microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis
BACKGROUND and AIMS: miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis.
METHODS: miR-122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet.
RESULTS: Liver and hepatocyte miR-122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR-122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR-122 target gene, was induced at all stages of non-alcoholic steatohepatitis (NASH; 3-8 weeks) only at the mRNA level. Increased NF-kappaB activation was found in MCD diet-fed mice and MAP3K3 regulated the NF-kappaB DNA binding in naive hepatocytes. HIF-1alpha mRNA and DNA binding and expression of the HIF-1alpha target gene, profibrotic lysyl oxidase, was increased in advanced steatohepatitis (8 weeks). In addition, increase in vimentin and Sirius red staining (liver fibrosis) was found at 8 weeks of MCD diet. Using miR-122 overexpression and inhibition approaches, we confirmed that HIF-1alpha, vimentin and MAP3K3 are novel miR-122 targets in hepatocytes. We report transcriptional repression of miR-122 in NASH. Decreased liver miR-122 was associated with elevated circulating miR-122 in both exosome-rich and protein-rich serum fractions.
CONCLUSIONS: Our novel data suggest that decreased liver miR-122 contributes to upregulation of modulators of tissue remodelling (HIF-1alpha, vimentin and MAP3K3) and might play a role in NASH-induced liver fibrosis.
AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge.
METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o staining; biochemical studies to look at ALT and triglyceride levels; RNA analysis using quantitative polymerase chain reaction; and cytokine analysis, which included the enzyme-linked immunosorbent assay method to look at interleukin (IL)-1beta and tumor necrosis factor-alpha (TNFalpha) levels. Furthermore, at each length of feeding we also looked at insulin resistance and glucose tolerance using insulin tolerance tests (ITT) and glucose tolerance tests.
RESULTS: There was no insulin resistance, steatosis, or inflammasome activation at 6 wk. In contrast, at 16 wk we found significant insulin resistance demonstrated by impaired glucose and ITT in male, but not female mice. In males, elevated alanine aminotransferase and triglyceride levels, indicated liver damage and steatosis, respectively. Increased liver TNFalpha and monocyte chemoattractant protein-1 mRNA and protein, correlated with steatohepatitis. The inflammasome components, adaptor molecule, Aim2, and NOD-like receptor 4, increased at the mRNA level, and functional inflammasome activation was indicated by increased caspase-1 activity and IL-1beta protein levels in male mice fed a long-term HFD. Male mice on HFD had increased alpha-smooth muscle actin and pro-collagen-1 mRNA indicating evolving fibrosis. In contrast, female mice displayed only elevated triglyceride levels, steatosis, and no fibrosis.
CONCLUSION: Our data indicate gender differences in NASH. Male mice fed a long-term HFD display steatohepatitis and inflammasome activation, whereas female mice have steatosis without inflammation.
Micro-RNA-155 Deficiency Prevents Alcohol-Induced Serum Endotoxin Increase and Small Bowel Inflammation in Mice
BACKGROUND: Chronic alcohol impairs gut barrier function and induces inflammatory cytokines. The effects of acute alcohol binge on the gut are partially understood. Micro-RNA-155 (miR-155), a modulator of cytokine and T-cell immune response in the gut, stabilizes tumor necrosis factor-alpha (TNFalpha) mRNA. Here, we investigated the role of the inflammation modulator miR-155 as well as the effects of acute binge and chronic alcohol feeding in the small bowel (SB) in mice.
METHODS: For the acute alcohol binge, wild-type (WT) mice received 5 g/kg 50% alcohol/d or equal amount of water oral gavage for 3 days. WT and miR-155-deficient (miR-155-knockout [KO]) mice received ethanol containing Lieber-DeCarli or isocaloric control diet for 5 weeks. MiR-155, antimicrobial peptide, regenerating islet-derived 3-beta (Reg3b), inflammation markers, Src homology 2-containing inositol phosphatase-1 (SHIP1), TNFalpha, and nuclear factor-kappaB (NF-kappaB) were measured in proximal intestinal tissue. Endotoxin was measured in the serum.
RESULTS: Acute alcohol binge enhanced, whereas chronic alcohol feeding decreased, Reg3b mRNA and protein levels in the SB. Both acute binge and chronic alcohol feeding increased serum endotoxin levels, intestinal NF-kappaB activation and TNFalpha mRNA levels. However, TNFalpha protein and miR-155 were increased only after chronic alcohol feeding in the SB. Furthermore, miR-155-KO mice were protected from chronic alcohol-induced increase in serum endotoxin, intestinal TNFalpha, and NF-kappaB activation. Also, alcohol-fed miR-155-KO mice had no decrease of Reg3b and SHIP1 levels.
CONCLUSIONS: These results demonstrate that both acute binge and chronic ethanol administration result in increased serum-endotoxin levels. Our study identifies a novel role for miR-155 in chronic alcohol-induced intestinal inflammation and barrier dysfunction.
An electronic health record-based intervention to increase follow-up office visits and decrease rehospitalization in older adults
OBJECTIVES: To assess the effect of an electronic health record-based transitional care intervention involving automated alerts to primary care providers and staff when older adults were discharged from the hospital.
DESIGN: Randomized controlled trial.
SETTING: Large multispecialty group practice.
PARTICIPANTS: Individuals aged 65 and older discharged from hospital to home.
INTERVENTION: In addition to notifying primary care providers about the individual's recent discharge, the system provided information about new drugs added during the inpatient stay, warnings about drug-drug interactions, recommendations for dose changes and laboratory monitoring of high-risk medications, and alerts to the primary care provider's support staff to schedule a posthospitalization office visit.
MEASUREMENTS: An outpatient office visit with a primary care provider after discharge and rehospitalization within 30 days after discharge.
RESULTS: Of the 1,870 discharges in the intervention group, 27.7% had an office visit with a primary care provider within 7 days of discharge. Of the 1,791 discharges in the control group, 28.3% had an office visit with a primary care provider within 7 days of discharge. In the intervention group, 18.8% experienced a rehospitalization within the 30-day period after discharge, compared with 19.9% in the control group. The hazard ratio for an office visit with a primary care physician did not significantly differ between the intervention and control groups. The hazard ratio for rehospitalization in the 30-day period after hospital discharge in the intervention versus the control group was 0.94 (95% confidence interval = 0.81-1.1).
CONCLUSION: This electronic health record-based intervention did not have a significant effect on the timeliness of office visits to primary care providers after hospitalization or risk of rehospitalization. Geriatrics Society.
Rates of insurance for injured patients before and after health care reform in Massachusetts: a possible case of double jeopardy
OBJECTIVES: We determined how preinjury insurance status and injury-related outcomes among able-bodied, community-dwelling adults treated at a Level I Trauma Center in central Massachusetts changed after health care reform.
METHODS: We compared insurance status at time of injury among non-Medicare-eligible adult Massachusetts residents before (2004-2005) and after (2009-2010) health care reform, adjusted for demographic and injury covariates, and modeled associations between insurance status and trauma outcomes.
RESULTS: Among 2148 patients before health care reform and 2477 patients after health care reform, insurance rates increased from 77% to 84% (P < .001). Younger patients, men, minorities, and penetrating trauma victims were less likely to be insured irrespective of time period. Uninsured patients were more likely to be discharged home without services (adjusted odds ratio = 3.46; 95% confidence interval = 2.65, 4.52) compared with insured patients.
CONCLUSIONS: Preinjury insurance rates increased for trauma patients after health care reform but remained lower than in the general population. Certain Americans may be in "double jeopardy" of both higher injury incidence and worse outcomes because socioeconomic factors placing them at risk for injury also present barriers to compliance with an individual insurance mandate.
BACKGROUND: Stroke is a major cause of morbidity and mortality. We describe trends in the incidence, outcomes, and risk factors for stroke in the US Medicare population from 1988 to 2008.
METHODS: We analyzed data from a 20% sample of hospitalized Medicare beneficiaries with a principal discharge diagnosis of ischemic (n = 918,124) or hemorrhagic stroke (n = 133,218). Stroke risk factors were determined from the National Health and Nutrition Examination Survey (years 1988-1994, 2001-2008) and medication uptake from the Medicare Current Beneficiary Survey (years 1992-2008). Primary outcomes were stroke incidence and 30-day mortality after stroke hospitalization.
RESULTS: Ischemic stroke incidence decreased from 927 per 100,000 in 1988 to 545 per 100,000 in 2008, and hemorrhagic stroke decreased from 112 per 100,000 to 94 per 100,000. Risk-adjusted 30-day mortality decreased from 15.9% in 1988 to 12.7% in 2008 for ischemic stroke and from 44.7% to 39.3% for hemorrhagic stroke. Although observed stroke rates decreased, the Framingham stroke model actually predicted increased stroke risk (mean stroke score 8.3% in 1988-1994, 8.8% in 2005-2008). Statin use in the general population increased (4.0% in 1992, 41.4% in 2008), as did antihypertensive use (53.0% in 1992, 73.5% in 2008).
CONCLUSIONS: Incident strokes in the Medicare population aged >/=65 years decreased by approximately 40% over the last 2 decades, a decline greater than expected on the basis of the population's stroke risk factors. Case fatality from stroke also declined. Although causality cannot be proven, declining stroke rates paralleled increased use of statins and antihypertensive medications.
Long-term survival for patients with acute decompensated heart failure according to ejection fraction findings
Limited data exist about the long-term prognosis of patients with acute decompensated heart failure (ADHF) further stratified according to ejection fraction (EF) findings. The primary objective of this population-based observational study was to characterize and compare trends in long-term prognosis after an episode of ADHF across 3 EF strata. Hospital medical records were reviewed for 3,604 residents of the Worcester, Massachusetts, metropolitan area who were discharged after ADHF from all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004 and had EF measurements during their index hospitalizations. The average age of this population was 75 years, most were white, and 44% were men. Approximately 49% of the population had heart failure (HF) with preserved EF (EF >/=50%), 37% had HF with reduced EF (EF
A review of the published literature found 60 congenital and acquired disorders with symptoms that include psychosis in youth. The prevalence, workup, genetics, and associated neuropsychiatric features of each disorder are described. Eighteen disorders (30%) have distinct phenotypes (doorway diagnoses); 18 disorders (30%) are associated with intellectual disability; and 43 disorders (72%) have prominent neurologic signs. Thirty-one disorders (52%) can present without such distinct characteristics, and are thus more easily overlooked. A systematic and cost-effective differential diagnostic approach based on estimated prevalence and most prominent associated signs is recommended.
A recently published study by the present authors reported evidence that functional changes in the anterior cingulate cortex within a sample of 96 criminal offenders who were engaged in a Go/No-Go impulse control task significantly predicted their rearrest following release from prison. In an extended analysis, we use discrimination and calibration techniques to test the accuracy of these predictions relative to more traditional models and their ability to generalize to new observations in both full and reduced models. Modest to strong discrimination and calibration accuracy were found, providing additional support for the utility of neurobiological measures in predicting rearrest.
Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia
OBJECTIVE: The present study aimed to examine the changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia. METHODS: Sixty-two drug naive, first-episode schizophrenia (SZ group) and 60 healthy individuals (control group) were enrolled in the study. Serum interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) levels, and body weight were measured at baseline for both groups, and repeated for the SZ group at five different time points during 6-month risperidone treatment. RESULTS: At baseline, serum IL-1beta, IL-6, and TNF-alpha levels in the SZ group (53.28 +/- 12.62, 33.98 +/- 14.13, 50.08 +/- 12.86 pg/mL, respectively) were significantly higher than those in the control group (23.49 +/- 15.27, 15.53 +/- 7.16, 32.12 +/- 15.23 pg/mL, respectively) (p's < 0.001). Within the SZ group, serum IL-1beta levels decreased significantly at 2 weeks (48.02 +/- 16.00 pg/mL, p < 0.01) and 1 month (44.70 +/- 16.63 pg/mL, p < 0.001), but then gradually increased at 2 months (48.49 +/- 18.87 pg/mL), 3 months (50.59 +/- 18.48 pg/mL) and 6 months (53.64 +/- 16.22 pg/mL) to the levels comparable to baseline; serum IL-6 levels changed significantly over the course of treatment (p = 0.001), but reached the levels comparable to baseline at 6 months (37.13 +/- 13.23 pg/mL); serum levels of TNF-alpha increased significantly at 3 months (55.02 +/- 16.69 pg/mL, p < 0.01) and 6 months (58.69 +/- 13.57 pg/mL, p < 0.001); steady and significant weight gain was observed at each follow-up time point (p's < 0.001), from 56.71 +/- 9.25 kg at baseline to 62.72 +/- 9.53 kg at 6 months. CONCLUSIONS: Risperidone treatment is associated with changes in serum pro-inflammatory cytokines levels and weight. There is an initial anti-inflammatory effect that reduces with treatment, potentially due to its weight gain side effect.
OBJECTIVE: The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance. METHOD: The NTCB was administered to a sample of 1,020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States. RESULTS: General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores. CONCLUSIONS: The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.
Influence of sex and menopausal status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: analysis of data from the PREVENT study
OBJECTIVE: To evaluate the effects of sex and menopausal status on acute-, continuation-, and maintenance-phase treatment outcomes in patients with recurrent major depressive disorder (MDD). METHOD: This was a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) trial, a multiphase, multicenter, double-blind study in which adult outpatients with recurrent MDD (by DSM-IV criteria) were randomly assigned to 10 weeks of acute-phase venlafaxine extended release (ER) (75-300 mg/d) or fluoxetine (20-60 mg/d). Patients achieving response or remission had 6 months of continuation-phase treatment. Responding or remitting patients in the venlafaxine ER group were randomly assigned to venlafaxine ER or placebo for 2 consecutive 12-month maintenance phases; fluoxetine-treated patients continued receiving fluoxetine. The outcome measures for this analysis were acute- and continuation-phase response and remission rates (as measured by the 17-item Hamilton Depression Rating Scale) and time to depression recurrence in the maintenance phases according to sex and menopausal status at baseline. RESULTS: The intent-to-treat population comprised 781 patients in the venlafaxine ER group (65% women) and 266 patients in the fluoxetine group (61% women); 64% of all women were premenopausal, and 25% were postmenopausal (5% perimenopausal; not analyzed). At acute-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 44% vs 47% in men, 51% vs 52% in women, 50% vs 52% in premenopausal women, and 52% vs 55% in postmenopausal women. At continuation-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 71% vs 74% in men, 72% vs 67% in women, 72% vs 69% in premenopausal women and 71% vs 63% in postmenopausal women. Response rates were consistent with these findings. Based on a Cox proportional hazards model, sex was not a significant predictor of recurrence during the first or second maintenance phase (hazard ratio [HR] = 1.233; P = .3712 and HR = 1.103; P = .8075, respectively), and neither was menopausal status at acute-phase baseline (HR = 0.941; P = .8234 and HR = 0.531; P = .2065, respectively). CONCLUSIONS: In this study of patients with recurrent MDD, treatment outcomes with venlafaxine ER and fluoxetine did not differ on the basis of sex or menopausal status. Our confidence in these findings is limited by the lack of a placebo arm during the acute and continuation phases and by the small sample sizes for subgroup analyses in the maintenance phases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00046020.
The real world needs of the clinical community require a domain-specific solution to integrate disparate information available from various web-based resources for data, materials, and tools into routine clinical and clinical research setting. We present a child-psychiatry oriented portal as an effort to deliver a knowledge environment wrapper that provides organization and integration of multiple information and data sources. Organized semantically by resource context, the portal groups information sources by context type, and permits the user to interactively "narrow" or "broaden" the scope of the information resources that are available and relevant to the specific context. The overall objective of the portal is to bring information from multiple complex resources into a simple single uniform framework and present it to the user in a single window format.
Recent neuroscientific evidence indicates that psychopathy is associated with abnormal function and structure in limbic and paralimbic areas. Psychopathy and substance use disorders are highly comorbid, but clinical experience suggests that psychopaths abuse drugs for different reasons than non-psychopaths, and that psychopaths do not typically experience withdrawal and craving upon becoming incarcerated. These neurobiological abnormalities may be related to psychopaths' different motivations for-and symptoms of-drug use. This study examined the modulatory effect of psychopathic traits on the neurobiological craving response to pictorial drug stimuli. Drug-related pictures and neutral pictures were presented and rated by participants while hemodynamic activity was monitored using functional magnetic resonance imaging. These data were collected at two correctional facilities in New Mexico using the Mind Research Network mobile magnetic resonance imaging system. The sample comprised 137 incarcerated adult males and females (93 females) with histories of substance dependence. The outcome of interest was the relation between psychopathy scores (using the Hare Psychopathy Checklist-Revised) and hemodynamic activity associated with viewing drug-related pictures vs. neutral pictures. There was a negative association between psychopathy scores and hemodynamic activity for viewing drug-related cues in the anterior cingulate, posterior cingulate, hippocampus, amygdala, caudate, globus pallidus, and parts of the prefrontal cortex. Psychopathic traits modulate the neurobiological craving response and suggest that individual differences are important for understanding and treating substance abuse.
The relationship between change in apathy and changes in cognition and functional outcomes in currently non-depressed SSRI-treated patients with major depressive disorder
AIMS: Apathy in the context of treated major depressive disorder (MDD) is a frequently observed phenomenon in clinical practice. This study aimed to assess the validity of the Rothschild Scale for Antidepressant Tachyphylaxis(R) (RSAT) and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) for measuring apathy, and to assess the relationship between apathy and possible contributing factors, in patients with MDD and residual apathy in the absence of depressed mood. METHODS: The underlying structure and validity of the RSAT and CPFQ were assessed via factor analysis and correlation with the Apathy Evaluation Scale-Clinician rated version (AES-C) in 483 patients who had previously responded to treatment with a selective serotonin reuptake inhibitor. The relationship between apathy and contributing variables was investigated via structural equation modeling. Correlation and regression analyses were conducted to examine the relationship between the Sheehan Disability Scale (SDS) and the RSAT, CPFQ, and AES-C. RESULTS: The RSAT and CPFQ were validated with the AES-C with respect to energy and motivation. The latent variable "Energy and Interest", based on the energy, motivation, and interest items (RSAT and CPFQ), was a major contributing factor to apathy. Improvements in function (SDS) were significantly correlated with, and predicted by, improvements in apathy and cognitive and physical functioning (assessed by the RSAT, CPFQ, and AES-C). CONCLUSIONS: These analyses provide further information on apathy and its assessment in the context of treated MDD. A better understanding of apathy will aid further investigation of this phenomenon and, ultimately, determination of the most appropriate approach for its clinical management.
The Development of Comorbid Conduct Problems in Children With ADHD: An Example of an Integrative Developmental Psychopathology Perspective
Objective: We describe interactions among factors that contribute to the development of conduct problems among children with ADHD. Method: An integrative developmental psychopathology analysis combines various approaches and posits one model of how diverse risk factors operate together to contribute to the development of conduct problems among children with ADHD. Results: Substantial genetic risk increases covariation between ADHD and conduct problems. Candidate genes are associated with CNS monoaminergic neurotransmission. Subsequent neurodevelopmental impairment interferes with executive function, with impaired verbal working memory playing an important role. Parent/child bi-directional influences exacerbate the risk for conduct problems when ADHD symptoms increase the likelihood of a coercive parenting style. Parent stress in reaction to child comorbid ADHD and conduct problems, and parent attribution for the child's conduct problem behavior, add to the potential for coercion and reduce constructive parent-child interaction that might otherwise enhance the development of verbal working memory. Conclusion: In an integrated manner, these variables increase the risk that a child with ADHD will subsequently develop conduct problems. (J. of Att. Dis. 2013; XX(X) 1-XX).
Exploring Knowledge Exchange at the Research-Policy-Practice Interface in Children's Behavioral Health Services
This case study explored core components of knowledge exchange among researchers, policymakers, and practitioners within the context of the Rosie D. versus Romney class action lawsuit in Massachusetts and the development and implementation of its remedial plan. We identified three distinct, sequential knowledge exchange episodes with different purposes, stakeholders, and knowledge exchanged, as decision-making moved from Federal Medicaid policy to state Medicaid program standards and to community-level practice. The knowledge exchanged included research regarding Wraparound, a key component of the remedial plan, as well as contextual information critical for implementation (e.g., Federal Medicaid policy, managed care requirements, community organizations' characteristics).
Enhancement in cognitive function recovery by granulocyte-colony stimulating factor in a rodent model of traumatic brain injury
Traumatic brain injury (TBI) is characterized by neuronal damage and commonly, secondary cell death, leading to functional and neurological dysfunction. Despite the recent focus of TBI research on developing therapies, affective therapeutic strategies targeting neuronal death associated with TBI remain underexplored. This study explored the efficacy of granulocyte-colony stimulating factor (G-CSF) as an intervention for improving cognitive deficits commonly associated with TBI. Although G-CSF has been studied with histological techniques, to date, its effects on functional outcome remain unknown. To this end, we used a closed head injury (CHI) model in Wistar rats that were randomly assigned to one of four groups (untreated TBI, G-CSF treated TBI, G-CSF treated Control, Control). The treatment groups were administered subcutaneous injections of G-CSF 30 min (120 mug/kg) and 12 h (60 mug/kg) post-trauma. The Morris Water Maze test was used to measure any treatment-associated changes in cognitive deficits observed in TBI animals at days 2-6 post-injury. Our findings demonstrate a significant improvement in cognitive performance in the G-CSF treated TBI animals within a week of injury, compared to untreated TBI, indicative of immediate and beneficial effect of G-CSF on cognitive performance post CHI. Our model suggests that early G-CSF exposure may be a promising therapeutic approach in recovery of cognitive deficits due to TBI.