Ketamine for mood disorders, anxiety, and suicidality in children and adolescents: a systematic review.

Mood disorders, anxiety, and suicidality in youth are increasing and rapid-acting treatments are urgently needed. One potential is ketamine or its enantiomer esketamine, which was FDA approved in 2019 to treat major depressive disorder with suicidality in adults. This systematic review evaluated the evidence for the clinical use of ketamine to treat mood disorders, anxiety, and suicidality in youth. The PRISMA guidelines were used, and a protocol registered prospectively ( https://osf.io/9ucsg/ ). The literature search included Pubmed/MEDLINE, Ovid/MEDLINE, Scopus, CINAHL, PsychInfo, and Google Scholar. Trial registries and preprint servers were searched, and authors contacted for clarification. Studies reported on the clinical use of ketamine to treat anxiety, depression, bipolar disorder, or suicidality in youth ≤19 years old and assessed symptoms before and after ketamine use. Study screening and data extraction were conducted independently by 2-4 authors. Safety, tolerability, and efficacy data were collected. The Cochrane Risk of Bias guidelines assessed the quality of the evidence. Twenty-two published reports based on 16 studies were identified: 7 case studies, 6 observational studies, 3 randomized trials, and 6 secondary data analyses. Studies reported immediate improvements in depression, anxiety, and suicidality. Improvements were maintained for weeks-months following treatment. Ketamine was well-tolerated with the most common side effects being dizziness, nausea, and mild dissociation. Transient hemodynamic changes were reported, all of which resolved quickly and did not require medical intervention. Initial evidence suggests ketamine is safe and may be effective for mood disorders, anxiety, and suicidality in youth. Further randomized trials are warranted.

Parental Cannabis Use, Negative Parenting, and Behavior Problems of Young Children.

Introduction: Cannabis use in the United States is increasingly accepted and legal. Rise in use among childbearing aged adults is potentially concerning, as the impacts of parental cannabis use on children are largely unknown, especially for young children. This study examined whether cannabis use is associated with increased risk for negative parenting and child emotional and behavioral problems among the parents of young children. Methods: We conducted a cross-sectional survey of parents and child behavior, recruited through five primary care practices in three states. Parents of children aged 1.5-5 years reported on family demographics, last 6-months cannabis use, negative parenting, parent mental health, parents' adverse childhood experiences (ACEs), and child emotional/behavioral problems. We conducted hierarchical regressions to determine if parental cannabis use predicts negative parenting and/or child emotional/behavioral problems when controlling for other risk factors. Results: Of 266 responding parents, 34 (13%) reported cannabis use in the last 6 months. Parents who endorsed cannabis use reported significantly more negative parenting, ACEs, anxiety, depression, and child emotional/behavioral problems. Adjusting for the effects of other risk factors, cannabis use significantly predicted more negative parenting, but was not uniquely and significantly associated with child emotional/behavioral problems. Conclusion: Parental cannabis predicted negative parenting, which in turn predicted early childhood emotional/behavioral problems; however, parental cannabis use did not predict child emotional/behavioral problems when other risk factors were considered. Further research is needed to elucidate the nature and direction of relationships between parent cannabis use, negative parenting, child psychological outcomes, and other risk factors.

Identification of Split-GAL4 Drivers and Enhancers That Allow Regional Cell Type Manipulations of the Drosophila melanogaster Intestine.

The Drosophila adult midgut is a model epithelial tissue composed of a few major cell types with distinct regional identities. One of the limitations to its analysis is the lack of tools to manipulate gene expression based on these regional identities. To overcome this obstacle, we applied the intersectional split-GAL4 system to the adult midgut and report 653 driver combinations that label cells by region and cell type. We first identified 424 split-GAL4 drivers with midgut expression from ∼7300 drivers screened, and then evaluated the expression patterns of each of these 424 when paired with three reference drivers that report activity specifically in progenitor cells, enteroendocrine cells, or enterocytes. We also evaluated a subset of the drivers expressed in progenitor cells for expression in enteroblasts using another reference driver. We show that driver combinations can define novel cell populations by identifying a driver that marks a distinct subset of enteroendocrine cells expressing genes usually associated with progenitor cells. The regional cell type patterns associated with the entire set of driver combinations are documented in a freely available website, providing information for the design of thousands of additional driver combinations to experimentally manipulate small subsets of intestinal cells. In addition, we show that intestinal enhancers identified with the split-GAL4 system can confer equivalent expression patterns on other transgenic reporters. Altogether, the resource reported here will enable more precisely targeted gene expression for studying intestinal processes, epithelial cell functions, and diseases affecting self-renewing tissues.

NS-Pten adult knockout mice display both quantitative and qualitative changes in urine-induced ultrasonic vocalizations.

The NS-Pten knockout (KO) mouse exhibits hyperactivity of the mammalian target of rapamycin (mTOR) and is a model of autism spectrum disorder (ASD). ASD presents with marked deficits in communication which can be elucidated by investigating their counterpart in mice, ultrasonic vocalizations (USVs). While USVs have been found to be altered in NS-Pten KO pups, no study has assessed whether this communication deficit persists into adulthood. In the present study, we investigate female urine-induced USVs, scent marking behavior, and open field activity in NS-Pten KO and wildtype (WT) adult male mice. Results showed that there was no difference in the quantity of vocalizations produced between groups, however, there were extensive alterations in the spectral properties of USVs. KO mice emitted vocalizations of a lower peak frequency, shorter duration, and higher peak amplitude compared to WT mice. KO animals also emitted a significantly different distribution of call-types relative to controls, displaying increased complex and short calls, but fewer upward, chevron, frequency steps, and composite calls. No significant differences between groups were observed for scent marking behavior and there was no difference between groups in the amount of time spent near the female urine. Overall, this study demonstrated that mTOR hyperactivity contributes to communication deficits in adult mice.

Association between high-fat diet feeding and male fertility in high reproductive performance mice.

The increasing worldwide prevalence of metabolic syndrome (MetS), especially in younger populations, is a risk factor for fertility disorders. However, a direct correlation of MetS with male infertility still remains unclear. In this work, we evaluated whether MetS has a negative impact on fertility of hybrid male mice with high reproductive performance. To induce a MetS-like condition, (C57BL/6xBALB/c) F1 male mice were fed a high-fat diet (HFD, 30% fat) for 19 weeks, while controls received a normal-fat diet (NFD, 6% fat). HFD-fed animals exhibited increased body weight, hypercholesterolemia, hyperglycemia and glucose intolerance. In vivo fertilisation assays performed along the treatment period showed no differences in fertilisation nor in vitro embryo development rates between groups. While testicular weight and morphology were similar in both groups, HFD-fed mice presented lighter epididymides and higher amounts of gonadal fat. Moreover, sperm count was lower in HFD-fed mice, despite normal sperm viability, morphology, motility or acrosome reaction. Finally, no differences were observed in in vitro fertilisation rates between groups. In summary, although HFD feeding altered some reproductive parameters, it did not impair male fertility in high performance breeders suggesting the possibility that a fertility impairment could be the result of the cumulative combination of environmental and/or genetic factors.

The SOAR stroke score predicts hospital length of stay in acute stroke: an external validation study.

AIMS: The objective of this study is to externally validate the SOAR stroke score (Stroke subtype, Oxfordshire Community Stroke Project Classification, Age and prestroke modified Rankin score) in predicting hospital length of stay (LOS) following an admission for acute stroke. METHODS: We conducted a multi-centre observational study in eight National Health Service hospital trusts in the Anglia Stroke & Heart Clinical Network between September 2008 and April 2011. The usefulness of the SOAR stroke score in predicting hospital LOS in the acute settings was examined for all stroke and then stratified by discharge status (discharged alive or died during the admission). RESULTS: A total of 3596 patients (mean age 77 years) with first-ever or recurrent stroke (92% ischaemic) were included. Increasing LOS was observed with increasing SOAR stroke score (p < 0.001 for both mean and median) and the SOAR stroke score of 0 had the shortest mean LOS (12 ± 20 days) while the SOAR stroke score of 6 had the longest mean LOS (26 ± 28 days). Among patients who were discharged alive, increasing SOAR stroke score had a significantly higher mean and median LOS (p < 0.001 for both mean and median) and the LOS peaked among patients with score value of 6 [mean (SD) 35 ± 31 days, median (IQR) 23 (14-48) days]. For patients who died as in-patient, there was no significant difference in mean or median LOS with increasing SOAR stroke score (p = 0.68 and p = 0.79, respectively). CONCLUSION: This external validation study confirms the usefulness of the SOAR stroke score in predicting LOS in patients with acute stroke especially in those who are likely to survive to discharge. This provides a simple prognostic score useful for clinicians, patients and service providers.

Modeling the microstructurally dependent mechanical properties of poly(ester-urethane-urea)s.

Poly(ester-urethane-urea) (PEUU) is one of many synthetic biodegradable elastomers under scrutiny for biomedical and soft tissue applications. The goal of this study was to investigate the effect of the experimental parameters on mechanical properties of PEUUs following exposure to different degrading environments, similar to that of the human body, using linear regression, producing one predictive model. The model utilizes two independent variables of poly(caprolactone) (PCL) type and copolymer crystallinity to predict the dependent variable of maximum tangential modulus (MTM). Results indicate that comparisons between PCLs at different degradation states are statistically different (p < 0.0003), while the difference between experimental and predicted average MTM is statistically negligible (p < 0.02). The linear correlation between experimental and predicted MTM values is R(2) = 0.75.

Effect of physician strategies for coping with the US medical malpractise crisis on healthcare delivery and patient access to healthcare.

The medical liability system in the USA is once again mired in a major malpractise crisis. Physicians have struggled to acquire liability coverage during the crisis, because malpractise insurance has been unaffordable and unavailable. This limited access to affordable liability coverage has prompted some physicians to utilize strategies that reduce their malpractise risk. These strategies have included eliminating high-risk services, defensive medicine, and establishing medical practises in states with affordable malpractise insurance. The fear of malpractise liability and possible financial ruin may justify the use of these strategies. However, these tactics could create a serious public health problem, because they are having a negative impact on healthcare delivery and patient access to healthcare.

Serotonin 1B and 2C receptor interactions in the modulation of feeding behaviour in the mouse.

RATIONALE: To examine the functional relationship between 5-HT1B receptors (5-HT1B-R) and 5-HT2C receptors (5-HT2C-R) in the control of food intake. OBJECTIVES: To compare the hypophagic effect of the 5-HT(2C/1B)-R agonist m-chlorophenylpiperazine (mCPP), with that of the selective 5-HT1B-R agonist CP-94,253 in both wildtype (WT) and 5-HT2C knockout (KO) mice. METHODS: The hypophagic effects of mCPP (1, 3 and 5.6 mg/kg) and CP-94,253 (5, 10 and 20 mg/kg) were assessed in WT and 5-HT2C KO mice using the behavioural satiety sequence paradigm. The effects of pre-treatment with the selective 5-HT2C-R antagonist SB 242,084 (0.5 and 1.5 mg/kg) were assessed in two groups of WT mice, with each group given only mCPP or CP-94,253. RESULTS: The 5-HT(2C/1B) receptor agonist mCPP and the selective 5-HT1B receptor agonist CP-94,253 both suppressed food intake in WT mice. 5-HT2C KO mice were insensitive to the hypophagic effects of mCPP but were more sensitive to CP-94,253-induced hypophagia than WT controls. mCPP induced a significant increase in post-prandial activity in 5-HT2C KO mice, but this effect was absent in 5-HT2C KO mice who were given CP-94,253. Data from WT mice, who were pre-treated with the 5-HT2C receptor antagonist SB 242,084 and then challenged with either mCPP or CP-94,253, were similar to those obtained from 5-HT2C KO mice. CONCLUSIONS: 5-HT2C-R and 5-HT1B-R activation are each sufficient to induce a hypophagic response. However, concurrent 5-HT2C-R inactivation can potentiate the hypophagic response to 5-HT1B-R activation, consistent with an inhibitory role for the 5-HT2C-R in behaviour mediated by the activation of other 5-HT receptors. These results also confirm that 5-HT1B-R activation alone cannot account for the hyperactive response of 5-HT2C KO mice to mCPP.

mCPP-induced hyperactivity in 5-HT2C receptor mutant mice is mediated by activation of multiple 5-HT receptor subtypes.

The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist. As previously reported, mCPP (3 mg/kg) induced hyperactivity in 5-HT2C KO mice. A combination of the 5-HT1B receptor agonist CP-94,253 (20 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg) induced marked hyperactivity in WT but not in 5-HT2C KO mice, nor in mice treated with the selective 5-HT2C receptor antagonist, SB 242084 (1.5 mg/kg). Neither CP-94,253 nor 8-OH-DPAT had any intrinsic effect on locomotion in WTs. mCPP-induced hyperactivity was attenuated in 5-HT2C KO mice by the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg), and the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg) and M100907 (0.01 mg/kg) but not by the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg). The 5-HT(2A/2B/2C) receptor agonist, Ro 60-0175 (3 mg/kg), induced a modest increase in locomotor activity in WT mice pre-treated with SB 242084. However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity. Thus, joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion in WT mice but this response is dependent on a functional 5-HT2C receptor population and hence is absent in 5-HT2C KO mice. By contrast, mCPP-induced hyperactivity depends on the inactivation of a separate 5-HT2C receptor population and is mediated by 5-HT2A and 5-HT1B receptor activation.

New upper limit on the total neutrino mass from the 2 degree field galaxy redshift survey.

We constrain f(nu) identical with Omega(nu)/Omega(m), the fractional contribution of neutrinos to the total mass density in the Universe, by comparing the power spectrum of fluctuations derived from the 2 Degree Field Galaxy Redshift Survey with power spectra for models with four components: baryons, cold dark matter, massive neutrinos, and a cosmological constant. Adding constraints from independent cosmological probes we find f(nu)<0.13 (at 95% confidence) for a prior of 0.1

Complications of achilles and posterior tibial tendon surgeries.

Surgery of the Achilles and posterior tibial tendons requires finesse to achieve optimal function. Although superficial in anatomic location, various critical neurovascular structures exist in close proximity. The superficial blood supply is fragile, requiring a delicate touch to prevent problems with wound healing. Damaged tendon tissue often is friable, making it difficult to sew or anchor. Adjusting the tendon length to the appropriate tension requires good judgment and affects long-term outcome through power and range of motion. Finally, surgery on these two tendons significantly affects function of the ankle and longitudinal arch, where small changes are magnified into large changes in maintaining normal gait. The current authors review the complications encountered in various common surgeries of the Achilles and posterior tibial tendons.

A measurement of the cosmological mass density from clustering in the 2dF Galaxy Redshift Survey.

The large-scale structure in the distribution of galaxies is thought to arise from the gravitational instability of small fluctuations in the initial density field of the Universe. A key test of this hypothesis is that forming superclusters of galaxies should generate a systematic infall of other galaxies. This would be evident in the pattern of recessional velocities, causing an anisotropy in the inferred spatial clustering of galaxies. Here we report a precise measurement of this clustering, using the redshifts of more than 141,000 galaxies from the two-degree-field (2dF) galaxy redshift survey. We determine the parameter beta = Omega0.6/b = 0.43 +/- 0.07, where Omega is the total mass-density parameter of the Universe and b is a measure of the 'bias' of the luminous galaxies in the survey. (Bias is the difference between the clustering of visible galaxies and of the total mass, most of which is dark.) Combined with the anisotropy of the cosmic microwave background, our results favour a low-density Universe with Omega approximately 0.3.

Intra-uterine growth retardation results in increased cardiac arrhythmias and raised diastolic blood pressure in adult rats.

OBJECTIVES: Epidemiological evidence in humans suggests that intrauterine growth retardation is associated with an increased risk of hypertension and coronary heart disease in later life. To begin to understand the mechanisms involved, we developed and exploited a rat model of intrauterine growth retardation to assess predisposition to arrhythmias and resting blood pressure levels at defined ages from 4 to 18 months. METHODS: Isolated working heart experiments were carried out on rats that had been subjected to intrauterine growth retardation by prenatal protein deprivation and age-matched male Wistar controls to measure susceptibility to wall stress-induced arrhythmias. In addition, resting systolic and diastolic blood pressures were measured in conscious rats via an indwelling arterial catheter. RESULTS: Hearts from intrauterine growth retarded animals showed significantly more ventricular premature beats and more episodes of ventricular tachycardia at all ages examined (4, 9 and 18 months), and at 4 and 18 months, a reduction in coronary blood flow. Diastolic pressure was significantly raised by intrauterine growth retardation in both groups examined (4 and 9 months). CONCLUSIONS: Protein malnutrition during the intrauterine period results in profound intrauterine growth retardation that is associated with a raised diastolic blood pressure and an increased predisposition to cardiac arrhythmias in later life. These results are consistent with epidemiological observations made in human populations, and as similar pathophysiological changes may operate in both situations, intrauterine protein deprivation may be a useful model to help define some of the mechanisms involved.

Experimental studies on myocardial stretch and ventricular arrhythmia in hypertrophied and non-hypertrophied hearts.

Hypertension affects about 5% of western populations and in the majority of cases it is of unknown aetiology. It exposes the heart to greater levels of myocardial stretch as a result of increased systolic pressure and peripheral resistance. Under certain circumstances myocardial stretch may trigger arrhythmias but the mechanisms and clinical importance of this phenomenon are unclear. This article outlines the risks of sudden cardiac death conferred by hypertension and left ventricular hypertrophy, presents the results of experiments using an animal model of myocardial stretch and discusses some possible mechanisms underlying stretch-induced arrhythmias which may be important in hypertensive patients.

Changes in contractile protein gene expression with ageing and with captopril-induced regression of hypertrophy in the spontaneously hypertensive rats.

BACKGROUND: Left ventricular hypertrophy (LVH) is present in young spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) rats and treatment of SHR with captopril leads to regression of LVH. Hypertrophy produces changes in gene expression for myofibrillar proteins with increased ratios of skeletal to cardiac actin and beta to alpha-myosin heavy chain (MHC). OBJECTIVES: The objective of this study was to follow changes in transcript prevalence for these four proteins during ageing and with captopril treatment in SHR and WKY rats. METHODS: Untreated SHR and WKY rats were studied at 100, 156, 350 and 450 days. Groups at 100 and 350 days were divided into a treatment group (given captopril) and untreated controls. Transcripts were measured using in situ hybridization. RESULTS: Both cardiac and skeletal actin were increased in untreated SHR compared to WKY rats (P<0.01 and P<0.05, respectively). alpha-MHC was increased (P<0.01) whilst beta-MHC was normal in 100-day-old SHR (an age when LVH was present) compared with WKY rats. With ageing, alpha-MHC declined and beta-MHC increased giving the increased ratio of beta to alpha-MHC transcripts reported by other investigators. Treatment of SHR led to a significant decline in skeletal actin transcripts (P< 0.01) and reversed the rise in beta-MHC expression that occurred with ageing (P< 0.01). CONCLUSIONS: LVH in SHR is associated with increased skeletal and cardiac actin transcripts. Despite unequivocal LVH in SHR at 100 days of age, alpha rather than beta-MHC transcripts were increased. Only with ageing did the classically reported increased ratio of beta to alpha-MHC transcripts become apparent Captopril treatment reduced skeletal actin transcripts and reversed the increase in beta-MHC that occurred with ageing.

Role of intracellular sodium overload in the genesis of cardiac arrhythmias.

A number of clinical cardiac disorders may be associated with a rise of the intracellular Na concentration (Na(i)) in heart muscle. A clear example is digitalis toxicity, in which excessive inhibition of the Na/K pump causes the Na(i) concentration to become raised above the normal level. Especially in digitalis toxicity, but also in many other situations, the rise of Na(i) may be an important (or contributory) cause of increased cardiac arrhythmias. In this review, we consider the mechanisms by which a raised Na(i) may cause cardiac arrhythmias. First, we describe the factors that regulate Na(i), and we demonstrate that the equilibrium level of Na(i) is determined by a balance between Na entry into the cell, and Na extrusion from the cell. A number of mechanisms are responsible for Na entry into the cell, whereas the Na/K pump appears to be the main mechanism for Na extrusion. We then consider the processes by which an increased level of Nai might contribute to cardiac arrhythmias. A rise of Na(i) is well known to result in an increase of intracellular Ca, via the important and influential Na/Ca exchange mechanism in the cell membrane of cardiac muscle cells. A rise of intracellular Ca modulates the activity of a number of sarcolemmal ion channels and affects release of intracellular Ca from the sarcoplasmic reticulum, all of which might be involved in causing arrhythmia. It is possible that the increase in contractile force that results from the rise of intracellular Ca may initiate or exacerbate arrhythmia, since this will increase wall stress and energy demands in the ventricle, and an increase in wall stress may be arrhythmogenic. In addition, the rise of Na(i) is anticipated to modulate directly a number of ion channels and to affect the regulation of intracellular pH, which also may be involved in causing arrhythmia. We also present experiments in this review, carried out on the working rat heart preparation, which suggest that a rise of Na(i) causes an increase of wall stress-induced arrhythmia in this model. In addition, we have investigated the effect on wall stress-induced arrhythmia of maneuvers that might be anticipated to change intracellular Ca, and this has allowed identification of some of the factors involved in causing arrhythmia in the working rat heart.

Effect of streptomycin on wall-stress-induced arrhythmias in the working rat heart.

OBJECTIVE: To assess whether streptomycin, an inhibitor of mechano-sensitive cation channels, has an effect on arrhythmias-induced by an increase of ventricular wall stress in the rat heart. METHODS: The isolated working rat heart preparation was used. Arrhythmias were induced by increasing the afterload (i.e., aortic pressure) against which the left ventricle (LV) pumped for 20 s. This led to an increase of LV pressure, stretch of the LV and an increase in LV wall stress. The number of ventricular premature beats induced by each afterload step was compared in the absence and presence of streptomycin, a compound known to block mechano-sensitive cation channels in the heart. RESULTS: Perfusion with 200 microM streptomycin caused a significant reduction in wall-stress-induced arrhythmias. The effect of streptomycin on arrhythmias reached steady-state within 10 min of application. In the presence of streptomycin, arrhythmias elicited by a 40 mmHg afterload increase were reduced to 38% of control. Arrhythmias induced by an 80 mmHg afterload increase were reduced to 61% of control. Complex arrhythmias (ventricular tachycardia) induced by an afterload increase were also reduced in the presence of 200 microM streptomycin. There was no change in inotropic state with streptomycin, as assessed either by cardiac output or by maximum developed LV pressure. Streptomycin 50 microM (a typical therapeutic plasma concentration in patients) had no effect on wall-stress-induced arrhythmias. CONCLUSIONS: The results were inconsistent with streptomycin acting by modulating inositol phosphate production, or altering the level of intracellular calcium or inotropic state. The anti-arrhythmic effect of streptomycin appears more consistent with inhibition of mechano-sensitive cation channels, suggesting that these ion channels might be involved in causing wall-stress-induced arrhythmias.