Animals use circadian rhythms to anticipate daily environmental changes. Circadian clocks have a profound effect on behavior. In Drosophila, for example, brain pacemaker neurons dictate that flies are mostly active at dawn and dusk. miRNAs are small, regulatory RNAs ( approximately 22 nt) that play important roles in posttranscriptional regulation. Here, we identify miR-124 as an important regulator of Drosophila circadian locomotor rhythms. Under constant darkness, flies lacking miR-124 (miR-124(KO)) have a dramatically advanced circadian behavior phase. However, whereas a phase defect is usually caused by a change in the period of the circadian pacemaker, this is not the case in miR-124(KO) flies. Moreover, the phase of the circadian pacemaker in the clock neurons that control rhythmic locomotion is not altered either. Therefore, miR-124 modulates the output of circadian clock neurons rather than controlling their molecular pacemaker. Circadian phase is also advanced under temperature cycles, but a light/dark cycle partially corrects the defects in miR-124(KO) flies. Indeed, miR-124(KO) shows a normal evening phase under the latter conditions, but morning behavioral activity is suppressed. In summary, miR-124 controls diurnal activity and determines the phase of circadian locomotor behavior without affecting circadian pacemaker function. It thus provides a potent entry point to elucidate the mechanisms by which the phase of circadian behavior is determined.
SIGNIFICANCE STATEMENT: In animals, molecular circadian clocks control the timing of behavioral activities to optimize them with the day/night cycle. This is critical for their fitness and survival. The mechanisms by which the phase of circadian behaviors is determined downstream of the molecular pacemakers are not yet well understood. Recent studies indicate that miRNAs are important regulators of circadian outputs. We found that miR-124 shapes diurnal behavioral activity and has a striking impact on the phase of circadian locomotor behavior. Surprisingly, the period and phase of the neural circadian pacemakers driving locomotor rhythms are unaffected. Therefore, miR-124 is a critical modulator of the circadian output pathways that control circadian behavioral rhythms.
Dye-Sensitized Core/Active Shell Upconversion Nanoparticles for Optogenetics and Bioimaging Applications
Near-infrared (NIR) dye-sensitized upconversion nanoparticles (UCNPs) can broaden the absorption range and boost upconversion efficiency of UCNPs. Here, we achieved significantly enhanced upconversion luminescence in dye-sensitized core/active shell UCNPs via the doping of ytterbium ions (Yb(3+)) in the UCNP shell, which bridged the energy transfer from the dye to the UCNP core. As a result, we synergized the two most practical upconversion booster effectors (dye-sensitizing and core/shell enhancement) to amplify upconversion efficiency. We demonstrated two biomedical applications using these UCNPs. By using dye-sensitized core/active shell UCNP embedded poly(methyl methacrylate) polymer implantable systems, we successfully shifted the optogenetic neuron excitation window to a biocompatible and deep tissue penetrable 800 nm wavelength. Furthermore, UCNPs were water-solubilized with Pluronic F127 with high upconversion efficiency and can be imaged in a mouse model.
Studies of the migration of the eastern North American monarch butterfly (Danaus plexippus) have revealed mechanisms behind its navigation. The main orientation mechanism uses a time-compensated sun compass during both the migration south and the remigration north. Daylight cues, such as the sun itself and polarized light, are processed through both eyes and integrated through intricate circuitry in the brain's central complex, the presumed site of the sun compass. Monarch circadian clocks have a distinct molecular mechanism, and those that reside in the antennae provide time compensation. Recent evidence shows that migrants can also use a light-dependent inclination magnetic compass for orientation in the absence of directional daylight cues. The monarch genome has been sequenced, and genetic strategies using nuclease-based technologies have been developed to edit specific genes. The monarch butterfly has emerged as a model system to study the neural, molecular, and genetic basis of long-distance animal migration.
Microglia are resident macrophages of the central nervous system (CNS), representing 5-10% of total CNS cells. Recent findings reveal that microglia enter the embryonic brain, take up residence before the differentiation of other CNS cell types, and become critical regulators of CNS development. Here, we discuss exciting new work implicating microglia in a range of developmental processes, including regulation of cell number and spatial patterning of CNS cells, myelination, and formation and refinement of neural circuits. Furthermore, we review studies suggesting that these cellular functions result in the modulation of behavior, which has important implications for a variety of neurological disorders.
Functional neural competence and integrity require interactive exchanges among sensory and motor neurons, interneurons and glial cells. Recent studies have attributed some of the tasks needed for these exchanges to extracellular vesicles (such as exosomes and microvesicles), which are most prominently involved in shuttling reciprocal signals between myelinating glia and neurons, thus promoting neuronal survival, the immune response mediated by microglia, and synapse assembly and plasticity. Such vesicles have also been identified as important factors in the spread of neurodegenerative disorders and brain cancer. These extracellular vesicle functions add a previously unrecognized level of complexity to transcellular interactions within the nervous system.
This dataset is the primary data source for a manuscript submitted for publication.
Importance: Irritable bowel syndrome (IBS) is associated with significant morbidity in children and adolescents, and the therapeutic efficacy of available treatment options is limited. The role of vitamin D supplementation in pediatric IBS is unclear as the vitamin D status of pediatric patients with IBS is unknown. Equally the relationship of vitamin D status with psychosomatic symptoms in children and adolescents is unclear.
Aim: To characterize the vitamin D status of pediatric patients with IBS using a case-control study design.
Hypothesis: Serum 25-hydroxyvitamin D [25(OH)D] concentration will be similar between patients with IBS and controls.
Subjects and Methods: A retrospective case-controlled study of 116 controls (age 14.6 ± 4.3 y), male (n=49; 42.2%) and 55 subjects with IBS (age 16.5 ± 3.1y), male (n=11; 20%). Vitamin D deficiency was defined as 25(OH)D of /L; overweight as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Seasons were categorized as summer, winter, spring, and fall. Major psychosomatic manifestations included in the analysis were depression, anxiety, and migraine.
Results: More than 50% of IBS subjects had vitamin D deficiency at a cut-off point of/L (52.7% vs. 26.7%, p=0.001); and >90% of IBS subjects had vitamin D deficiency at a cut-off point of/L (92.7% vs. 75%, p=0.006). IBS subjects had significantly lower mean 25(OH)D: 53.2 ± 15.8 nmol/L vs. 65.2 ± 28.0 nmol/L, p=0.003; and albumin: 6.2 ± 0.6 vs. 6.5 ± 0.6 µmol/L, p = 0.014. IBS subjects with migraine had significantly lower mean 25(OH)D level compared to controls (p=0.012). BMI z-score was similar between the controls and IBS subjects (0.5 ± 1.4 vs. 1.2 ± 2.9, p = 0.109).
Conclusion: In this study, patients with IBS had similar BMI as controls, but significantly lower 25(OH)D concentration. More than 50% of children and adolescents with IBS had vitamin D deficiency, while only 7.3% of patients with IBS were vitamin D sufficient. Randomized control trials are warranted to determine the role of adjunctive vitamin D therapy in pediatric IBS.
The Huntingtin (Htt) protein is essential for a wealth of intracellular signaling cascades and when mutated, causes multifactorial dysregulation of basic cellular processes. Understanding the contribution to each of these intracellular pathways is essential for the elucidation of mechanisms that drive pathophysiology. Using appropriate models of Huntington's disease (HD) is key to finding the molecular mechanisms that contribute to neurodegeneration. While mouse models and cell lines expressing mutant Htt have been instrumental to HD research, there has been a significant contribution to our understating of the disease from studies utilizing Drosophila melanogaster. Flies have an Htt protein, so the endogenous pathways with which it interacts are likely conserved. Transgenic flies engineered to overexpress the human mutant HTT gene display protein aggregation, neurodegeneration, behavioral deficits and a reduced lifespan. The short life span of flies, low cost of maintaining stocks and genetic tools available for in vivo manipulation make them ideal for the discovery of new genes that are involved in HD pathology. It is possible to do rapid genome wide screens for enhancers or suppressors of the mutant Htt-mediated phenotype, expressed in specific tissues or neuronal subtypes. However, there likely remain many yet unknown genes that modify disease progression, which could be found through additional screening approaches using the fly. Importantly, there have been instances where genes discovered in Drosophila have been translated to HD mouse models.
OBJECTIVE: Although combat experiences can have a profound impact on individuals' spirituality, there is a dearth of research in this area. Our recent study indicates that one unique spiritual need of veterans who are at the end of life is to resolve distress caused by combat-related events that conflict with their personal beliefs. This study sought to gain an understanding of chaplains' perspectives on this type of spiritual need, as well as the spiritual care that chaplains provide to help veterans ease this distress.
METHOD: We individually interviewed five chaplains who have provided spiritual care to veterans at the end of life in a Veterans Administration hospital. The interviews were recorded, transcribed, and analyzed based on "grounded theory."
RESULTS: Chaplains reported that they frequently encounter veterans at the end of life who are still suffering from thoughts or images of events that occurred during their military career. Although some veterans are hesitant to discuss their experiences, chaplains reported that they have had some success with helping the veterans to open up. Additionally, chaplains reported using both religious (e.g., confessing sins) and nonreligious approaches (e.g., recording military experience) to help veterans to heal.
SIGNIFICANCE OF RESULTS: Our pilot study provides some insight into the spiritual distress that many military veterans may be experiencing, as well as methods that a chaplain can employ to help these veterans. Further studies are needed to confirm our findings and to examine the value of integrating the chaplain service into mental health care for veterans.
Mental health and quality of life among veterans employed as peer and vocational rehabilitation specialists
OBJECTIVE: The study compared employment experiences, mental health recovery, and quality of life among peer specialists and vocational rehabilitation (VR) specialists hired by the U.S. Department of Veterans Affairs (VA), the VR specialists under the Homeless Veterans Supported Employment Program. Employment characteristics associated with mental health recovery were examined.
METHODS: The study was a national, observational survey of 152 peer specialists and 222 VR specialists across 138 VA health care systems in 49 states. The survey, administered over the Internet, included measures describing participant characteristics, employment factors, mental health, and quality of life. The two cohorts were compared by using t tests or chi square tests. Multiple regression analysis controlling for participant characteristics was used to identify employment factors associated with mental health and quality of life.
RESULTS: Peer specialists were more likely than VR specialists to share recovery stories, serve as a role model or mentor, and advocate for veterans. Activities by VR specialists tended to focus more narrowly on job skills. Overall, after adjusting for multiple comparisons, the analysis found high levels of mental health and average quality of life for both cohorts, with no significant differences between the groups. Satisfaction with amount of supervision was consistently associated with aspects of mental health recovery, including work-related and helping-related quality of life, for both cohorts.
CONCLUSIONS: The results highlight the value of work and the importance of supervision in realizing both the adoption of recovery-oriented services and the promotion of mental health in a community of veterans serving each other.
OBJECTIVES: Department of Veterans Affairs (VA) peer specialists and vocational rehabilitation specialists are Veterans employed in mental health services to help other Veterans with similar histories and experiences. Study objectives were to (a) examine job satisfaction among these employees, (b) compare them to other VA mental health workers, and (c) identify factors associated with job satisfaction across the 3 cohorts.
METHODS: The study sample included 152 VA-employed peer specialists and 222 vocational rehabilitation specialists. A comparison group included 460 VA employees from the same job categories. All participants completed the Job Satisfaction Index (11 aspects and overall satisfaction ratings). Linear regression was used to compare job satisfaction and identify its predictors among the 3 cohorts.
RESULTS: Job satisfaction was fairly high, averaging "somewhat satisfied" to "very satisfied" in 6 (peer specialists) and 9 (vocational rehabilitation specialists) of the 11 aspects and overall job ratings. Adjusting for length of employment, age and gender resulted in no significant group differences with 2 exceptions: White peer specialists were less satisfied with pay and promotion opportunities than vocational rehabilitation specialists and comparison-group employees. Across all cohorts, shorter length of time employed in the job was associated with higher job satisfaction.
CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The high job satisfaction levels among the 2 peer cohorts suggest support for the policy of hiring peer specialists in the VA. Furthermore, the results are consistent with those of the nonveteran samples, indicating that integrating peer providers into mental health care is possible in VA and non-VA settings.
OBJECTIVE: This study evaluated three domains of job burnout (emotional exhaustion, depersonalization, and personal accomplishment) and factors associated with burnout in a national sample of peer specialists (PSs) employed at 138 Veterans Health Administration (VHA) health care systems in 49 states.
METHODS: Data were drawn from an observational study in which participants (N=152) completed online, self-report surveys about their mental health recovery, quality of life, and employment experiences at baseline, six months, and 12 months. Levels of burnout were analyzed at each time point, and regression analyses that controlled for baseline levels identified potential predictors of burnout (demographic, clinical, and employment characteristics) at six and 12 months.
RESULTS: Compared with previously published burnout levels of other mental health workers in the VHA, PSs reported similar levels of emotional exhaustion, depersonalization, and personal accomplishment. At baseline, increased burnout was correlated with white race, fewer hours providing direct services, greater psychiatric symptoms, and lower self-efficacy. However, analyses did not reveal strong predictors of burnout scores at six or 12 months.
CONCLUSIONS: In the first study to prospectively examine job burnout among PSs employed by the VHA, results illustrate the nuanced experience of burnout over a 12-month period and suggest the need for replication and further research on employment experiences of this emerging workforce.
Research into the role of diet in health faces a number of methodologic challenges in the choice of study design, measurement methods, and analytic options. Heavier reliance on randomized controlled trial (RCT) designs is suggested as a way to solve these challenges. We present and discuss 7 inherent and practical considerations with special relevance to RCTs designed to study diet: 1) the need for narrow focus; 2) the choice of subjects and exposures; 3) blinding of the intervention; 4) perceived asymmetry of treatment in relation to need; 5) temporal relations between dietary exposures and putative outcomes; 6) strict adherence to the intervention protocol, despite potential clinical counter-indications; and 7) the need to maintain methodologic rigor, including measuring diet carefully and frequently. Alternatives, including observational studies and adaptive intervention designs, are presented and discussed. Given high noise-to-signal ratios interjected by using inaccurate assessment methods in studies with weak or inappropriate study designs (including RCTs), it is conceivable and indeed likely that effects of diet are underestimated. No matter which designs are used, studies will require continued improvement in the assessment of dietary intake. As technology continues to improve, there is potential for enhanced accuracy and reduced user burden of dietary assessments that are applicable to a wide variety of study designs, including RCTs.
Psychiatric history, post-discharge distress, and personality characteristics among incident female cases of takotsubo cardiomyopathy: A case-control study
BACKGROUND: The role of psychological factors in the onset of takotsubo cardiomyopathy (TC) is still controversial. Associations with previous psychiatric conditions are registry-based; associations with personality characteristics and psychological sequelae of TC have been largely unexplored. This case-control study sought to study pre-admission psychiatric morbidity, personality traits, and post-discharge distress in incident cases of TC.
METHODS: TC cases (Mayo clinic criteria) and acute myocardial infarction (MI) controls were recruited among women admitted to two Emergency Departments in New England. Healthy controls (HC) were recruited from a volunteers' registry. Preadmission psychiatric history (DSM-IV-TR) was abstracted from the medical record. PTSD symptoms (Impact of Events Scale); distress (Hospital Anxiety and Depression Scale); perceived stress (PS scale) and personality traits (optimism; hostility, type D personality) were collected via phone interview one month after discharge.
RESULTS: From March 2013 through October 2015, 107 participants (45 TC, 32 MI and 30 HC) were enrolled. The prevalence of preadmission anxiety disorders was 24.4% in TC, 9.4% in MI, and 0 in HC (p = 0.007) while that of mood disorders was similar across groups. TC had higher psychological distress, perceived stress, and PTSD symptoms post-discharge vs. MI and HC. In adjusted models, PTSD symptoms remained higher in TC vs. MI (b = 0.55, p < 0.05) and vs. HC (b = 0.92, p < 0.01). Optimism and hostility scores were similar across groups, while type D (social inhibition) scores were higher in TC and MI vs. HC.
CONCLUSIONS: Preadmission anxiety, but not depression, was associated with the occurrence of TC. High distress and PTSD symptoms post-discharge indicate that TC women may be at risk for poor psychological adjustment.
Approximately 5000 children present to the emergency department annually with unintentional carbon monoxide poisoning. Children may be more vulnerable to carbon monoxide poisoning because of their increased metabolic demand and their inability to vocalize symptoms or recognize a dangerous exposure, and newborn infants are more vulnerable to carbon monoxide poisoning because of the persistence of fetal hemoglobin. Mild carbon monoxide poisoning may present as viral symptoms in the absence of fever. While headache, nausea, and vomiting are the most common presenting symptoms in children, the most common symptom in infants is consciousness disturbance. This review discusses the limitations of routine pulse oximetry and carboxyhemoglobin measurement in determining carbon monoxide exposure, and notes effects of co-ingestions and comorbidities. Although the mainstay of treatment is 100% oxygen, the current evidence and controversies in the use of hyperbaric oxygen therapy in pediatric patients is reviewed, along with its possible benefit in preventing delayed neurologic sequelae.
OBJECTIVE: To determine the association between a widely used individual-level assessment of the medical home derived from parental perception and practice-level assessment of the medical home.
METHODS: Thirty parents at each of 6 Boston-area community health centers (CHCs) were administered the 19-question medical home measure of the 2011 National Survey of Children's Health (NSCH). Each CHC was scored in accordance with the National Committee for Quality Assurance (NCQA) 2011 Patient-Centered Medical Home Standards and Guidelines. Bivariate analysis of the independent variables against the dependent variable (the NCQA measure, assessed as both a continuous score and a categorical tier) was performed. Linear and logistical regression models accounting for the cluster design were then constructed, with the NSCH measure as the primary predictor.
RESULTS: Of the 180 parents, 52% had a medical home according to the NSCH criteria. Of the 6 CHCs, 5 were a medical home according to the NCQA Standards (2 at Tier 3, 3 at Tier 2). Regression modeling demonstrated nonsignificant associations between both the continuous and categorical (tier) NCQA scores and the NSCH assessment of the medical home, with a beta of -2.80 (95% confidence interval, -7.75 to 13.35) and an adjusted odds ratio of 2.17 (95% confidence interval, 0.82 to 5.74), respectively.
CONCLUSIONS: There was no significant association between the individual-level and practice-level assessments of the medical home. Given this discrepancy, our results suggest that we may need to temper our expectations that the medical home transformation currently being implemented at the practice level will lead to the child health and health care utilization outcomes extensively demonstrated in the literature.
A novel behavioral intervention in adolescents with type 1 diabetes mellitus improves glycemic control: preliminary results from a pilot randomized control trial
PURPOSE: The purpose of this study was to develop and pilot-test an innovative behavioral intervention in adolescents with type 1 diabetes mellitus (T1DM) incorporating structured care of a pet to improve glycemic control. METHODS: Twenty-eight adolescents with A1C > 8.5% (69 mmol/mol) were randomly assigned to either the intervention group (care of a Betta splendens pet fish) or the control group (usual care). Adolescents in the intervention group were given instructions to associate daily and weekly fish care duties with diabetes self-management tasks, including blood glucose testing and parent-adolescent communication. RESULTS: After 3 months, the participants in the intervention group exhibited a statistically significant decrease in A1C level (-0.5%) compared with their peers in the control group, who had an increase in A1C level (0.8%) (P = .04). The younger adolescents (10-13 years of age) demonstrated a greater response to the intervention, which was statistically significant (-1.5% vs 0.6%, P = .04), compared with the older adolescents (14-17 years of age). CONCLUSIONS: Structured care of a pet fish can improve glycemic control in adolescents with T1DM, likely by providing cues to perform diabetes self-management behaviors.
Targeted gene delivery to the enteric nervous system using AAV: a comparison across serotypes and capsid mutants
Recombinant adeno-associated virus (AAV) vectors are one of the most widely used gene transfer systems in research and clinical trials. AAV can transduce a wide range of biological tissues, however to date, there has been no investigation on targeted AAV transduction of the enteric nervous system (ENS). Here, we examined the efficiency, tropism, spread, and immunogenicity of AAV transduction in the ENS. Rats received direct injections of various AAV serotypes expressing green fluorescent protein (GFP) into the descending colon. AAV serotypes tested included; AAV 1, 2, 5, 6, 8, or 9 and the AAV2 and AAV8 capsid mutants, AAV2-Y444F, AAV2-tripleY-F, AAV2-tripleY-F+T-V, AAV8-Y733F, and AAV8-doubeY-F+T-V. Transduction, as determined by GFP-positive cells, occurred in neurons and enteric glia within the myenteric and submucosal plexuses of the ENS. AAV6 and AAV9 showed the highest levels of transduction within the ENS. Transduction efficiency scaled with titer and time, was translated to the murine ENS, and produced no vector-related immune response. A single injection of AAV into the colon covered an area of ~47 mm(2). AAV9 primarily transduced neurons, while AAV6 transduced enteric glia and neurons. This is the first report on targeted AAV transduction of neurons and glia in the ENS.
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.