The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin.

Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms affect the biological responses to metformin in a complex manner.

Circadian repressors CRY1 and CRY2 broadly interact with nuclear receptors and modulate transcriptional activity.

Nuclear hormone receptors (NRs) regulate physiology by sensing lipophilic ligands and adapting cellular transcription appropriately. A growing understanding of the impact of circadian clocks on mammalian transcription has sparked interest in the interregulation of transcriptional programs. Mammalian clocks are based on a transcriptional feedback loop featuring the transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), and transcriptional repressors cryptochrome (CRY) and period (PER). CRY1 and CRY2 bind independently of other core clock factors to many genomic sites, which are enriched for NR recognition motifs. Here we report that CRY1/2 serve as corepressors for many NRs, indicating a new facet of circadian control of NR-mediated regulation of metabolism and physiology, and specifically contribute to diurnal modulation of drug metabolism.

Correlates of Subjective Caregiver Strain in Caregivers of Youth Evaluated in a Pediatric Psychiatric Emergency Room.

BACKGROUND: Although caregiver burden is relevant to the outcome for psychiatrically ill youth, most studies have focused on caregiver burden in the community or research settings. Therefore, we aimed at evaluating the subjective caregiver strain (SCS) at the time of presentation of youth to a pediatric psychiatric emergency room (PPER), assessing potential correlates to provide leads for improvements in formal support systems. METHODS: In this retrospective cohort study, the internalized, externalized, and total SCS were assessed in caregivers of youth <18 years of age consecutively evaluated at a PPER during a 1 year period using the Caregiver Strain Questionnaire. Sociodemographic and a broad range of clinical data were collected during the PPER visit using a 12-page semistructured institutional evaluation form. The Appropriateness of Pediatric Psychiatric Emergency Room Contact scale, incorporating acuity, severity and harm potential, was used to rate appropriateness of the visit. RESULTS: In caregivers of 444 youth, the internalized SCS was significantly higher than the externalized SCS (p < 0.001). Multivariable analyses indicated that higher total and externalized SCS were associated with disruptive behavior or substance abuse/dependent disorder diagnosis, presenting complaint of aggression, and discharge plan to the police. Higher total and internalized SCS were associated with lower child functioning, whereas total and internalized SCS were lower in adopted children. In addition, higher externalized SCS was associated with investigator-rated inappropriateness of the emergency visit, presenting complaint of defiance, and a lack of prior psychiatric ER visits. CONCLUSIONS: High levels of CS in PPER highlight the necessity to adhere to existing guidelines regarding the inclusion of caregivers' perceptions into comprehensive psychiatric assessments. The particularly high strain in caregivers of children with externalizing disorders and in families with low-functioning youth may need to prompt PPER staff to provide efficient information on appropriate treatment options for these children and on support facilities for the parents.

Suicidality and hospitalization as cause and outcome of pediatric psychiatric emergency room visits.

The aim of this study was to identify predictors of suicidality in youth presenting to a pediatric psychiatric emergency room service (PPERS). To this end, we conducted a retrospective cohort study of youth aged <18 years consecutively assessed by a PPERS 01.01.2002-12.31.2002, using a 12-page semi-structured institutional evaluation form and the Columbia Classification Algorithm for Suicide Assessment. Multivariate regression analyses were conducted to identify correlates of suicidal thoughts and attempts/preparation and their relationship to outpatient/inpatient disposition. Of 1,062 youth, 265 (25.0%) presented with suicidal ideation (16.2%) or attempt/preparation (8.8%). Suicidal ideation was associated with female sex, depression, adjustment disorder, absent referral by family/friend/self, school referral, precipitant of peer conflict, and no antipsychotic treatment (p < 0.0001). Suicidal attempt/preparation was associated with female sex, depression, lower GAF score, past suicide attempt, precipitant of peer conflict, and no stimulant treatment (p < 0.0001). Compared to suicidal attempt/preparation, suicidal ideation was associated with school referral, and higher GAF score (p < 0.0001). Of the 265 patients with suicidality, 58.5% were discharged home (ideation = 72.1% vs. attempt/preparation = 33.7%, p < 0.0001). In patients with suicidal ideation, outpatient disposition was associated with higher GAF score, school referral, and adjustment disorder (p < 0.0001). In patients with suicidal attempt/preparation, outpatient disposition was associated with higher GAF score, lower acuity rating, and school referral (p < 0.0001). Suicidality is common among PPERS evaluations. Higher GAF score and school referral distinguished suicidal ideation from suicidal attempt/preparation and was associated with outpatient disposition in both presentations. Increased education of referral sources and establishment of different non-PPERS evaluation systems may improve identification of non-emergent suicidal presentations and encourage more appropriate outpatient referrals.

Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice.

The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolism pathways. We previously demonstrated that NR4A nuclear receptors are highly induced in macrophages in response to inflammatory stimuli and modulate the expression of genes linked to inflammation in vitro. Here we used mouse genetic models to assess the impact of NR4A expression on atherosclerosis development and macrophage polarization. Transplantation of wild-type, Nur77⁻/⁻, or Nor1⁻/⁻ null hematopoetic precursors into LDL receptor (LDLR)⁻/⁻ recipient mice led to comparable development of atherosclerotic lesions after high-cholesterol diet. We also observed comparable induction of genes linked to M1 and M2 responses in wild-type and Nur77-null macrophages in response to lipopolysaccharides and interleukin (IL)-4, respectively. In contrast, activation of the nuclear receptor liver X receptor (LXR) strongly suppressed M1 responses, and ablation of signal transductor and activator of transcription 6 (STAT6) strongly suppressed M2 responses. Recent studies have suggested that alterations in levels of Ly6C(lo) monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6C(lo) monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice.

Frequency and correlates of inappropriate pediatric psychiatric emergency room visits.

BACKGROUND: Despite increasing pediatric psychiatric emergency room service (PPERS) visits, data are lacking regarding visit characteristics and appropriateness. METHOD: This retrospective cohort study consecutively assessed youngsters aged < 18 years between January 1 and December 31, 2002, utilizing data from a 12-page semistructured institutional evaluation form. Appropriateness, severity, acuity, and harm potential of PPERS visits were rated on a Likert scale. RESULTS: Of 1,062 PPERS patient visits (mean +/- SD age: 13.5 +/- 3.1 years, 51.1% male, and 51.2% white), 305 (28.7%) led to hospitalization. Although most patients (68.7%) were in outpatient care, only 21.9% sought and 11.5% completed an outpatient evaluation prior to reaching the emergency room. As many as 34.4% of PPERS visits were somewhat/very inappropriate (optimal care: outpatient evaluation/treatment, even if delayed), 26.6% were somewhat appropriate/neutral (best served by outpatient evaluation/treatment, but timely appointment unavailable), and only 39.0% were fully appropriate. Main reasons for inappropriate PPERS visits were direct emergency room referral from school (P = .0056) or mental health provider (P = .0438) without prior psychiatrist evaluation, or unavailable appointment (P = .0304). Multivariate predictors of inappropriate PPERS visits (r(2) = .296, P < .0001) included current Global Assessment of Functioning score > 48 (P < .0001), absent suicidal ideation/attempt (P < .0001), low harm potential (< 4.4, P < .0001) and severity (< 4.8, P = .0136) (1- to 7-point scale) of presenting complaint, and absent psychosis (P = .0008). CONCLUSIONS: Over one third of PPERS visits were inappropriate, characterized by better functioning, low harm potential or severity of presenting complaint, and absent suicidality or psychosis. Development of and improved access to urgent child and adolescent psychiatric outpatient care services in the community and referral agent educational programs may minimize inappropriate PPERS visits.