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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
18.  N-octanoyl-Dopamine Is an Agonist at the Capsaicin Receptor TRPV1 and Mitigates Is Chemia-Induced Acute Kidney Injury in Rat 
PLoS ONE  2012;7(8):e43525.
Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNFα stimulated proximal tubular epithelial cells, inhibition of NFκB and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.
PMCID: PMC3423369  PMID: 22916273
19.  Development of High Content Imaging Methods for Cell Death Detection in Human Pluripotent Stem Cell-Derived Cardiomyocytes 
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) are being investigated as a new source of cardiac cells for drug safety assessment. We developed a novel scalable high content microscopy-based method for the detection of cell death in hPSC-CM that can serve for future predictive in vitro cardio-toxicological screens. Using rat neonatal ventricular cardiomyocytes (RVNC) or hPSC-CM, assays for nuclear remodelling, mitochondrial status, apoptosis and necrosis were designed using a combination of fluorescent dyes and antibodies on an automated microscopy platform. This allowed the observation of a chelerythrine-induced concentration-dependent apoptosis to necrosis switch and time-dependent progression of early apoptotic cells towards a necrotic-like phenotype. Susceptibility of hPSC-CM to chelerythrine-stimulated apoptosis varied with time after differentiation, but at most time points, hPSC-CM were more resistant than RVNC. This simple and scalable humanized high-content assay generates accurate cardiotoxicity profiles that can serve as a base for further assessment of cardioprotective strategies and drug safety.
Electronic supplementary material
The online version of this article (doi:10.1007/s12265-012-9396-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3447146  PMID: 22896035
Stem cell; Methods; Cardiomyocytes apoptosis; Necrosis; Automated assay; High content microscopy
20.  Therapy of the burnout syndrome 
The prevalence, diagnostics and therapy of the burnout syndrome are increasingly discussed in the public. The unclear definition and diagnostics of the burnout syndrome are scientifically criticized. There are several therapies with unclear evidence for the treatment of burnout in existence.
The health technology assessment (HTA) report deals with the question of usage and efficacy of different burnout therapies.
For the years 2006 to 2011, a systematic literature research was done in 31 electronic databases (e.g. EMBASE, MEDLINE, PsycINFO). Important inclusion criteria are burnout, therapeutic intervention and treatment outcome.
17 studies meet the inclusion criteria and are regarded for the HTA report. The studies are very heterogeneous (sample size, type of intervention, measuring method, level of evidence). Due to their study design (e.g. four reviews, eight randomized controlled trials) the studies have a comparable high evidence: three times 1A, five times 1B, one time 2A, two times 2B and six times 4. 13 of the 17 studies are dealing with the efficacy of psychotherapy and psychosocial interventions for the reduction of burnout (partly in combination with other techniques). Cognitive behaviour therapy leads to the improvement of emotional exhaustion in the majority of the studies. The evidence is inconsistent for the efficacy of stress management and music therapy. Two studies regarding the efficacy of Qigong therapy do not deliver a distinct result. One study proves the efficacy of roots of Rhodiola rosea (evidence level 1B). Physical therapy is only in one study separately examined and does not show a better result than standard therapy.
Despite the number of studies with high evidence the results for the efficacy of burnout therapies are preliminary and do have only limited reach. The authors of the studies complain about the low number of skilled studies for the therapy of burnout. Furthermore, they point to the insufficient evaluation of the therapy studies and the need for further research. Some authors report the effects of considerable natural recovering.
Numerous limitations affect the quality of the results. Intervention contents and duration, study design and study size are very diverse and do not permit direct comparison. Most of the samples are small by size with low statistical power, long-term follow-ups are missing. Comorbidities and parallel utilized therapies are insufficient documented or controlled. Most of the studies use the Maslach Burnout Inventory (MBI) as diagnostic or outcome-tool, but with different cut-off-points. It should be noticed that the validity of the MBI as diagnostic tool is not proved. Ethical, juridical and social determining factors are not covered or discussed in the studies.
The efficacy of therapies for the treatment of the burnout syndrome is insufficient investigated. Only for cognitive behavioural therapy (CBT) exists an adequate number of studies which prove its efficacy. Big long-term experimental studies are missing which compare the efficacy of the single therapies and evaluate their evidence. The natural recovering without any therapy needs further research. Additionally, it has to be examined to what extent therapies and their possible effects are thwarted by the conditions of the working place and the working conditions.
PMCID: PMC3434360  PMID: 22984372
burnout; burnout intervention study; burnout, professional; CBT; cognitive behavior therapy; cognitive behavior treatment; cognitive behaviour therapy; cognitive behaviour treatment; cognitive therapy; cognitive-behavioral therapy; cognitive-behavioral treatment; cognitive-behavioural therapy; cognitive-behavioural treatment; depression; depressive disorder; EBM; evidence based medicine; evidence-based medicine; health technology assessment; HTA; HTA report; HTA-report; humans; individual-focused intervention; mind-body therapies; mind-body therapy; music therapy; person-directed intervention; phytotherapy; prognostic instrument; psychotherapy; qigong; relaxation; review; review literature; review literature as topic; rhodiola; rhodiola rosea; stress management training; systematic review; TA; technology assessment; technology assessment, biomedical; therapeutics; therapy; treatment; treatment outcome
21.  Predictive power of hepatitis B 1762T/1764A mutations in plasma for hepatocellular carcinoma risk in Qidong, China 
Carcinogenesis  2011;32(6):860-865.
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with nearly 700 000 deaths occurring annually. Hepatitis B virus (HBV) is a major contributor to HCC and acquired mutations in the HBV genome may accelerate its pathogenesis. In this study, a matched case–control investigation of 345 men who died of HCC and 625 controls were nested within a cohort of male hepatitis B surface antigen (HBsAg) carriers from Qidong, China. Matched preserving odds ratios (ORs) were used as a measure of association and 95% confidence intervals (CIs) as a measure of precision. Real-time polymerase chain reaction allowed for a quantitative comparison of the levels of the HBV 1762T/1764A mutation in cases and controls. A total of 278 (81%) of the cases were positive for the HBV 1762T/1764A mutation compared with 250 (40%) of the controls. The matched preserving OR of 6.72 (95% CI: 4.66 to 9.68) strongly indicated that cases were significantly more probably than controls to have the mutation. Plasma levels of DNA harboring the HBV mutation were on average 15-fold higher in cases compared with controls (P < 0.001). Most strikingly, the level of the mutation in the 20 controls who later developed and died of HCC were on average 274-fold higher than controls who did not develop HCC. Thus, within this cohort of HBsAg carriers at high risk of developing HCC, individuals positive for the HBV 1762T/1764A mutation at enrollment were substantially more probably to subsequently develop HCC, with a higher concentration of the mutation in plasma enhancing predisposition for cancer development.
PMCID: PMC3106439  PMID: 21474708
22.  Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo 
PLoS ONE  2012;7(5):e38438.
Fibroblast growth factors 19 (FGF19) and 21 (FGF21) have emerged as key regulators of energy metabolism. Several studies have been conducted to understand the mechanism of FGF19 and FGF21 action, however, the data presented has often been inconsistent and at times contradictory. Here in a single study we compare the mechanisms mediating FGF19/FGF21 actions, and how similarities/differences in actions at the cellular level between these two factors translate to common/divergent physiological outputs. Firstly, we show that in cell culture FGF19/FGF21 are very similar, however, key differences are still observed differentiating the two. In vitro we found that both FGF's activate FGFRs in the context of βKlotho (KLB) expression. Furthermore, both factors alter ERK phosphorylation and glucose uptake with comparable potency. Combination treatment of cells with both factors did not have additive effects and treatment with a competitive inhibitor, the FGF21 delta N17 mutant, also blocked FGF19's effects, suggestive of a shared receptor activation mechanism. The key differences between FGF21/FGF19 were noted at the receptor interaction level, specifically the unique ability of FGF19 to bind/signal directly via FGFR4. To determine if differential effects on energy homeostasis and hepatic mitogenicity exist we treated DIO and ob/ob mice with FGF19/FGF21. We find comparable efficacy of the two proteins to correct body weight and serum glucose in both DIO and ob/ob mice. Nevertheless, FGF21 and FGF19 had distinctly different effects on proliferation in the liver. Interestingly, in vivo blockade of FGF21 signaling in mice using ΔN17 caused profound changes in glycemia indicative of the critical role KLB and FGF21 play in the regulation of glucose homeostasis. Overall, our data demonstrate that while subtle differences exist in vitro the metabolic effects in vivo of FGF19/FGF21 are indistinguishable, supporting a shared mechanism of action for these two hormones in the regulation of energy balance.
PMCID: PMC3365001  PMID: 22675463
23.  Mid-term results of 155 patients treated with a collum femoris preserving (CFP) short stem prosthesis 
International Orthopaedics  2010;35(5):655-660.
Short stem prostheses that preserve the femoral neck are becoming more and more popular. The CFP (collum femoris preserving) has been introduced especially for the treatment of younger patients. However, information about remodelling, complications and learning curve are thus far rare. We present a retrospective study of 155 patients (average age 59.3 ± 9.9 years) who underwent total hip replacement with the CFP prosthesis. Follow-up was obtained 74.3 ± 9.4 months postoperatively. The Harris hip score revealed excellent and good results in 96%. One stem had to be exchanged due to aseptic loosening revealing a survival rate of 99% and 100% for stem and cup, respectively. Radiological analysis showed typical patterns of remodelling with apearance of cortical thickening predominantly in the distal part of the prosthesis. Implant related revision rate was <1%, with further complication rate independent of the surgeon’s individual experience. With regard to outcome, survivorship and complication rate, the medium-term results of the CFP prosthesis are promising.
PMCID: PMC3080504  PMID: 20437260
24.  Health effects of dietary phospholipids 
Beneficial effects of dietary phospholipids (PLs) have been mentioned since the early 1900's in relation to different illnesses and symptoms, e.g. coronary heart disease, inflammation or cancer. This article gives a summary of the most common therapeutic uses of dietary PLs to provide an overview of their approved and proposed benefits; and to identify further investigational needs.
From the majority of the studies it became evident that dietary PLs have a positive impact in several diseases, apparently without severe side effects. Furthermore, they were shown to reduce side effects of some drugs. Both effects can partially be explained by the fact that PL are highly effective in delivering their fatty acid (FA) residues for incorporation into the membranes of cells involved in different diseases, e.g. immune or cancer cells. The altered membrane composition is assumed to have effects on the activity of membrane proteins (e.g. receptors) by affecting the microstructure of membranes and, therefore, the characteristics of the cellular membrane, e.g. of lipid rafts, or by influencing the biosynthesis of FA derived lipid second messengers. However, since the FAs originally bound to the applied PLs are increased in the cellular membrane after their consumption or supplementation, the FA composition of the PL and thus the type of PL is crucial for its effect. Here, we have reviewed the effects of PL from soy, egg yolk, milk and marine sources. Most studies have been performed in vitro or in animals and only limited evidence is available for the benefit of PL supplementation in humans. More research is needed to understand the impact of PL supplementation and confirm its health benefits.
PMCID: PMC3316137  PMID: 22221489
Phospholipid; glycerophospholipid; therapy; plasma membrane

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