Evidence has accumulated supporting a role for 5-hydroxytryptamine (5-HT)7 receptors in circadian rhythms, sleep, and mood disorders, presumably as a consequence of the modulation of 5-HT-mediated neuronal activity. We hypothesized that a selective 5-HT7 receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB-269970), should increase activity of 5-HT neurons and potentiate the effect of selective serotonin reuptake inhibitors (citalopram). In rats, administration of 3 mg/kg s.c. citalopram alone increased the extracellular concentration of 5-HT. This effect of citalopram on extracellular 5-HT concentration was significantly enhanced by an ineffective dose of SB-269970. Combining this dose of SB-269970 with a low dose of citalopram also resulted in a significant increase in extracellular concentration of 5-HT, suggesting a potentiation of neurochemical effects. In mice, citalopram and SB-269970 dose-dependently decreased immobility time in the tail suspension test. The dose-effect curve of citalopram was shifted leftward by coadministration of an effective dose of SB-269970. Furthermore, combining ineffective doses of citalopram and SB-269970 also resulted in a significant decrease of immobility time in the tail suspension test, suggesting potentiation of antidepressant-like effects. In rats, SB-269970 potentiated the increase of rapid eye movement (REM) latency and the REM sleep decrease induced by citalopram. SB-269970 also reversed the increase in sleep fragmentation induced by citalopram. Rat plasma and brain concentrations of citalopram were not affected by coadministration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. Overall, these results indicate that selective blockade of 5-HT7 receptors may enhance the antidepressant efficacy of citalopram and may provide a novel therapy to alleviate sleep disturbances associated with depression. 相似文献
BackgroundEnhanced Recovery After Surgery (ERAS) is a global surgical quality-improvement initiative. Little is known about the economic effects of implementing multiple ERAS guidelines in both the short and long term.MethodsWe performed a return on investment (ROI) analysis of the implementation of multiple ERAS guidelines (for colorectal, pancreas, cystectomy, liver and gynecologic oncology procedures) across multiple sites (9 hospitals) in Alberta using 30-, 180- and 365-day time horizons. The effects of ERAS on health services utilization (length of stay of the primary admission, number of readmissions, length of stay of the readmissions, number of emergency department visits, number of outpatient clinic visits, number of specialist visits and number of general practitioner visits) were assessed by mixed-effect multilevel multivariate negative binomial regressions. Net benefits and ROI were estimated by a decision analytic modelling analysis. All costs were reported in 2019 Canadian dollars.ResultsThe net health system savings per patient ranged from $26.35 to $3606.44 and ROI ranged from 1.05 to 7.31, meaning that every dollar invested in ERAS bro-brought $1.05 to $7.31 in return. Probabilities for ERAS to be cost-saving were from 86.5% to 99.9%. The effects of ERAS were found to be larger in the longer time horizons, indicating that if only the 30-day time horizon had been used, the benefits of ERAS would have been underestimated.ConclusionThese results demonstrated that ERAS multiguideline implementation was cost-saving in Alberta. To produce a better ROI, it is important to consider a broad range of health service utilizations, long-term impact, economies of scale, productive efficiency and allocative efficiency for sustainability, scale and spread of ERAS implementations. 相似文献
Obesity is associated with increased morbidity and mortality in abdominal trauma patients. The characteristics of abdominal trauma patients with poor outcomes related to obesity require evaluation. We hypothesize that obesity is related to increased mortality and length of stay (LOS) among abdominal trauma patients undergoing laparotomies.
Methods
Abdominal trauma patients were identified from the National Trauma Data Bank between 2013 and 2015. Patients who received laparotomies were analyzed using propensity score matching (PSM) to evaluate the mortality rate and LOS between obese and non-obese patients. Patients without laparotomies were analyzed as a control group using PSM cohort analysis.
Results
A total of 33,798 abdominal trauma patients were evaluated, 10,987 of them received laparotomies. Of these patients, the proportion of obesity in deceased patients was significantly higher when compared to the survivors (33.1% vs. 26.2%, p < 0.001). Elevation of one kg/m2 of body mass index independently resulted in 2.5% increased odds of mortality. After a well-balanced PSM, obese patients undergoing laparotomies had significantly higher mortality rates [3.7% vs. 2.4%, standardized difference (SD) = 0.241], longer hospital LOS (11.1 vs. 9.6 days, SD = 0.135), and longer intensive care unit LOS (3.5 vs. 2.3 days, SD = 0.171) than non-obese patients undergoing laparotomies.
Conclusions
Obesity is associated with increased mortality in abdominal trauma patients who received laparotomies versus those who did not. Obesity requires a careful evaluation of alternatives to laparotomy in injured patients.
Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h2 = 0.79, P = 3.97e−15) and AVP (h2 = 0.78, P = 3.93e−11). Higher levels of OT were associated with better emotion recognition (β = 0.40, P < .001) and general neuropsychological function (β = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.Key words: oxytocin, vasopressin, schizophrenia, bipolar disorder, emotion recognition相似文献
In prior research by Witkiewitz and colleagues, African American adults receiving refusal skills training (RST) had fewer heavy drinking days and were categorized as having more successful outcomes. This study extends findings to adolescents receiving the Adolescent Community Reinforcement Approach (A-CRA). Propensity score matching was used to create three groups equivalent on baseline characteristics, including: African Americans receiving refusal skills training (AA + RST; n = 214), African Americans not receiving RST (AA-RST; n = 212), and Caucasians receiving RST (CA + RST; n = 214). In propensity weighted regression models that controlled for overall A-CRA exposure, racial group by RST status was not a significant predictor of substance use frequency or abstinence/early remission outcomes. Higher exposure to A-CRA, however, was a significant predictor of both outcomes. Universal receipt of RST may not improve the outcomes of African American adolescents with substance use problems, and outcomes may be driven more by the overall number of A-CRA procedures received. 相似文献
The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus. 相似文献