pre-HAART BMI became overweight at some point; of those overweight, 46% remained overweight and 47% became obese; 71% of obese women remained obese and 27% became morbidly obese. Each year of nucleoside analog reverse transcriptase inhibitor use was associated with a 3% decreased odds of reaching a higher BMI category (OR 0.97, 95% CI: 0.95, 0.99), while each year of protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor use were associated with a 6% (OR 1.06, 95% CI: 1.04, 1.08) and 5%(OR 1.05, 95% CI: 1.01, 1.08) increased odds of having a higher BMI category, respectively.
Although overweight and obesity are highly prevalent in this large cohort of HIV-infected, minority women, HAART use was associated with only a modest increase in BMI over time.
PMCID: PMC4285631  PMID: 25580365
Obesity; Body mass index; HIV; Women; HAART; Women's interagency HIV study
4.  Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice 
Scientific Reports  2014;4:7158.
Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.
PMCID: PMC4241509  PMID: 25418008
5.  Combining Physicochemical and Evolutionary Information for Protein Contact Prediction 
PLoS ONE  2014;9(10):e108438.
We introduce a novel contact prediction method that achieves high prediction accuracy by combining evolutionary and physicochemical information about native contacts. We obtain evolutionary information from multiple-sequence alignments and physicochemical information from predicted ab initio protein structures. These structures represent low-energy states in an energy landscape and thus capture the physicochemical information encoded in the energy function. Such low-energy structures are likely to contain native contacts, even if their overall fold is not native. To differentiate native from non-native contacts in those structures, we develop a graph-based representation of the structural context of contacts. We then use this representation to train an support vector machine classifier to identify most likely native contacts in otherwise non-native structures. The resulting contact predictions are highly accurate. As a result of combining two sources of information—evolutionary and physicochemical—we maintain prediction accuracy even when only few sequence homologs are present. We show that the predicted contacts help to improve ab initio structure prediction. A web service is available at
PMCID: PMC4206277  PMID: 25338092
6.  Aberrant α-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells 
Stem Cell Reports  2014;3(5):905-914.
Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.
•Human iPSC-CMs are unresponsive to α-adrenergic hypertrophic signals•Silenced ADRA1A is accompanied by ADRA1B upregulation during differentiation•ADRA1B signal supports hypertrophy in hESC-CMs but is inhibited in hiPSC-CMs•Similar phenotype of hESC-CMs and hiPSC-CMs may mask differences in signaling
In this article, Földes and colleagues show that hiPSC-derived cardiomyocytes are relatively unresponsive to α-adrenergic hypertrophic signals compared to hESC cardiomyocytes. The main difference in hiPSC-CMs that accounts for the defective response is the suppression of growth by tonic antihypertrophic pathways. Superficial similarities in phenotype between cardiomyocytes derived from hESCs or hiPSCs may mask complex differences in signaling.
PMCID: PMC4235744  PMID: 25418732
7.  CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury 
EMBO Molecular Medicine  2014;6(10):1231-1245.
CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes.
PMCID: PMC4287929  PMID: 25193973
apoptosis; Ca2+/calmodulin-dependent protein kinase II; cardiac remodeling; gene replacement; ischemia/reperfusion injury
8.  Charlemagne's Summit Canal: An Early Medieval Hydro-Engineering Project for Passing the Central European Watershed 
PLoS ONE  2014;9(9):e108194.
The Central European Watershed divides the Rhine-Main catchment and the Danube catchment. In the Early Medieval period, when ships were important means of transportation, Charlemagne decided to link both catchments by the construction of a canal connecting the Schwabian Rezat and the Altmühl rivers. The artificial waterway would provide a continuous inland navigation route from the North Sea to the Black Sea. The shortcut is known as Fossa Carolina and represents one of the most important Early Medieval engineering achievements in Europe. Despite the important geostrategic relevance of the construction it is not clarified whether the canal was actually used as a navigation waterway. We present new geophysical data and in situ findings from the trench fills that prove for the first time a total length of the constructed Carolingian canal of at least 2300 metres. We have evidence for a conceptual width of the artificial water course between 5 and 6 metres and a water depth of at least 60 to 80 cm. This allows a crossing way passage of Carolingian cargo scows with a payload of several tons. There is strong evidence for clayey to silty layers in the trench fills which reveal suspension load limited stillwater deposition and, therefore, the evidence of former Carolingian and post-Carolingian ponds. These findings are strongly supported by numerous sapropel layers within the trench fills. Our results presented in this study indicate an extraordinarily advanced construction level of the known course of the canal. Here, the excavated levels of Carolingian trench bottoms were generally sufficient for the efficient construction of stepped ponds and prove a final concept for a summit canal. We have evidence for the artificial Carolingian dislocation of the watershed and assume a sophisticated Early Medieval hydrological engineering concept for supplying the summit of the canal with adequate water.
PMCID: PMC4177111  PMID: 25251589
9.  Insulin-like growth factor-1 induces regulatory T cell-mediated suppression of allergic contact dermatitis in mice 
Disease Models & Mechanisms  2014;7(8):977-985.
Allergic contact dermatitis (ACD) is triggered by an aberrant hyperinflammatory immune response to innocuous chemical compounds and ranks as the world’s most prevalent occupational skin condition. Although a variety of immune effector cells are activated during ACD, regulatory T (Treg) cells are crucial in controlling the resulting inflammation. Insulin-like growth factor-1 (IGF-1) regulates cell proliferation and differentiation and accelerates wound healing and regeneration in several organs including the skin. Recently IGF-1 has also been implicated in protection from autoimmune inflammation by expansion of Treg cells. Here, we demonstrate that ectopic expression of IGF-1 in mouse skin suppresses ACD in a Treg cell-specific manner, increasing the number of Foxp3+ Treg cells in the affected area and stimulating lymphocyte production of the anti-inflammatory cytokine interleukin 10. Similar therapeutic effects can be achieved with systemic or topical delivery of IGF-1, implicating this growth factor as a promising new therapeutic option for the treatment of ACD.
PMCID: PMC4107326  PMID: 25056699
Insulin-like growth factor-1; Atopic dermatitis; Contact hypersensitivity; Regulatory T cells; Treg
10.  Comparison of non-surgical treatment methods for patients with lumbar spinal stenosis: protocol for a randomized controlled trial 
Lumbar spinal stenosis is the most common reason for spinal surgery in older adults. Previous studies have shown that surgery is effective for severe cases of stenosis, but many patients with mild to moderate symptoms are not surgical candidates. These patients and their providers are seeking effective non-surgical treatment methods to manage their symptoms; yet there is a paucity of comparative effectiveness research in this area. This knowledge gap has hindered the development of clinical practice guidelines for non-surgical treatment approaches for lumbar spinal stenosis.
This study is a prospective randomized controlled clinical trial that will be conducted from November 2013 through October 2016. The sample will consist of 180 older adults (>60 years) who have both an anatomic diagnosis of stenosis confirmed by diagnostic imaging, and signs/symptoms consistent with a clinical diagnosis of lumbar spinal stenosis confirmed by clinical examination. Eligible subjects will be randomized into one of three pragmatic treatment groups: 1) usual medical care; 2) individualized manual therapy and rehabilitative exercise; or 3) community-based group exercise. All subjects will be treated for a 6-week course of care. The primary subjective outcome is the Swiss Spinal Stenosis Questionnaire, a self-reported measure of pain/function. The primary objective outcome is the Self-Paced Walking Test, a measure of walking capacity. The secondary objective outcome will be a measurement of physical activity during activities of daily living, using the SenseWear Armband, a portable device to be worn on the upper arm for one week. The primary analysis will use linear mixed models to compare the main effects of each treatment group on the changes in each outcome measure. Secondary analyses will include a responder analysis by group and an exploratory analysis of potential baseline predictors of treatment outcome.
Our study should provide evidence that helps to inform patients and providers about the clinical benefits of three non-surgical approaches to the management of lumbar spinal stenosis symptoms.
Trial registration identifier: NCT01943435
PMCID: PMC4036105  PMID: 24872875
Lumbar spinal stenosis; Spine; Rehabilitation; Physical therapy; Chiropractic; Non-surgical treatment
11.  CD38 Controls the Innate Immune Response against Listeria monocytogenes 
Infection and Immunity  2013;81(11):4091-4099.
CD38, adenosine-5′-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murine Listeria monocytogenes infection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. CD38 was expressed on neutrophils and inflammatory monocytes, and especially inflammatory monocytes further upregulated CD38 during infection. Absence of CD38 caused alterations of the migration pattern of both cell types to sites of infection. We observed impaired accumulation of cells in the spleen but surprisingly similar or even higher accumulation of cells in the liver. CD38 KO and wild-type mice showed similar changes in the composition of neutrophils and inflammatory monocytes in blood and bone marrow, indicating that mobilization of these cells from the bone marrow was CD38 independent. In vitro, macrophages of CD38 KO mice were less efficient in uptake of listeria but still able to kill the bacteria. Dendritic cells also displayed enhanced CD38 expression following infection. However, absence of CD38 did not impair the capacity of mice to prime CD8+ T cells against L. monocytogenes, and CD38 KO mice could efficiently control secondary listeria infection. In conclusion, our results demonstrate an essential role for CD38 in the innate immune response against L. monocytogenes.
PMCID: PMC3811837  PMID: 23980105
12.  Genetic Variants in the Genes of the Stress Hormone Signalling Pathway and Depressive Symptoms during and after Pregnancy 
BioMed Research International  2014;2014:469278.
Purpose. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes of the stress hormone signaling pathway, specifically FKBP5, NR3C1, and CRHR1, are associated with depressive symptoms during and after pregnancy. Methods. The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health including the assessment of depressiveness. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of the pregnancy, visit 2 was shortly after birth, and visit 3 was 6–8 months after birth. Germline DNA was collected from 361 pregnant women. Nine SNPs in the above mentioned genes were genotyped. After construction of haplotypes for each gene, a multifactorial linear mixed model was performed to analyse the depression values over time. Results. EPDS values were within expected ranges and comparable to previously published studies. Neither did the depression scores differ for comparisons among haplotypes at fixed time points nor did the change over time differ among haplotypes for the examined genes. No haplotype showed significant associations with depressive symptoms severity during pregnancy or the postpartum period. Conclusion. The analysed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show an association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
PMCID: PMC3972848  PMID: 24741566
13.  A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart 
Human Molecular Genetics  2012;22(2):372-383.
The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca2+-induced Ca2+ release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload.
In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca2+ transient dysynchrony without whole heart and cellular dysfunction. Ca2+ spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca2+ transients. Ca2+ spark frequency was elevated and the L-type Ca2+ channel was depressed at 8 months only.
After mechanical overload obtained by aortic banding constriction, the Ca2+ transient was prolonged in both wild type and KO. Mechanical overload increased the Ca2+ spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
PMCID: PMC3526164  PMID: 23100327
14.  Virgin birth: engineered heart muscle from parthenogenetic stem cells  
The Journal of Clinical Investigation  2013;123(3):1010-1013.
Cardiac muscle restitution, or true regeneration, is an unmet need in the treatment of myocardial infarction (MI), prompting a decade of study with stem cells of many kinds. Among key obstacles to effective cardiac cell grafting are the cost of autologous stem cell–derived cardiomyocytes, the ethical implications of using embryonic stem cell (ESC) products, immunological barriers to allogeneic cells, functional maturation beyond just the correct lineage decision, and the lack of durable engraftment. In this issue of the JCI, Didié and colleagues show that cardiomyocytes made from parthenogenetic stem cells (PSCs) and deployed as engineered heart muscle (EHM) may overcome all of these formidable barriers.
PMCID: PMC3582151  PMID: 23434596
15.  Addressing the “It Is Just Placebo” Pitfall in CAM: Methodology of a Project to Develop Patient-Reported Measures of Nonspecific Factors in Healing 
CAM therapies are often dismissed as “no better than placebo;” however, this belief may be overcome through careful analysis of nonspecific factors in healing. To improve trial methodology, we propose that CAM (and conventional) RCTs should evaluate and adjust for the effects of intrapersonal, interpersonal, and environmental factors on outcomes. However, measurement of these is challenging, and there are no brief, precise instruments that are suitable for widespread use in trials and clinical settings. This paper describes the methodology of a project to develop a set of patient-reported instruments that will quantify the nonspecific or “placebo” effects that are in fact specific and active ingredients in healing. The project uses the rigorous instrument-development methodology of the NIH-PROMIS initiative. The methods include (1) integration of patients' and clinicians' opinions with existing literature; (2) development of relevant items; (3) calibration of items on large samples; (4) classical test theory and modern psychometric methods to select the most useful items; (5) development of computerized adaptive tests (CATs) that maximize information while minimizing patient burden; and (6) initial validation studies. The instruments will have the potential to revolutionize clinical trials in both CAM and conventional medicine through quantifying contextual factors that contribute to healing.
PMCID: PMC3880690  PMID: 24454501
16.  Association of HIV infection with Incident Diabetes Mellitus: Impact of using Hemoglobin A1C as a Criterion for Diabetes 
Data regarding the association between HIV and DM are conflicting, with little known regarding the impact of including hemoglobin A1C (A1C) as a criterion for DM.
Pooled logistic regression was used to quantify the association between HIV and DM in 1501 HIV-infected and 550 HIV-uninfected participants from the Women’s Interagency HIV Study. Incident DM was defined using three DM definitions: (I) fasting glucose (FG) ≥126mg/dl, anti-DM medication, or reporting DM diagnosis (with confirmation by FG≥126mg/dl or anti-DM medication); (II) confirmation with a second FG≥126mg/dl; and (III) addition of A1C≥6.5% confirmed by FG≥126mg/dl or anti-DM medication.
DM incidence per 100 person-years was 2.44, 1.55, and 1.70 for HIV-infected women; 1.89, 0.85, and 1.13 for HIV-uninfected women, using definition I, II, and III, respectively. After adjustment for traditional DM risk factors, HIV infection was associated with 1.23, 1.90, and 1.38-fold higher risk of incident DM, respectively; the association reached statistical significance only when confirmation with a second FG≥126mg/dl was required. Older age, obesity, and a family history of DM were each consistently and strongly associated with increased DM risk.
HIV infection is consistently associated with greater risk of DM. Inclusion of an elevated A1C to define DM increases the accuracy of the diagnosis and only slightly attenuates the magnitude of the association otherwise observed between HIV and DM. By contrast, a DM diagnosis made without any confirmatory criteria for FG ≥126mg/dl overestimates the incidence, while also underestimating the effects of HIV on DM risk, and should be avoided.
PMCID: PMC3480977  PMID: 22878421
Diabetes mellitus; HIV; Women; Hemoglobin A1C
17.  The Epidemiological Boehringer Ingelheim Employee Study—Part I: Impact of Overweight and Obesity on Cardiometabolic Risk 
Journal of Obesity  2013;2013:159123.
Objective. Obesity-dependent diseases cause economic burden to companies. Large-scale data for working populations are lacking. Prevalence of overweight and obesity in the Boehringer Ingelheim (BI) Employee cohort and the relationship between body mass index (BMI) and cardiometabolic risk factors and diseases were estimated. Design and Methods. Employees (≥38 years, employed in Ingelheim ≥2 years; n = 3151) of BI Pharma GmbH & Co. KG were invited by the medical corporate department to participate in intensive health checkups. Cross-sectional analysis of baseline data collected through 2006–2011 was performed. Results. 90% of eligible subjects participated (n = 2849). Prevalences of overweight and obesity were 40% and 18% and significantly higher in men and participants ≥50 years. Cardiometabolic risk factor levels and prevalences of cardiometabolic diseases significantly increased with BMI and were higher in overweight and obese participants. Cut-points for increased risk estimated from ROC curves were ≈25 kg/m2 for hypertension, hypercholesterolemia, arteriosclerosis, and hypertriglyceridemia and 26.7–28.0 kg/m2 for the metabolic syndrome, insulin resistance, hyperinsulinemia, increased intima media thickness, and type 2 diabetes. Conclusion. This is the first large-scale occupational health care cohort from a single company. Cardiometabolic risk factors and diseases accumulate with increasing BMI. Occupational weight reduction programs seem to be reasonable strategies.
PMCID: PMC3753749  PMID: 23997947
18.  TAK1 Is Essential for Osteoclast Differentiation and Is an Important Modulator of Cell Death by Apoptosis and Necroptosis 
Molecular and Cellular Biology  2013;33(3):582-595.
Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), a mitogen-activated protein 3 (MAP3) kinase, plays an essential role in inflammation by activating the IκB kinase (IKK)/nuclear factor κB (NF-κB) and stress kinase (p38 and c-Jun N-terminal kinase [JNK]) pathways in response to many stimuli. The tumor necrosis factor (TNF) superfamily member receptor activator of NF-κB ligand (RANKL) regulates osteoclastogenesis through its receptor, RANK, and the signaling adaptor TRAF6. Because TAK1 activation is mediated through TRAF6 in the interleukin 1 receptor (IL-1R) and toll-like receptor (TLR) pathways, we sought to investigate the consequence of TAK1 deletion in RANKL-mediated osteoclastogenesis. We generated macrophage colony-stimulating factor (M-CSF)-derived monocytes from the bone marrow of mice with TAK1 deletion in the myeloid lineage. Unexpectedly, TAK1-deficient monocytes in culture died rapidly but could be rescued by retroviral expression of TAK1, inhibition of receptor-interacting protein 1 (RIP1) kinase activity with necrostatin-1, or simultaneous genetic deletion of TNF receptor 1 (TNFR1). Further investigation using TAK1-deficient mouse embryonic fibroblasts revealed that TNF-α-induced cell death was abrogated by the simultaneous inhibition of caspases and knockdown of RIP3, suggesting that TAK1 is an important modulator of both apoptosis and necroptosis. Moreover, TAK1-deficient monocytes rescued from programmed cell death did not form mature osteoclasts in response to RANKL, indicating that TAK1 is indispensable to RANKL-induced osteoclastogenesis. To our knowledge, we are the first to report that mice in which TAK1 has been conditionally deleted in osteoclasts develop osteopetrosis.
PMCID: PMC3554219  PMID: 23166301
19.  Music therapy in palliative setting 
The expectations on the care of humans with an incurable disease are to console, to relieve pain and to take away somebody’s fears. Therefore, palliative care tries to support terminally ill persons during the last stage of life and to ameliorate the living conditions. The question is how far music therapy can increase the quality of life. Until now, there is only small evidence for that, because there are too few applicable studies.
PMCID: PMC3728641  PMID: 23904890
end-of-life care; hospices; music; therapy; palliative care; terminal care
20.  Collection and Visualization of Dietary Behavior and Reasons for Eating Using Twitter 
Increasing an individual’s awareness and understanding of their dietary habits and reasons for eating may help facilitate positive dietary changes. Mobile technologies allow individuals to record diet-related behavior in real time from any location; however, the most popular software applications lack empirical evidence supporting their efficacy as health promotion tools.
The purpose of this study was to test the feasibility and acceptability of a popular social media software application (Twitter) to capture young adults’ dietary behavior and reasons for eating. A secondary aim was to visualize data from Twitter using a novel analytic tool designed to help identify relationships among dietary behaviors, reasons for eating, and contextual factors.
Participants were trained to record all food and beverages consumed over 3 consecutive days (2 weekdays and 1 weekend day) using their mobile device’s native Twitter application. A list of 24 hashtags (#) representing food groups and reasons for eating were provided to participants to guide reporting (eg, #protein, #mood). Participants were encouraged to annotate hashtags with contextual information using photos, text, and links. User experience was assessed through a combination of email reports of technical challenges and a 9-item exit survey. Participant data were captured from the public Twitter stream, and frequency of hashtag occurrence and co-occurrence were determined. Contextual data were further parsed and qualitatively analyzed. A frequency matrix was constructed to identify food and behavior hashtags that co-occurred. These relationships were visualized using GMap algorithmic mapping software.
A total of 50 adults completed the study. In all, 773 tweets including 2862 hashtags (1756 foods and 1106 reasons for eating) were reported. Frequently reported food groups were #grains (n=365 tweets), #dairy (n=221), and #protein (n=307). The most frequently cited reasons for eating were #social (activity) (n=122), #taste (n=146), and #convenience (n=173). Participants used a combination of study-provided hash tags and their own hash tags to describe behavior. Most rated Twitter as easy to use for the purpose of reporting diet-related behavior. “Maps” of hash tag occurrences and co-occurrences were developed that suggested time-varying diet and behavior patterns.
Twitter combined with an analytical software tool provides a method for capturing real-time food consumption and diet-related behavior. Data visualization may provide a method to identify relationships between dietary and behavioral factors. These findings will inform the design of a study exploring the use of social media and data visualization to identify relationships between food consumption, reasons for engaging in specific food-related behaviors, relevant contextual factors, and weight and health statuses in diverse populations.
PMCID: PMC3713881  PMID: 23796439
dietary behavior; data visualization; social media; mobile health; mHealth
21.  Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 
Circulation research  2001;88(3):333-339.
Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1±0.13 versus 1.66±0.06; P<0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.
PMCID: PMC3630465  PMID: 11179202
gap junction; connexin43; arrhythmia; conduction
22.  Improved Estimation of the Distribution of Suppressed Plasma HIV-1 RNA in Men Receiving Effective Antiretroviral Therapy 
Plasma HIV-1 RNA was measured in 306 samples, collected from 273 highly active antiretroviral therapy (HAART)-experienced men, using both the Roche COBAS TaqMan (limit of detection [LD]=20 copies/mL) and Roche Amplicor (LD=50 copies/mL) assays. Mixtures of Gaussian distributions incorporating left-censored data were used in analyses. The more sensitive TaqMan assay estimated that 23% and 0.0003% of HIV-1 RNA values would be below 1 copy/mL and 1 copy/3L, respectively. This is in sharp contrast to the overestimation provided by the less sensitive Amplicor assay, whereby the corresponding predicted percentages were 51% and 1%. Both assays appropriately characterized sub-optimal virologic response as the rightmost peaks of both distributions provided an excellent fit to the observed data. Our results based on a widely available 20 copies/mL sensitive assay reproduce those obtained using customized assays that quantified HIV-1 RNA values as low as 1 copy/mL.
PMCID: PMC3299865  PMID: 22217679
limit of detection; HIV-1 RNA; bimodal distribution; HAART
23.  Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C 
Kidney international  2012;82(4):445-453.
The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits one year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender and cystatin C measured by an immunoturbidimetric method; however the correlation coefficient of cystatin C and GFR (-0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91% and 45% of eGFR values were within 30% and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR.
PMCID: PMC3433576  PMID: 22622496
24.  Heart to heart: grafting cardiosphere-derived cells augments cardiac self-repair by both myocytes and stem cells 
EMBO Molecular Medicine  2013;5(2):177-179.
PMCID: PMC3569635  PMID: 23382000
cardiac regeneration; cell therapy; myocardial infarction; regeneration; stem cells
25.  Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice 
PLoS ONE  2012;7(12):e51228.
Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis.
PMCID: PMC3519594  PMID: 23251462

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