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The study aims to evaluate whether decreased tissue levels of 5-HT receptor are responsible for deaths in infants du e to sudden infant death syndrome (SIDS). The results indicate that there was an association between SIDS and a lower level or deficiency of the 5-HT receptor.

Patient falls in hospitals continue to be a global concern due to the poor health outcomes and costs that can occur. A large number of falls in hospitals are unwitnessed and mostly occur due to patient behaviours and not seeking assistance. Understanding these patient behaviours may help to direct fall prevention strategies, with evidence suggesting the need to integrate patients' perspectives into fall management. The aim of this scoping review was to explore the extent of the literature about patients' perceptions and experiences of their fall risk in hospital and/or of falling in hospital. This review was conducted using a five-stage methodological framework recommended by Arksey and O'Malley. A total of nine databases were searched using key search terms such as "fall*", "perception" and "hospital." International peer-reviewed and grey literature were searched between the years 2011 and 2021. A total of 41 articles, ranging in study design, met the inclusion criteria. After reporting on the article demographics and fall perception constructs and measures, the qualitative and quantitative findings were organised into five domains: Fall Risk Perception Measures, Patients' Perceptions of Fall Risk, Patients' Perceptions of Falling in Hospital, Patients' Fear of Falling and Barriers to Fall Prevention in Hospital. Approximately two-thirds of study participants did not accurately identify their fall risk compared to that defined by a health professional. This demonstrates the importance of partnering with patients and obtaining their insights on their perceived fall risk, as this may help to inform fall management and care. This review identified further areas for research that may help to inform fall prevention in a hospital setting, including the need for further research into fall risk perception measures. [ABSTRACT FROM AUTHOR]

Inhalants containing the volatile solvent toluene are misused to induce euphoria or intoxication. Inhalant abuse is most common during adolescence and can result in cognitive impairments during an important maturational period. Despite evidence suggesting that epigenetic modifications may underpin the cognitive effects of inhalants, no studies to date have thoroughly investigated toluene-induced regulation of the transcriptome or discrete epigenetic modifications within the brain. To address this, we investigated effects of adolescent chronic intermittent toluene (CIT) inhalation on gene expression and DNA methylation profiles within the rat medial prefrontal cortex (mPFC), which undergoes maturation throughout adolescence and has been implicated in toluene-induced cognitive deficits. Employing both RNA-seq and genome-wide Methyl CpG Binding Domain (MBD) Ultra-seq analysis, we demonstrate that adolescent CIT inhalation (10 000 ppm for 1 h/day, 3 days/week for 4 weeks) induces both transient and persistent changes to the transcriptome and DNA methylome within the rat mPFC for at least 2 weeks following toluene exposure. We demonstrate for the first time that adolescent CIT exposure results in dynamic regulation of the mPFC transcriptome likely relating to acute inflammatory responses and persistent deficits in synaptic plasticity. These adaptations may contribute to the cognitive deficits associated with chronic toluene exposure and provide novel molecular targets for preventing long-term neurophysiological abnormalities following chronic toluene inhalation. [ABSTRACT FROM AUTHOR]

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002–0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla—a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla. [ABSTRACT FROM AUTHOR]

Background: Substance abuse can cause a range of harmful secondary health consequences, including body weight changes. These remain poorly understood but can lead to metabolic disorders including obesity and diabetes. Energy balance is a function of the equation: energy balance = energy intake - energy expenditure; an imbalance to this equation results in body weight changes. Currently, in the clinical setting, changes to food intake (energy intake) are considered as the primary mediator of body weight changes related to substance abuse, reflected in the current treatment focus on nutritional intervention. The influence of substance abuse on energy expenditure receives less attention. The aim of this think-piece is to consider potential causes of body weight changes during active substance abuse and abstinence, by focussing on the components of the energy balance equation. Methods: We discuss both human and animal studies on the effects of substance abuse on energy balance, with particular focus on animal models utilising pair-feeding, which enable investigation of energy balance whilst controlling for the effects of altered food intake. Results: We demonstrate that whilst some drugs of abuse affect food intake, this effect is inconsistent. Furthermore, body weight changes do not match food intake changes. Conclusion: We provide evidence that drugs of abuse can affect both energy intake and energy expenditure; contributing to the observed body weight changes. This think-piece highlights that treatment strategies for body weight changes related to substance abuse cannot focus solely on nutritional interventions, but should consider the impact of broader disruptions to energy balance. [ABSTRACT FROM AUTHOR]

Background/Aims: Abuse of toluene products (e.g., glue-sniffing) primarily occurs during adolescence and has been associated with appetite suppression and weight impairments. However, the metabolic phenotype arising from adolescent inhalant abuse has never been fully characterised, and its persistence during abstinence and underlying mechanisms remain unknown. Methods: Adolescent male Wistar rats (post-natal day 27) were exposed to inhaled toluene (10,000 ppm) (n = 32) or air (n = 48) for 1 h/day, 3 days/week for 4 weeks, followed by 4 weeks of abstinence. Twenty air rats were pair-fed to the toluene group, to differentiate the direct effects of toluene from under-nutrition. Food intake, weight, and growth were monitored. Metabolic hormones were measured after exposure and abstinence periods. Energy expenditure was measured using indirect calorimetry. Adrenal function was assessed using adrenal histology and hormone testing. Results: Inhalant abuse suppressed appetite and increased energy expenditure. Reduced weight gain and growth were observed in both the toluene and pair-fed groups. Compared to the pair-fed group, and despite normalisation of food intake, the suppression of weight and growth for toluene-exposed rats persisted during abstinence. After exposure, toluene-exposed rats had low fasting blood glucose and insulin compared to the air and pair-fed groups. Consistent with adrenal insufficiency, adrenal hypertrophy and increased basal adrenocorticotropic hormone were observed in the toluene-exposed rats, despite normal basal corticosterone levels. Conclusions: Inhalant abuse results in negative energy balance, persistent growth impairment, and endocrine changes suggestive of adrenal insufficiency. We conclude that adrenal insufficiency contributes to the negative energy balance phenotype, potentially presenting a significant additional health risk for inhalant users. [ABSTRACT FROM AUTHOR]

Sudden infant death syndrome (SIDS) involves failure of arousal to potentially life threatening events, including hypoxia, during sleep. While neuronal dysfunction and abnormalities in neurotransmitter systems within the medulla oblongata have been implicated, the specific pathways associated with autonomic and cardiorespiratory failure are unknown. The neuropeptide substance P (SP) and its tachykinin neurokinin-1 receptor (NK1R) have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation, integration of cardiovascular control, and modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may therefore result in autonomic dysfunction during sleep and contribute to SIDS deaths. [125I] Bolton Hunter SP autoradiography was used to map the distribution and density of the SP, NK1R to 13 specific nuclei intimately related to cardiorespiratory function and autonomic control in the human infant medulla of 55 SIDS and 21 control (non-SIDS) infants. Compared to controls, SIDS cases exhibited a differential, abnormal developmental profile of the SP/NK1R system in the medulla. Furthermore the study revealed significantly decreased NK1R binding within key medullary nuclei in SIDS cases, principally in the nucleus tractus solitarii (NTS) and all three subdivisions of the inferior portion of the olivo-cerebellar complex; the principal inferior olivary complex (PIO), medial accessory olive (MAO) and dorsal accessory olive (DAO). Altered NK1R binding was significantly influenced by prematurity and male sex, which may explain the increased risk of SIDS in premature and male infants. Abnormal NK1R binding in these medullary nuclei may contribute to the defective interaction of critical medullary mechanisms with cerebellar sites, resulting in an inability of a SIDS infant to illicit appropriate respiratory and motor responses to life threatening challenges during sleep. These observations support the concept that abnormalities in a multi-neurotransmitter network within key nuclei of the medullary homeostatic system may underlie the pathogenesis of a subset of SIDS cases. [ABSTRACT FROM AUTHOR]

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use. [ABSTRACT FROM AUTHOR]

Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug-seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor-activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP. [ABSTRACT FROM AUTHOR]

Drug addiction is a chronic, relapsing disorder defined by cyclic patterns of compulsive drug seeking and taking interspersed with episodes of abstinence. While genetic variability may increase the risk of addictive behaviours in an individual, exposure to a drug results in neuroadaptations in interconnected brain circuits which, in susceptible individuals, are believed to underlie the transition to, and maintenance of, an addicted state. These adaptations can occur at the cellular, molecular, or (epi)genetic level and are associated with synaptic plasticity and altered gene expression, the latter being mediated via both factors affecting translation (epigenetics) and transcription (non coding microRNAs) of the DNA or RNA itself. New advances using techniques such as optogenetics have the potential to increase our understanding of the microcircuitry mediating addictive behaviours. However, the processes leading to addiction are complex and multifactorial and thus we face a major contemporary challenge to elucidate the factors implicated in the development and maintenance of an addicted state. [ABSTRACT FROM AUTHOR]

AbstractBackground:Lipopolysaccharide (LPS) delivered acutely to the ovine fetus induces cerebral white matter injury and brain inflammation. N-acetyl cysteine (NAC) is potentially neuroprotective as it blocks the production of inflammatory cytokines and increases glutathione levels; however, it is unknown whether NAC affects the physiological status of the fetus already exposed to an inflammatory environment. Objectives:Our objective was to determine whether NAC influences the physiological effects of LPS exposure in the ovine fetus. Methods:Catheterized fetal sheep underwent one of four treatments (saline, n = 6; LPS, n = 6; LPS + NAC, n = 6; NAC, n = 3) on 5 consecutive days from 95 days of gestation (term ∼147 days). Fetal arterial pressure and heart rate were recorded and blood samples collected. Results:LPS administration resulted in fetal hypoxemia and hypotension; simultaneous treatment with NAC exacerbated these effects and induced polycythemia. NAC treatment alone had no effect on the fetus. Conclusion:In the presence of LPS, NAC compromises fetal physiological status, suggesting that it may not be a suitable antenatal treatment for a fetus with evidence of inflammation.Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to five-fold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT1A receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors. [ABSTRACT FROM AUTHOR]

The high rate of the sudden infant death syndrome (SIDS) in American Indians in the Northern Plains (3.5/1000) may reflect the high incidence of cigarette smoking and alcohol consumption during pregnancy. Nicotine, a neurotoxic component of cigarettes, and alcohol adversely affect nicotinic receptor binding and subsequent cholinergic development in animals. We measured 3H-nicotine receptor binding in 16 brainstem nuclei in American Indian SIDS (n = 27) and controls (n = 6). In five nuclei related to cardiorespiratory control, 3H-nicotinic binding decreased with increasing number of drinks ( P < 0.03). There were no differences in binding in SIDS compared with controls, except upon stratification of prenatal exposures. In three mesopontine nuclei critical for arousal there were reductions ( P < 0.04) in binding in controls exposed to cigarette smoke compared with controls without exposure; there was no difference between SIDS cases with or without exposure. This study suggests that maternal smoking and alcohol affects 3H-nicotinic binding in the infant brainstem irrespective of the cause of death. It also suggests that SIDS cases are unable to respond to maternal smoking with the “normal” reduction seen in controls. Future studies are needed to establish the role of adverse prenatal exposures in altered brainstem neurochemistry in SIDS. [ABSTRACT FROM AUTHOR]

Previous studies on the effects of umbilical cord occlusion (UCO) on the fetal brain have focused on short-term alterations, and in most cases have used only subjective techniques to evaluate brain injury. Our aim was to assess quantitatively the persistent consequences of UCO on the developing brain; we also examined the retina.We subjected fetal sheep to a single episode of UCO at 126 days of gestation (term ∼147 days) to induce at least 10 minutes of isoelectric fetal electrocorticogram (ECoG).UCO resulted in fetal asphyxia and transient mild alterations in fetal mean arterial pressure (MAP). UCO did not result in significant injury to the developing brain or retina when assessed 15 days after the insult. There was no change in the endogenous expression of brain-derived neurotrophic factor (BDNF) protein in the hippocampus, nor was there a significant loss of CA1 hippocampal pyramidal cells. However, this insult did result in subtle neuropathologic alterations in the brain, including a reduction in the weight of the cerebral hemispheres, an increase in the areal density of cerebellar Purkinje cells, and enlarged perivascular spaces around blood vessels and inflammatory cells in the cerebral white matter. UCO did not affect the thickness of the central or peripheral retina or the numbers of retinal dopaminergic, cholinergic, and nitrergic amacrine cells.Thus, while 10 minutes of UCO did not result in overt injury to the fetal brain or retina, the observed changes in the fetal brain suggest altered growth of neural processes, which may contribute to neurologic deficits postnatally or to increased vulnerability of the brain to later insults during either the remainder of gestation or after birth. [Copyright &y& Elsevier]

The abuse of volatile solvents such as toluene is a significant public health concern, predominantly affecting adolescents. To date, inhalant abuse research has primarily focused on the central nervous system; however, inhalants also exert effects on other organ systems and processes, including metabolic function and energy balance. Adolescent inhalant abuse is characterized by a negative energy balance phenotype, with the peak period of abuse overlapping with the adolescent growth spurt. There are multiple components within the central and peripheral regulation of energy balance that may be affected by adolescent inhalant abuse, such as impaired metabolic signaling, decreased food intake, altered dietary preferences, disrupted glucose tolerance and insulin release, reduced adiposity and skeletal density, and adrenal hypertrophy. These effects may persist into abstinence and adulthood, and the long‐term consequences of inhalant‐induced metabolic dysfunction are currently unknown. The signs and symptoms resulting from chronic adolescent inhalant abuse may result in a propensity for the development of adult‐onset metabolic disorders such as type 2 diabetes, however, further research investigating the long‐term effects of inhalant abuse upon energy balance and metabolism are needed. This review addresses several aspects of the short‐ and long‐term effects of inhalant abuse relating to energy and metabolic processes, including energy balance, intake and expenditure; dietary preferences and glycemic control; and the dysfunction of metabolic homeostasis through altered adipose tissue, bone, and hypothalamic‐pituitary‐adrenal axis function. [ABSTRACT FROM AUTHOR]

Abstract: The mGlu5 receptor (mGluR5) has been implicated in the rewarding effect of various drugs of abuse and drug-seeking behaviour. In the present study we investigated the impact of antagonism of mGluR5 with the selective negative allosteric, modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine as well as cue-induced drug-seeking in adult CD1 mice. Administration of MTEP (20mg/kg, i.p.) attenuated operant responding for morphine (0.1mg/kg/infusion) and cue-induced morphine-seeking after a period of forced abstinence. Collectively, these data implicate mGluR5 in the reinforcing effects of opiates and support the proposition that mGluR5 is a potential therapeutic target for treatment of drug addiction. [Copyright &y& Elsevier]

Background: Inhalant misuse is the deliberate inhalation of products containing toluene to induce intoxication. Chronic harms associated with inhalant misuse are well described; including alcohol and other drug use, mental health disorders, and suicidal behaviours. However, the nature of the acute harms from inhalants and characteristics of people who experience those harms are not well understood. Therefore, this study aimed to identify the acute harms associated with inhalant misuse attendances, and to determine whether these differ by age or gender.Methods: Ambulance attendance data (Victoria, Australia) from January 2012 to June 2017 were extracted from a database of coded ambulance records. 779 ambulance attendances involving inhalant misuse were identified. Attendance characteristics were categorised by age and gender. Co-morbidities of current mental health, self-harm and suicidal behaviour were assessed, plus the involvement of alcohol and other drugs.Results: Overall, attendances related to the acute harms of inhalant misuse have decreased over time, although that trend has reversed from January 2015. Gender differentiated the acute harms associated with inhalant misuse. Males were older and presented with concurrent alcohol and other drug use. Females were younger and presented with concurrent suicidal ideation and self-injury. Attendances for under 15-year-olds are increasing; this age group was over-represented, predominantly female, with a strong association with self-injury.Conclusions: Ambulance presentations related to inhalant misuse were associated with acute and serious harms. This study highlights that the acute treatment needs of those misusing inhalants are complex and may need to be tailored to gender and age groups. [ABSTRACT FROM AUTHOR]