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1.  Comprehensive Approach to Lower Blood Pressure (CALM-BP): a randomized controlled trial of a multifactorial lifestyle intervention 
Journal of Human Hypertension  2013;27(10):594-600.
Complementary medicine advocates the use of a multifactorial approach to address the varied aspects of hypertension. The aim of this study was to compare the blood pressure (BP) effect and medication use of a novel Comprehensive Approach to Lowering Measured Blood Pressure (CALM-BP), based on complementary medicine principles, with the standard recommended Dietary Approach to Stop Hypertension (DASH). A total of 113 patients treated with antihypertensive drugs were randomly assigned to either CALM-BP treatment (consisting of rice diet, walks, yoga, relaxation and stress management) or to a DASH+exercise control group (consisting of DASH and walks). Ambulatory 24-h and home BP were monitored over a 16-week programme, followed by 6 months of maintenance period. Medications were reduced if systolic BP dropped below 110 mm Hg accompanied by symptoms. In addition to BP reduction, medications were reduced because of symptomatic hypotension in 70.7% of the CALM-BP group compared with 32.7% in the DASH group, P<0.0001. After 6 months, medication status was not altered in the majority of individuals. Significant reductions in body mass index, cholesterol and improved quality-of-life scores were observed only in the CALM-BP group. Lifestyle and diet modifications based on complementary medicine principles are highly effective with respect to BP control, medication use and cardiovascular risk factors.
PMCID: PMC3775127  PMID: 23595161
blood pressure; diet; lifestyle; stress; quality of life
2.  Transport Response is a filial-specific behavioral response to maternal carrying in C57BL/6 mice 
Frontiers in Zoology  2013;10:50.
A mother carries her young in many altricial mammals, such as cats, lions, rats and mice. During maternal carrying, the transported young assume a compact posture. We have recently shown that, in both humans and mice, the carried infants immediately calmed down and showed reductions in heart rate, distress vocalizations, and voluntary movement. The loss of the calming response in mouse pups hindered maternal retrieval efficacy. These findings suggested that the infant calming response functioned to reduce the maternal burden of carrying and was therefore conserved in a variety of mammalian species. However, it remains unclear how and when each component of this calming response develops and whether it is a filial-specific behavior.
We dissected various components of the carrying-induced responses in mouse pups, collectively called the “Transport Response” herein. We showed that during the second postnatal week, pups exhibited characteristic compact posture with limb ventroflexion. The body trunk remained paradoxically pliable, suggesting complex neural regulation throughout the body. Pups also showed an increased pain tolerance to a tail pinch during the Transport Response. Analyses of the developmental courses of distinct components of the Transport Response revealed the independent regulation of each component: in the first postnatal week, the cessation of ultrasonic vocalizations was exhibited prominently; in the second postnatal week, immobilization reached its peak; and toward the third postnatal week, the postural component became fully matured. At the end of the third postnatal week, when the pups are able to transport by themselves, the pups no longer exhibited the Transport Response.
This study has revealed the mouse Transport Response as a complex set of behavioral and physiological components, each of which has a specific postnatal time window but is orchestrated in a well-matched manner with the maturation of ambulatory ability in the pups. These findings collectively indicate that the Transport Response is a filial-specific, innate behavioral reaction and is distinct from a simple reflex or defensive freezing response. The Transport Response could be a novel index of primitive filial attachment behaviors, acting to smooth mother-infant interaction.
PMCID: PMC3751433  PMID: 23945354
Mouse pup; Transport response; Calming response; Filial behavior; Maternal carrying; Mother-infant relationship; Parental behavior
3.  Reduced systolic torsion in chronic “pure” mitral regurgitation 
Global left ventricular (LV) torsion declines with chronic ischemic mitral regurgitation (CIMR), which may accelerate the LV remodeling spiral toward global cardiomyopathy; however, it has not been definitively established whether this torsional decline is due to the infarct, the MR, or their combined effect. We tested the hypothesis that chronic “pure” MR alone reduces global LV torsion.
Methods and Results
Chronic “pure” MR was created in thirteen sheep by surgically punching a 3.5–4.8mm hole (HOLE) in the mitral valve posterior leaflet. Nine control (CNTL) sheep were operated upon concurrently. At one (WK-01) and twelve weeks (WK-12) postoperatively, the 4-D motion of implanted radiopaque markers was used to calculate global LV torsion. MR-grade in HOLE was greater than CNTL at WK-01 and WK-12 (2.5±1.1 vs. 0.6±0.5, P<0.001 at WK-12). HOLE LV mass index (LVMI) was larger at WK-12 compared to CNTL (195±14 vs. 170±17 g/m2, P<0.01), indicating LV remodeling. Global LV systolic torsion decreased in HOLE from WK-01 to WK-12 (4.1°±2.8° vs. 1.7°±1.7°, P<0.01), but did not change in CNTL (5.5°±1.8° vs. 4.2°±2.7°, P=N.S.). Global LV torsion was lower in HOLE relative to CNTL at WK-12 (P<0.05), but not at WK-01 (P=N.S.).
Twelve weeks of chronic “pure” MR resulting in mild global LV remodeling is associated with significantly increased LVMI and reduced global LV systolic torsion, but no other significant changes in hemodynamics. MR alone is a major component of torsional deterioration in “pure” MR and may be an important factor in CIMR.
PMCID: PMC2760031  PMID: 19808573
mechanics; mitral valve; myocardium; ventricles; torsion
4.  Reduction of AP180 and CALM Produces Defects in Synaptic Vesicle Size and Density 
Neuromolecular medicine  2012;15(1):10.1007/s12017-012-8194-x.
Clathrin assembly proteins AP180 and CALM regulate the assembly of clathrin-coated vesicles (CCVs), which mediate diverse intracellular trafficking processes, including synaptic vesicle (SV) recycling at the synapse. Although studies using several invertebrate model systems have indicated a role for AP180 in SV recycling, less is known about AP180’s or CALM’s function in the synapse of mammalian neurons. In this study, we examined synapses of rat hippocampal neurons in which the level of AP180 or CALM had been reduced by RNA interference (RNAi). Using light microscopy, we visualized synaptic puncta in these AP180- or CALM-reduced neurons by co-expressing Synaptophysin::EGFP (Syp::EGFP). We found that neurons with reduced AP180 or reduced CALM had smaller Syp::EGFP-illuminated puncta. Using electron microscopy, we further examined the ultrastructure of the AP180- or CALM-reduced presynaptic terminals. We found that SVs became variably enlarged in both the AP180-reduced and CALM-reduced presynaptic terminals. Lower AP180 and CALM also reduced the density of SVs and the size of SV clusters. Our findings demonstrate that in the presynaptic terminals of hippocampal neurons, AP180 and CALM have a similar role in regulating synaptic vesicles. This overlapping activity may be necessary for high-precision and high-efficacy SV formation during endocytosis.
PMCID: PMC3818133  PMID: 22851330
AP180; CALM; Hippocampal synapse; Synaptic vesicle
5.  Transcriptional Changes Common to Human Cocaine, Cannabis and Phencyclidine Abuse 
PLoS ONE  2006;1(1):e114.
A major goal of drug abuse research is to identify and understand drug-induced changes in brain function that are common to many or all drugs of abuse. As these may underlie drug dependence and addiction, the purpose of the present study was to examine if different drugs of abuse effect changes in gene expression that converge in common molecular pathways. Microarray analysis was employed to assay brain gene expression in postmortem anterior prefrontal cortex (aPFC) from 42 human cocaine, cannabis and/or phencyclidine abuse cases and 30 control cases, which were characterized by toxicology and drug abuse history. Common transcriptional changes were demonstrated for a majority of drug abuse cases (N = 34), representing a number of consistently changed functional classes: Calmodulin-related transcripts (CALM1, CALM2, CAMK2B) were decreased, while transcripts related to cholesterol biosynthesis and trafficking (FDFT1, APOL2, SCARB1), and Golgi/endoplasmic reticulum (ER) functions (SEMA3B, GCC1) were all increased. Quantitative PCR validated decreases in calmodulin 2 (CALM2) mRNA and increases in apolipoprotein L, 2 (APOL2) and semaphorin 3B (SEMA3B) mRNA for individual cases. A comparison between control cases with and without cardiovascular disease and elevated body mass index indicated that these changes were not due to general cellular and metabolic stress, but appeared specific to the use of drugs. Therefore, humans who abused cocaine, cannabis and/or phencyclidine share a decrease in transcription of calmodulin-related genes and increased transcription related to lipid/cholesterol and Golgi/ER function. These changes represent common molecular features of drug abuse, which may underlie changes in synaptic function and plasticity that could have important ramifications for decision-making capabilities in drug abusers.
PMCID: PMC1762434  PMID: 17205118
6.  The Clathrin-Binding Domain of CALM-AF10 Alters the Phenotype of Myeloid Neoplasms in Mice 
Oncogene  2011;31(4):494-506.
The PICALM (CALM) gene, whose product is involved in clathrin-mediated endocytosis, has been identified in two recurring chromosomal translocations, involving either MLL or MLLT10 (AF10). We developed a mouse model of CALM-AF10+ leukemia to examine the hypothesis that disruption of endocytosis contributes to leukemogenesis. Exclusion of the C-terminal portion of CALM from the fusion protein, which is required for optimal binding to clathrin, resulted in the development of a myeloproliferative disease, while inclusion of this domain led to the development of acute myeloid leukemia and changes in gene expression of several cancer-related genes, notably Pim1 and Crebbp. Nonetheless, the development of leukemia could not be attributed directly to interference with endocytosis or consequential changes in proliferation and signaling. In leukemia cells, full-length CALM-AF10 localized to the nucleus with no consistent effect on growth factor endocyctosis, and suppressed H3K79 methylation regardless of the presence of clathrin. Using FRET analysis, we show that CALM-AF10 has a propensity to homo-oligomerize, raising the possibility that the function of endocytic proteins involved in chimeric fusions may be to provide dimerization properties, a recognized mechanism for unleashing oncogenic properties of chimeric transcription factors, rather than disrupting the internalization of growth factor receptors.
PMCID: PMC3204175  PMID: 21706055
AML; MPD; endocytosis; Dot1l; H3K79 methylation; oligomerization
7.  Signs and Symptoms of Impending Death in End-of-life Elderly Dementia Sufferers: Point of View of Formal Caregivers in Rural Areas 
Objective: The aim of the present study was to clarify the signs and symptoms of impending death in end-of-life senile dementia from the point of view of formal caregivers in rural areas.
Patient/Materials and Methods: We used qualitative data based on retrospective analyses. The data was gathered following a workshop on end-of-life care of the elderly with dementia attended by formal caregivers that was held in Iga City, Mie Prefecture, Japan, in September 2011. There was a total of 29 workshop participants. The workshop products were created in the first session of the workshop entitled “Signs of death.” During the session, we used the brainstorming method, and participants took turns stating at least two signs, symptoms or premonitions of death. In the end, there were 93 cards in total displaying signs of impending death observed in the end stage of dementia. These 93 entries were then classified into clear categories.
Results: The categories defined were breathing disorder, consciousness decline, vital power decline, reduced oral intake, feces disorder, calm and peaceful character, blood pressure decline, change in skin color, patient odor, edema, preagonal vital power, body temperature decline, bedsore/wound deterioration, body weight reduction, cyanosis, and oliguria. The most frequently cited symptoms fell in the breathing disorder category (12 cards), followed by consciousness decline (9 cards), vital power decline (9 cards), reduced oral intake (6 cards), and feces disorder (6 cards). Also frequently mentioned were symptoms falling in the calm and peaceful character, patient odor and preagonal vital power categories.
Conclusion: The results show that formal caregivers in rural areas identified breathing disorder as a top indicator of impending death in end-of-life senile dementia cases. The results also highlight some other characteristic signs of impending death, such as preagonal vital power and calm and peaceful character. This research could help develop formal caregivers’ observational skills in the end-of-life care settings.
PMCID: PMC4309317
dementia; symptom; end-of-life; qualitative study; formal caregiver
8.  Shirodhara: A psycho-physiological profile in healthy volunteers 
Shirodhara is a classical and a well-established ayurvedic procedure of slowly and steadily dripping medicated oil or other liquids on the forehead. This procedure induces a relaxed state of awareness that results in a dynamic psycho-somatic balance.
The objective of the study is to evaluate the psychological and physiological effects of Shirodhara in healthy volunteers by monitoring the rating of mood and levels of stress, electrocardiogram (ECG), electroencephalogram (EEG), and selected biochemical markers of stress.
Materials and Methods:
The study was conducted in the human pharmacology laboratory. The study design was open labeled, comparing the baseline variables with values after Shirodhara. The subjects (n = 16) chosen were healthy human volunteers who gave an informed consent. Shirodhara was preceded by Abhyanga – whole body massage. The Shirodhara method was standardized for rate of dripping with peristaltic pump and temperature was controlled with a thermostat. Mood and stress levels were assessed by validated rating scales. The pre- and post-Shirodhara ECG and EEG records were evaluated.
Student's paired “t” test was applied to the means + SE of the variables to calculate statistical significance at P <0.05. There was a significant improvement in mood scores and the level of stress (P <0.001). These changes were accompanied by significant decrease in rate of breathing and reduction in diastolic blood pressure along with reduction in heart rate. The relaxed alert state, after Shirodhara, was co-related with an increase in alfa rhythm in EEG.
A standardized Shirodhara leads to a state of alert calmness similar to the relaxation response observed in meditation. The clinical benefits observed with Shirodhara in anxiety neurosis, hypertension, and stress aggravation due to chronic degenerative diseases could be mediated through these adaptive physiological effects.
PMCID: PMC3667433  PMID: 23741161
Ayurveda; Shirodhara; stress
9.  Family nurture intervention (FNI): methods and treatment protocol of a randomized controlled trial in the NICU 
BMC Pediatrics  2012;12:14.
The stress that results from preterm birth, requisite acute care and prolonged physical separation in the Neonatal Intensive Care Unit (NICU) can have adverse physiological/psychological effects on both the infant and the mother. In particular, the experience compromises the establishment and maintenance of optimal mother-infant relationship, the subsequent development of the infant, and the mother's emotional well-being. These findings highlight the importance of investigating early interventions that are designed to overcome or reduce the effects of these environmental insults and challenges.
This study is a randomized controlled trial (RCT) with blinded assessment comparing Standard Care (SC) with a novel Family Nurture Intervention (FNI). FNI targets preterm infants born 26-34 weeks postmenstrual age (PMA) and their mothers in the NICU. The intervention incorporates elements of mother-infant interventions with known efficacy and organizes them under a new theoretical context referred to collectively as calming activities. This intervention is facilitated by specially trained Nurture Specialists in three ways: 1) In the isolette through calming interactions between mother and infant via odor exchange, firm sustained touch and vocal soothing, and eye contact; 2) Outside the isolette during holding and feeding via the Calming Cycle; and 3) through family sessions designed to engage help and support the mother. In concert with infant neurobehavioral and physiological assessments from birth through 24 months corrected age (CA), maternal assessments are made using standard tools including anxiety, depression, attachment, support systems, temperament as well as physiological stress parameters. Quality of mother-infant interaction is also assessed. Our projected enrolment is 260 families (130 per group).
The FNI is designed to increase biologically important activities and behaviors that enhance maternally-mediated sensory experiences of preterm infants, as well as infant-mediated sensory experiences of the mother. Consequently, we are enlarging the testing of preterm infant neurodevelopment beyond that of previous research to include outcomes related to mother-infant interactions and mother-infant co-regulation. Our primary objective is to determine whether repeated engagement of the mother and her infant in the intervention's calming activities will improve the infant's developmental trajectory with respect to multiple outcomes. Our secondary objective is to assess the effectiveness of FNI in the physiological and psychological co-regulation of the mother and infant. We include aspects of neurodevelopment that have not been comprehensively measured in previous NICU interventions.
Trial Registration NCT01439269
PMCID: PMC3394087  PMID: 22314029
10.  Physical activity, but not environmental complexity, facilitates HPA axis response habituation to repeated audiogenic stress despite neurotrophin mRNA regulation in both conditions 
Brain research  2010;1362:68-77.
Stress exacerbates several physical and psychological disorders. Voluntary exercise can reduce susceptibility to many of these stress-associated disorders. In rodents, voluntary exercise can reduce hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to various stressors as well as upregulate several brain neurotrophins. An important issue regarding voluntary exercise is whether its effect on the reduction of HPA axis activation in response to stress is due to the physical activity itself or simply the enhanced environmental complexity provided by the running wheels. The present study compared the effects of physical activity and environmental complexity (that did not increase physical activity) on HPA axis habituation to repeated stress and modulation of brain neurotrophin mRNA expression. For six weeks, male rats were given free access to running wheels (exercise group), given 4 objects that were repeatedly exchanged (increased environmental complexity group), or housed in standard cages. On week 7, animals were exposed to 11 consecutive daily 30-min sessions of 98-dBA noise. Plasma corticosterone and adrenocorticotropic hormone were measured from blood collected directly after noise exposures, and brains, thymi, and adrenal glands were collected on day 11. Although rats in both the exercise and enhanced environmental complexity groups expressed higher levels of BDNF and NGF mRNA in several brain regions, only exercise animals showed quicker glucocorticoid habituation to repeated audiogenic stress. These results suggest that voluntary exercise, independently from other environmental manipulations, accounts for the reduction in susceptibility to stress.
PMCID: PMC2975821  PMID: 20851112
voluntary physical activity; HPA- axis; stress habituation; BDNF; in situ hybridization
11.  Trajectories of Change in Anxiety Severity and Impairment During and After Treatment with Evidence-Based Treatment for Multiple Anxiety Disorders in Primary Care 
Depression and anxiety  2013;30(11):1099-1106.
Coordinated Anxiety Learning and Management (CALM) is a model for delivering evidence-based treatment for anxiety disorders in primary care. Compared to usual care, CALM produced greater improvement in anxiety symptoms. However, mean estimates can obscure heterogeneity in treatment response. This study aimed to identify (1) clusters of participants with similar patterns of change in anxiety severity and impairment (trajectory groups); and (2) characteristics that predict trajectory group membership.
The CALM randomized controlled effectiveness trial was conducted in 17 primary care clinics in 4 US cities in 2006–2009. 1,004 English- or Spanish-speaking patients age 18–75 with panic, generalized anxiety, social anxiety, and/or posttraumatic stress disorder participated. The Overall Anxiety Severity and Impairment Scale was administered repeatedly to 482 participants randomized to CALM treatment. Group-based trajectory modeling was applied to identify trajectory groups and multinomial logit to predict trajectory group membership.
Two predicted trajectories, representing about two-thirds of participants, were below the cut-off for clinically significant anxiety a couple of months after treatment initiation. The predicted trajectory for the majority of remaining participants was below by nine months. A small group of participants did not show consistent improvement. Being sicker at baseline, not working, and reporting less social support were associated with less favorable trajectories.
There is heterogeneity in patient response to anxiety treatment. Adverse circumstances appear to hamper treatment response. To what extent anxiety symptoms improve insufficiently because adverse patient circumstances contribute to suboptimal treatment delivery, suboptimal treatment adherence, or suboptimal treatment response requires further investigation.
Clinical Trial Registration Identifier: NCT00347269
PMCID: PMC3902647  PMID: 23801589
Anxiety/anxiety disorders; CBT/cognitive behavior therapy; primary care; treatment; life events/stress
12.  Delivery of Evidence-Based Treatment for Multiple Anxiety Disorders in Primary Care: A Randomized Controlled Trial 
Improving the quality of mental health care requires moving clinical interventions from controlled research settings into “real world” practice settings. While such advances have been made for depression, little work has been done for anxiety disorders.
To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders (panic, generalized anxiety, social anxiety, and/or posttraumatic stress disorders) would be superior to usual care.
Design, Setting, and Participants
Randomized controlled effectiveness trial of CALM (“Coordinated Anxiety Learning and Management”) compared to usual care (UC) in 17 primary care clinics in 4 US cities. Between June 2006 and April 2008, 1004 patients with anxiety disorders (with or without major depression), age 18–75, English- or Spanish-speaking, enrolled and subsequently received treatment for 3–12 months. Blinded follow-up assessments at 6, 12, and 18 months after baseline were completed in October 2009.
CALM allowed choice of cognitive behavioral therapy (CBT), medication, or both; included real-time web-based outcomes monitoring to optimize treatment decisions and a computer-assisted program to optimize delivery of CBT by non-expert care managers who also assisted primary care providers in promoting adherence and optimizing medications.
Main Outcome Measure(s)
12-item Brief Symptom Inventory (anxiety and somatic symptoms) score. Secondary outcomes: Proportion of responders (≥ 50% reduction from pre-treatment BSI-12 score) and remitters (total BSI-12 score < 6).
Significantly greater improvement for CALM than UC in global anxiety symptoms: BSI-12 group differences of −2.49 (95% CI, −3.59 to −1.40), −2.63 (95% CI, −3.73 to −1.54), and −1.63 (95% CI, −2.73 to −0.53) at 6, 12, and 18 months, respectively. At 12 months, response and remission rates (CALM vs. UC) were 63.66% (58.95–68.37) vs. 44.68% (39.76–49.59), and 51.49% (46.60–56.38) vs. 33.28% (28.62–37.93), with a number needed to treat (NNT) of 5.27 (4.18–7.13) for response and 5.5 (4.32–7.55) for remission.
For patients with anxiety disorders treated in primary care clinics, a collaborative care intervention, compared to usual care, resulted in greater improvement in anxiety symptoms, functional disability, and quality of care over 18 months.
PMCID: PMC2928714  PMID: 20483968
13.  Incremental Benefits and Cost of Coordinated Anxiety Learning and Management for Anxiety Treatment in Primary Care 
Psychological medicine  2011;42(9):1937-1948.
Improving the quality of mental health care requires integrating successful research interventions into “real-world” practice settings. Coordinated Anxiety Learning and Management (CALM) is a treatment-delivery model for anxiety disorders encountered in primary care. CALM offers cognitive behavioral therapy (CBT), medication, or both; non-expert care managers assisting primary care clinicians with adherence promotion and medication optimization; computer-assisted CBT delivery; and outcome monitoring. This study describes incremental benefits, costs, and net benefits of CALM versus usual care.
The CALM randomized, controlled effectiveness trial was conducted in 17 primary care clinics in 4 US cities from 2006 to 2009. Of 1,062 eligible patients, 1,004 English- or Spanish-speaking patients age 18–75 years with panic, generalized anxiety, social anxiety, and/or posttraumatic stress disorder with or without major depression were randomized. Anxiety-free days, quality-adjusted life years (QALYs), and expenditures for outpatient visits, emergency room visits, inpatient stays, and psychiatric medications were estimated based on blinded telephone assessments at baseline, 6, 12, and 18 months.
Over 18 months, CALM participants, on average, experienced 57.1 more anxiety-free days [95% confidence interval (CI) 31–83] and $245 additional medical expenses (95% CI $ −733 to $1,223). The mean incremental net benefit of CALM versus usual care was positive when an anxiety-free day was valued ≥ $4. For QALYs based on the Short-Form Health Survey-12 and the EQ-5D the mean incremental net benefit was positive at ≥ $5,000.
Compared with usual care, CALM provides significant benefits with modest increases in health care expenditures.
PMCID: PMC3340455  PMID: 22152230
14.  Environmental Enrichment Alters Splenic Immune Cell Composition and Enhances Secondary Influenza Vaccine Responses in Mice 
Molecular Medicine  2014;20(1):179-190.
Chronic stress has deleterious effects on immune function, which can lead to adverse health outcomes. However, studies investigating the impact of stress reduction interventions on immunity in clinical research have yielded divergent results, potentially stemming from differences in study design and genetic heterogeneity, among other clinical research challenges. To test the hypothesis that reducing glucocorticoid levels enhances certain immune functions, we administered influenza vaccine once (prime) or twice (boost) to mice housed in either standard control caging or environmental enrichment (EE) caging. We have shown that this approach reduces mouse corticosterone production. Compared with controls, EE mice had significantly lower levels of fecal corticosterone metabolites (FCMs) and increased splenic B and T lymphocyte numbers. Corticosterone levels were negatively associated with the numbers of CD19+ (r2 = 0.43, p = 0.0017), CD4+ (r2 = 0.28, p = 0.0154) and CD8+ cells (r2 = 0.20, p = 0.0503). Vaccinated mice showed nonsignificant differences in immunoglobulin G (IgG) titer between caging groups, although EE mice tended to exhibit larger increases in titer from prime to boost than controls; the interaction between the caging group (control versus EE) and vaccine group (prime versus boost) showed a strong statistical trend (cage-group*vaccine-group, F = 4.27, p = 0.0555), suggesting that there may be distinct effects of EE caging on primary versus secondary IgG vaccine responses. Vaccine-stimulated splenocytes from boosted EE mice had a significantly greater frequency of interleukin 5 (IL-5)-secreting cells than boosted controls (mean difference 7.7, IL-5 spot-forming units/106 splenocytes, 95% confidence interval 0.24–135.1, p = 0.0493) and showed a greater increase in the frequency of IL-5–secreting cells from prime to boost. Our results suggest that corticosterone reduction via EE caging was associated with enhanced secondary vaccine responses, but had little effect on primary responses in mice. These findings help identify differences in primary and secondary vaccine responses in relationship to stress mediators that may be relevant in clinical studies.
PMCID: PMC4002849  PMID: 24687160
15.  Traffic calming policy can reduce inequalities in child pedestrian injuries: database study 
Injury Prevention  2005;11(3):152-156.
Objectives: To determine whether area wide traffic calming distribution reflects known inequalities in child pedestrian injury rates. To determine whether traffic calming is associated with changes in childhood pedestrian injury rates.
Design: Small area ecological study, longitudinal analysis of injury rates with cross sectional analysis of traffic calming and method of travel to school.
Settings: Two cities in the United Kingdom.
Participants: 4–16 year old children between 1992 and 2000.
Main outcome measures: Area wide traffic calming distribution by area deprivation status and changes in injury rate/1000.
Results: The most deprived fourth of city A had 4.8 times (95% CI 3.71 to 6.22) the number of traffic calming features per 1000 population compared with the most affluent fourth. Injury rates among the most deprived dropped from 9.42 to 5.07 from 1992–94 to 1998–2000 (95% CI for change 2.82 to 5.91). In city B, the traffic calming ratio of the most to least deprived fourth was 1.88 (95% CI 1.46 to 2.42); injury rates in the deprived areas dropped from 8.92 to 7.46 (95% CI for change –0.84 to 3.77). Similar proportions of 9–12 year olds walked to school in both cities.
Conclusions: Area wide traffic calming is associated with absolute reductions in child pedestrian injury rates and reductions in relative inequalities in child pedestrian injury rates.
PMCID: PMC1730223  PMID: 15933407
16.  The role of CALM-AF10 gene fusion in acute leukemia 
Chromosomal translocations are important genetic perturbations frequently associated with hematologic malignancies; characterization of these events has been a rich source of insights into the mechanisms that lead to malignant transformation. The t(10;11)(p13;q14–21) results in a recently identified rare but recurring chromosomal translocation seen in patients with ALL as well as AML, and results in the production of a CALM-AF10 fusion gene. Although the details by which the CALM-AF10 fusion protein exerts its leukemogenic effect remain unclear, emerging data suggests that the CALM-AF10 fusion impairs differentiation of hematopoietic cells, at least in part via an upregulation of HOXA cluster genes. This review discusses the normal structure and function of CALM and AF10; describes the spectrum of clinical findings seen in patients with CALM-AF10 fusions; summarizes recently published CALM-AF10 mouse models; and highlights the role of HOXA cluster gene activation in CALM-AF10 leukemia.
PMCID: PMC2366104  PMID: 18094714
CALM-AF10; acute leukemia; chromosomal translocations; t(10;11)
17.  Numerical simulation on the effects of drug eluting stents at different Reynolds numbers on hemodynamic and drug concentration distribution 
BioMedical Engineering OnLine  2015;14(Suppl 1):S16.
The changes of hemodynamics and drug concentration distribution caused by the implantation of drug eluting stents (DESs) in curved vessels have significant effects on In-Stent Restenosis.
A 3D virtual stent with 90°curvature was modelled and the distribution of wall shear stress (WSS) and drug concentration in this model were numerically studied at Reynolds numbers of 200, 400, 600, 800.
The results showed that (1) the intensity of secondary flow at the 45° cross-section was stronger than that at the 90° cross-section; (2) As the Reynolds number increases, the WSS decreases. When the Reynolds number reaches 600, the low-WSS region only accounts for 3% of the total area. (3) The effects of Reynolds number on drug concentration in the vascular wall decreases in proportionally and then the blood velocity increased 4 times, the drug concentration in the vascular wall decreased by about 30%. (4) The size of the high drug concentration region is inversely proportional to the Reynolds number. As the blood velocity increases, the drug concentration in the DES decreases, especially at the outer bend.
It is beneficial for the patient to decrease vigorous activities and keep calm at the beginning of the stent implantation, because a substantial amount of the drug is released in the first two months of stent implantation, thus a calm status is conducive to drug release and absorption; Subsequently, appropriate exercise which increases the blood velocity is helpful in decreasing regions of low-WSS.
PMCID: PMC4306105  PMID: 25602685
DES; curved artery; secondary flow; Reynolds number; WSS; drug concentration
18.  Effect of Compassion Meditation on Neuroendocrine, Innate Immune and Behavioral Responses to Psychosocial Stress 
Psychoneuroendocrinology  2008;34(1):87-98.
Meditation practices may impact physiological pathways that are modulated by stress and relevant to disease. While much attention has been paid to meditation practices that emphasize calming the mind, improving focused attention, or developing mindfulness, less is known about meditation practices that foster compassion. Accordingly, the current study examined the effect of compassion meditation on innate immune, neuroendocrine and behavioral responses to psychosocial stress and evaluated the degree to which engagement in meditation practice influenced stress-reactivity. Sixty-one healthy adults were randomized to 6 weeks of training in compassion meditation (n=33) or participation in a health discussion control group (n=28) followed by exposure to a standardized laboratory stressor (Trier Social Stress Test [TSST]). Physiologic and behavioral responses to the TSST were determined by repeated assessments of plasma concentrations of interleukin (IL)-6 and cortisol as well as total distress scores on the Profile of Mood States (POMS). No main effect of group assignment on TSST responses was found for IL-6, cortisol or POMS scores. However, within the meditation group, increased meditation practice was correlated with decreased TSST-induced IL-6 (rp =-0.46, p=0.008) and POMS distress scores (rp =-0.43, p=0.014). Moreover, individuals with meditation practice times above the median exhibited lower TSST-induced IL-6 and POMS distress scores compared to individuals below the median, who did not differ from controls. These data suggest that engagement in compassion meditation may reduce stress-induced immune and behavioral responses, although future studies are required to determine whether individuals who engage in compassion meditation techniques are more likely to exhibit reduced stress reactivity.
PMCID: PMC2695992  PMID: 18835662
meditation; compassion; mindfulness; Trier Social Stress Test; cortisol; interleukin-6
19.  Abrogation of MLL-AF10 and CALM-AF10 mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l 
Leukemia  2012;27(4):813-822.
The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL-AF10 and CALM-AF10 fusion oncoproteins respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here we demonstrate that MLL-AF10 and CALM-AF10 mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia.. Treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively suppressed proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemias bearing chromosomal translocations that involve the AF10 gene may benefit from small molecule therapeutics that inhibit H3K79 methylation.
PMCID: PMC3932800  PMID: 23138183
MLL-AF10; CALM-AF10; MLL fusions; leukemia; Dot1l; EPZ004777
20.  Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid 
Inflammation is associated with Aβ pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1β and TNF-α which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces Aβ pathology and is neuroprotective. Low concentrations of IFN-γ modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17–19 months) Tg2576 mice to a response that reduces Aβ pathology.
TG (n = 29) and WT (n = 27) mice were divided into sedentary (SED) and exercised (RUN) groups. RUN animals were provided an in-cage running wheel for 3 weeks. Tissue was harvested and hippocampus and cortex dissected out. Quantitative data was analyzed using 2 × 2 ANOVA and student's t-tests.
IL-1β and TNF-α were significantly greater in hippocampi from sedentary Tg2576 (TGSED) mice than in wildtype (WTSED) (p = 0.04, p = 0.006). Immune response proteins IFN-γ and MIP-1α are lower in TGSED mice than in WTSED (p = 0.03, p = 0.07). Following three weeks of voluntary wheel running, IL-1β and TNF-α decreased to levels indistinguishable from WT. Concurrently, IFN-γ and MIP-1α increased in TGRUN. Increased CD40 and MHCII, markers of antigen presentation, were observed in TGRUN animals compared to TGSED, as well as CD11c staining in and around plaques and vasculature. Additional vascular reactivity observed in TGRUN is consistent with an alternative activation immune pathway, involving perivascular macrophages. Significant decreases in soluble Aβ40 (p = 0.01) and soluble fibrillar Aβ (p = 0.01) were observed in the exercised transgenic animals.
Exercise shifts the immune response from innate to an adaptive or alternative response. This shift in immune response coincides with a decrease in Aβ in advanced pathological states.
PMCID: PMC2329612  PMID: 18400101
21.  Voluntary Exercise Prevents Lead-Induced Elevation of Oxidative Stress and Inflammation Markers in Male Rat Blood 
The Scientific World Journal  2013;2013:320704.
Regular mild exercise enhances antioxidant and anti-inflammatory systems of the body. The present study investigates voluntary exercise effects on lead toxicity as a known oxidative stressor. Male Sprague-Dawley rats were randomly divided into 2 groups. Sedentary control: the animals were housed 7 weeks in the regular cages. Exercise group: the animals were housed 7 weeks in the running wheel equipped cages, that is, the animal model of voluntary exercise. During the 7th week, all animals were administered lead acetate. Blood samples were collected at the end of the 6th week and 7th week (before and after lead administrations). Glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and tumor necrosis factor (TNF-α) were measured in the samples. Our results showed that lead administration reduced blood SOD, GPx and CAT and increased TNF-α; in the controls, but in the exercise group, changes were not statistically significant. MDA in both groups increased after lead injections but it was significantly lower in exercise group compared to the sedentary animals. We concluded that voluntary exercise may be considered as a preventive tool against lead-induced oxidative stress and inflammation.
PMCID: PMC3814097  PMID: 24222729
22.  Voluntary Running in Young Adult Mice Reduces Anxiety-Like Behavior and Increases the Accumulation of Bioactive Lipids in the Cerebral Cortex 
PLoS ONE  2013;8(12):e81459.
Combinatorial therapies using voluntary exercise and diet supplementation with polyunsaturated fatty acids have synergistic effects benefiting brain function and behavior. Here, we assessed the effects of voluntary exercise on anxiety-like behavior and on total FA accumulation within three brain regions: cortex, hippocampus, and cerebellum of running versus sedentary young adult male C57/BL6J mice. The running group was subjected to one month of voluntary exercise in their home cages, while the sedentary group was kept in their home cages without access to a running wheel. Elevated plus maze (EPM), several behavioral postures and two risk assessment behaviors (RABs) were then measured in both animal groups followed immediately by blood samplings for assessment of corticosterone levels. Brains were then dissected for non-targeted lipidomic analysis of selected brain regions using gas chromatography coupled to mass spectrometry (GC/MS). Results showed that mice in the running group, when examined in the EPM, displayed significantly lower anxiety-like behavior, higher exploratory and risky behaviors, compared to sedentary mice. Notably, we found no differences in blood corticosterone levels between the two groups, suggesting that the different EPM and RAB behaviors were not related to reduced physiological stress in the running mice. Lipidomics analysis revealed a region-specific cortical decrease of the saturated FA: palmitate (C16:0) and a concomitant increase of polyunsaturated FA, arachidonic acid (AA, omega 6-C20: 4) and docosahexaenoic acid (DHA, omega 3-C22: 6), in running mice compared to sedentary controls. Finally, we found that running mice, as opposed to sedentary animals, showed significantly enhanced cortical expression of phospholipase A2 (PLA2) protein, a signaling molecule required in the production of both AA and DHA. In summary, our data support the anxiolytic effects of exercise and provide insights into the molecular processes modulated by exercise that may lead to its beneficial effects on mood.
PMCID: PMC3859495  PMID: 24349072
23.  Combined Effects of Turbulence and Different Predation Regimes on Zooplankton in Highly Colored Water—Implications for Environmental Change in Lakes 
PLoS ONE  2014;9(11):e111942.
In aquatic ecosystems, predation is affected both by turbulence and visibility, but the combined effects are poorly known. Both factors are changing in lakes in the Northern Hemisphere; the average levels of turbulence are predicted to increase due to increasing wind activities, while water transparency is decreasing, e.g., due to variations in precipitation, and sediment resuspension. We explored experimentally how turbulence influenced the effects of planktivorous fish and invertebrate predators on zooplankton when it was combined with low visibility caused by high levels of water color. The study was conducted as a factorial design in 24 outdoor ponds, using the natural zooplankton community as a prey population. Perch and roach were used as vertebrate predators and Chaoborus flavicans larvae as invertebrate predators. In addition to calm conditions, the turbulent dissipation rate used in the experiments was 10−6 m2 s−3, and the water color was 140 mg Pt L−1. The results demonstrated that in a system dominated by invertebrates, predation pressure on cladocerans increased considerably under intermediate turbulence. Under calm conditions, chaoborids caused only a minor reduction in the crustacean biomass. The effect of fish predation on cladocerans was slightly reduced by turbulence, while predation on cyclopoids was strongly enhanced. Surprisingly, under turbulent conditions fish reduced cyclopoid biomass, whereas in calm water it increased in the presence of fish. We thus concluded that turbulence affects fish selectivity. The results suggested that in dystrophic invertebrate-dominated lakes, turbulence may severely affect the abundance of cladocerans. In fish-dominated dystrophic lakes, on the other hand, turbulence-induced changes in planktivory may considerably affect copepods instead of cladocerans. In lakes inhabited by both invertebrates and fish, the response of top-down regulation to turbulence resembles that in fish-dominated systems, due to intraguild predation. The changes in planktivorous predation induced by abiotic factors may possibly cascade to primary producers.
PMCID: PMC4223065  PMID: 25375952
24.  Pre-infection physical exercise decreases mortality and stimulates neurogenesis in bacterial meningitis 
Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily). Experiments were terminated either 30 hours or 4 days (short-term) or 7 weeks (long-term) after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test). At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher’s Exact test). Hippocampal neurogenesis – assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells - was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.
PMCID: PMC3419614  PMID: 22781194
Exercise; Survival; Mortality; Neurogenesis; Streptococcus pneumoniae; Bacterial meningitis
25.  Effect of Exercise on Photoperiod-Regulated Hypothalamic Gene Expression and Peripheral Hormones in the Seasonal Dwarf Hamster Phodopus sungorus 
PLoS ONE  2014;9(3):e90253.
The Siberian hamster (Phodopus sungorus) is a seasonal mammal responding to the annual cycle in photoperiod with anticipatory physiological adaptations. This includes a reduction in food intake and body weight during the autumn in anticipation of seasonally reduced food availability. In the laboratory, short-day induction of body weight loss can be reversed or prevented by voluntary exercise undertaken when a running wheel is introduced into the home cage. The mechanism by which exercise prevents or reverses body weight reduction is unknown, but one hypothesis is a reversal of short-day photoperiod induced gene expression changes in the hypothalamus that underpin body weight regulation. Alternatively, we postulate an exercise-related anabolic effect involving the growth hormone axis. To test these hypotheses we established photoperiod-running wheel experiments of 8 to 16 weeks duration assessing body weight, food intake, organ mass, lean and fat mass by magnetic resonance, circulating hormones FGF21 and insulin and hypothalamic gene expression. In response to running wheel activity, short-day housed hamsters increased body weight. Compared to short-day housed sedentary hamsters the body weight increase was accompanied by higher food intake, maintenance of tissue mass of key organs such as the liver, maintenance of lean and fat mass and hormonal profiles indicative of long day housed hamsters but there was no overall reversal of hypothalamic gene expression regulated by photoperiod. Therefore the mechanism by which activity induces body weight gain is likely to act largely independently of photoperiod regulated gene expression in the hypothalamus.
PMCID: PMC3946023  PMID: 24603871

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