Sex differences in the glutamate system: Implications for addiction.

Clinical and preclinical research have identified sex differences in substance use and addiction-related behaviors. Historically, substance use disorders are more prevalent in men than women, though this gap is closing. Despite this difference, women appear to be more susceptible to the effects of many drugs and progress to substance abuse treatment more quickly than men. While the glutamate system is a key regulator of addiction-related behaviors, much of the work implicating glutamate signaling and glutamatergic circuits has been conducted in men and male rodents. An increasing number of studies have identified sex differences in drug-induced glutamate alterations as well as sex and estrous cycle differences in drug seeking behaviors. This review will describe sex differences in the glutamate system with an emphasis on implications for substance use disorders, highlighting the gaps in our current understanding of how innate and drug-induced alterations in the glutamate system may contribute to sex differences in addiction-related behaviors.

Reexamining Echidna Physiology: The Big Picture for Tachyglossus aculeatus acanthion.

The early divergence of monotremes and therian mammals has resulted in considerable interest in the comparative physiology of the short-beaked echidna (Tachyglossus aculeatus), the most common and widespread living monotreme. However, there are many and varied interpretations of its physiology, reflecting the many and varied studies, limitations and uncertainties of aspects of some previous studies, and potential differences between the various subspecies. Consequently, we thoroughly examine here the standardized physiology of the most widely distributed subspecies of short-beaked echidna (T. aculeatus acanthion) over a wide range of ambient temperatures to definitively assess its physiology in a comparative context. We conclude that the low and variable body temperature of the short-beaked echidna is physiologically "primitive," but it also reflects adaptation to its myrmecophagous niche. Other aspects of its physiology are more typically mammalian. A low metabolic rate reflects its low body temperature, and ventilatory variables are matched to accommodate a modest gas exchange requirement. Thermal conductance is typical for a mammal of equivalent mass. In contrast to previous studies, we demonstrate that short-beaked echidnas can enhance evaporative water loss above thermoneutrality, like other mammals, with a similar capacity for evaporative heat loss. Cooling of their nasal blood sinus with nasal mucous may contribute to this enhanced evaporative cooling. Their capacity to evaporatively cool explains how their distribution can include habitats where ambient temperature, even in shelters, exceeds their supposed critical thermal limit.

Stress-induced suppression of hippocampal neurogenesis in adult male rats is altered by prenatal ethanol exposure.

In adulthood, both alcohol (ethanol) and stress are known to suppress hippocampal neurogenesis in male rats. Similarly, most studies report that prenatal alcohol exposure (PAE) reduces cell proliferation and/or cell survival in the hippocampus of adult males. Furthermore, PAE is known to have marked effects on behavioral and hypothalamic-pituitary-adrenal (HPA) responsiveness to stressors. However, no studies have examined the modulation of adult hippocampal neurogenesis by stress in PAE animals. We hypothesized that, in accordance with previous data, PAE would suppress basal levels of adult hippocampal neurogenesis, and further that stress acting on a sensitized HPA axis would have greater adverse effects on adult hippocampal neurogenesis in PAE than in control rats. Adult male offspring from PAE, pair-fed (PF) control, and ad libitum-fed control (C) groups were subjected to restraint stress (9 days, 1 h/day) or left undisturbed. Rats were then injected with bromodeoxyuridine (BrdU) on day 10, perfused 24 h (proliferation) or 3 weeks (survival) later, and brains processed for BrdU immunohistochemistry. We found that (1) under non-stressed conditions, PAE rats had a small but statistically significant suppressive effect on levels of hippocampal neurogenesis and (2) unexpectedly, repeated restraint stress significantly reduced neurogenesis in C and PF, but not PAE rats. We speculate that the failure of PAE males to mount an appropriate (i.e. suppressive) neurogenic response to stressors, implies reduced plasticity and adaptability or resilience, which could impact negatively on hippocampal structure and function.

Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats.

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 mug/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.

Effect of oral insulin on insulin autoantibody levels in the Diabetes Prevention Trial Type 1 oral insulin study.

AIMS/HYPOTHESIS: Our aim was to evaluate insulin autoantibody (IAA) levels over time in the Diabetes Prevention Trial Type 1 (DPT-1) oral insulin study to determine the effect of oral insulin compared with placebo on IAA levels. SUBJECTS AND METHODS: The DPT-1 trial randomised 372 relatives of subjects with type 1 diabetes, positive for IAA and with normal IVGTTs and OGTTs, to oral insulin 7.5 mg daily or placebo. Subjects were followed with IVGTTs, OGTTs and serial IAA measurements. The change in IAA level over time was modelled statistically using mixed model longitudinal data analysis with spatial exponential law for unevenly spaced data. In a separate analysis, subjects were divided into four groups by treatment and diabetes status at the end of the study. IAA levels were compared amongst the groups at randomisation, last sampling and at the maximum level. RESULTS: Longitudinal data analysis showed that treatment did not affect levels of IAA over time. After controlling for age, the IAA levels at randomisation and the last visit and the maximum values were different in the four groups. Significantly higher levels were noted in groups that developed diabetes compared with those that did not, with no significant difference by treatment group. CONCLUSIONS/INTERPRETATION: This suggests that IAA levels over time were not influenced by oral insulin in subjects already positive for IAA at the start of treatment.

The DETECT system: portable, reduced-length neuropsychological testing for mild traumatic brain injury via a novel immersive environment.

Undiagnosed mild traumatic brain injury (mTBI) often leads to poor patient management and significant morbidity. The lack of an efficient screening tool is especially apparent in the athletic setting, where repetitive injuries can lead to prolonged disability. We have developed the Display Enhanced Testing for Concussions and mTBI system (DETECT), in order to create a portable immersive environment that could eliminate visual and audio distractions. Neuropsychological tests sensitive to mTBI were modified for use with the system and allow rapid neurological assessment independent of the environment or trained personnel. We evaluated the immersive qualities of the DETECT system in 42 uninjured controls. The system was successful in blocking out external audiovisual stimuli. The neuropsychological test results obtained in a stimulus rich environment were equivalent to those obtained in a controlled quiet environment. The immersive environment, portability, and brevity of the DETECT system allow for real-time cognitive testing in situations previously deemed impractical or unavailable for mTBI patients.

Where's my dinner? Adult neurogenesis in free-living food-storing rodents.

Postnatal hippocampal neurogenesis in wild mammals may play an essential role in spatial memory. We compared two species that differ in their reliance on memory to locate stored food. Yellow-pine chipmunks use a single cache to store winter food; eastern gray squirrels use multiple storage sites. Gray squirrels had three times the density of proliferating cells in the dentate gyrus (determined by Ki-67 immunostaining) than that found in chipmunks, but similar density of young neurons (determined by doublecortin immunostaining). Three explanations may account for these results. First, the larger population of young cells in squirrels may increase the flexibility of the spatial memory system by providing a larger pool of cells from which new neurons can be recruited. Second, squirrels may have a more rapid cell turnover rate. Third, many young cells in the squirrels may mature into glia rather than neurons. The densities of young neurons were higher in juveniles than in adults of both species. The relationship between adult age and cell density was more complex than that has been found in captive populations. In adult squirrels, the density of proliferating cells decreased exponentially with age, whereas in adult chipmunks the density of young neurons decreased exponentially with age.

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

A methodology for evidence-based health policymaking: the Welsh Protocol Enhancement Project.

The emergence of evidence-based health care at an operational level is well underway in the National Health Service, driven on by clinical effectiveness initiatives. Unless evidence-based care is supported by evidence-based policymaking, the environment will not be conducive to effective professional practice. The article describes a methodology that has been developed to meet the needs of the Project for the Enhancement of the Welsh-Protocols for Investment in Health Gain. A detailed description of the background, aims, methods, planning, and supporting documentation of the project is given. The methodological principles are transferable to other policymaking scenarios.

A case-control study to assess possible triggers and cofactors in chronic fatigue syndrome.

PURPOSE: To assess possible triggers and cofactors for chronic fatigue syndrome (CFS) and to compare levels of selected cytokines between cases and an appropriately matched control group. PATIENTS AND METHODS: We conducted a case-control study of 47 cases of CFS obtained through a regional CFS research program maintained at a tertiary care medical center. One age-, gender-, and neighborhood-matched control was identified for each case through systematic community telephone sampling. Standardized questionnaires were administered to cases and controls. Sera were assayed for transforming growth factor-beta (TGF-beta), interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and antibody to Borrelia burgdorferi and Babesia microti. RESULTS: Cases were more likely to have exercised regularly before illness onset than controls (67% versus 40%; matched odds ratio (MOR) = 3.4; 95% CI = 1.2 to 11.8; P = 0.02). Female cases were more likely to be nulliparous prior to onset of CFS than controls (51% versus 31%; MOR = 8.0; 95% CI = 1.03 to 170; P = 0.05). History of other major factors, including silicone-gel breast implants (one female case and one female control), pre-morbid history of depression (15% of cases, 11% of controls) and history of allergies (66% of cases, 51% of controls) were similar for cases and controls. However, cases were more likely to have a diagnosis of depression subsequent to their diagnosis of CFS compared to a similar time frame for controls (MOR = undefined; 95% CI lower bound = 2.5; P < 0.001). Positive antibody titers to B burgdorferi (one case and one control) and B microti (zero cases and two controls) were also similar. CONCLUSIONS: Further investigation into the role of prior routine exercise as a cofactor for CFS is warranted. This study supports the concurrence of CFS and depression, although pre-morbid history of depression was similar for both groups.

Crew resource management: a simulator study comparing fixed versus formed aircrews.

BACKGROUND: Most airline and military transport planes are flown by crews that have been teamed together for a short amount of time before disbanding and becoming part of a different crew (formed crew concept). Some military operations use a fixed crew concept, pairing crewmembers together for an indefinite period. This research investigated the effect of crew formation policy on aircrew performance during missions in U.S. Air Force KC-135 (tanker) simulators. METHOD: The performance of fixed aircrews is compared to formed aircrews flying the same simulator mission scenario, which included an in-flight emergency. Cockpit resource management (CRM) behavioral data and error data were collected by trained observers for 17 crews (9 fixed and 8 formed). RESULTS: The results show that fixed crews committed more minor errors (4.4 per mission) than formed crews (2.6 per mission), t(14) = 2.32, p = 0.036. No differences were found concerning major errors or CRM behavioral indicators. CONCLUSIONS: The results suggest the possibility of a "familiarity decline," where aircrew performance declines when crewmembers become too familiar with each other and may affect flight safety.

Comparison of fixed versus formed aircrews in military transport.

Historically, transport crews are formed to fly a brief series of sorties together. But what would be the effect of keeping crews together longer? This research investigates the effect of crewing policies on accident rates. We compare the crew coordination performance of fixed teams that work together indefinitely with that of formed teams that work together for shorter periods. We researched 74 accident investigation records of two jet transport aircraft of the U.S. Air Force over 20-year periods. These aircraft used both fixed and formed crews. The "ineffective crew coordination" accident rates for formed crews were significantly safer (z = 12.5 for one aircraft and 2.1 for another p < 0.05). This may imply that airlines and military commands could enhance flight safety by following a formed crew policy. However, further study is needed to identify more completely the effects of crew policies on sortie effectiveness.

The effect of random breath testing on perception of likelihood of apprehension and on illegal drink-driving.

This study examines the links between random breath testing (RBT), driver perception of the likelihood of apprehension if illegally drink-driving, and drink-driving behaviour in Adelaide, South Australia. It is based on information gained from surveys of night-time drivers in metropolitan Adelaide, during 1987, 1989 and 1991. Overall, about 25% of the sample in each year thought that illegal drink-driving was likely to result in apprehension. This perception was consistently lower for males and for those aged less than 30 years than for their counterparts, however, there was evidence that it increased with exposure to RBT, notably when that exposure was recent. Also, compared with other drivers, fewer drivers who thought that apprehension was likely had an illegal blood alcohol concentration (BAC) when surveyed, or reported that they would be likely to drive if they thought that they had an illegal BAC. However, the majority of drivers who thought that detection was unlikely also reported that they would be unlikely to drink-drive. These results suggest the need for some re-direction of current RBT activities.

Human factors in rural road crashes.

An in-depth study of 79 vehicle crashes on rural roads in an area of about 100 km radius around Adelaide examined sociodemographic and psychophysiological characteristics of the drivers and riders involved. In many respects this sample of crashes was similar to a much larger number of police-reported crashes in the same area but included: relatively more crashes with severe or fatal injuries; more crashes on divided roads, on sealed roads and on curves; and more crashes involving trucks. Alcohol and lack of seat belt use were shown to be major problems in these rural crashes. The drivers and riders most strongly associated with these particular problems were males, in blue collar occupations and with limited education; they tended to be aged 30 years or more in the case of alcohol abuse, and were likely to be under 30 years in the case of restraint misuse. The attitudes of these drivers and riders, and other characteristics likely to have contributed to their involvement in a crash, are discussed. There is a need to develop specific and effective countermeasures to reduce drink-driving and increase seat belt wearing in rural areas.

Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells.

The paucity of virus-laden CD4+ cells in individuals infected with human immunodeficiency virus type-1 (HIV-1) contrasts with the greatly reduced numbers and function of these lymphocytes. A pathway is described whereby dendritic cells carry HIV-1 to uninfected T cells, amplifying the cytopathic effects of small amounts of virus. After exposure to HIV-1, dendritic cells continue to present superantigens and antigens, forming clusters with T cells that are driven to replicate. Infection of the dendritic cells cannot be detected, but the clustered T cells form syncytia, release virions, and die. Carriage of HIV-1 by dendritic cells may facilitate the lysis and loss of antigen specific CD4+ T cells in acquired immunodeficiency syndrome.