Cortisol reactivity and weight gain among adolescents who vary in prenatal drug exposure.

OBJECTIVE: Low inhibitory control is linked with weight gain among youth. Inhibitory problems are associated with disruption to the hypothalamic-pituitary-adrenal axis cortisol response. Increased cortisol predicts appetite and weight gain (though may be gender specific). This study hypothesized that cortisol reactivity explains the association between inhibition and weight gain while considering the moderating factors of early stressors to the hypothalamic-pituitary-adrenal axis (e.g. prenatal-drug exposure) and gender. METHODS: Adolescents with prenatal-drug exposure (n = 76) and non-exposed comparison adolescents (NE; n = 61) completed the Conner's Continuous Performance Test and provided salivary cortisol samples. BMI z-score were measured at the initial and 12-month follow-up evaluations. A bootstrapped moderated mediation analysis was conducted to test for conditional indirect effects of cortisol reactivity. RESULTS: Lower inhibition was associated with increased cortisol reactivity among youth who were NE, and increased cortisol reactivity was associated with weight gain among girls. Cortisol reactivity mediated the relation between inhibition and BMI z-score change for the girls in the group who was NE. CONCLUSION: Increased cortisol reactivity may play a mechanistic role in predicting weight gain among non-prenatally drug-exposed girls. Cortisol reactivity may be a biomarker for targeted interventions to improve biological regulation and ultimately health risk among girls.

The use of standard operating procedures in day case anterior cruciate ligament reconstruction.

The current rate of day-case anterior cruciate ligament reconstruction (ACLR) in the UK remains low. Although specialised care pathways with standard operating procedures (SOPs) have been effective in reducing length of stay following some surgical procedures, this has not been previously reported for ACLR. We evaluate the effectiveness of SOPs for establishing day-case ACLR in a specialist unit. Fifty patients undergoing ACLR between May and September 2010 were studied prospectively ("study group"). SOPs were designed for pre-operative assessment, anaesthesia, surgical procedure, mobilisation and discharge. We evaluated length of stay, readmission rates, patient satisfaction and compliance to SOPs. A retrospective analysis of 50 patients who underwent ACLR prior to implementation of the day-case pathway was performed ("standard practice group"). Eighty percent of patients in the study group were discharged on the day of surgery (mean length of stay=5.3h) compared to 16% in the standard practice group (mean length of stay=21.6h). This difference was statistically significant (p<0.05, Mann-Whitney U test). All patients were satisfied with the day case pathway. Ninety-two percent of the study group were discharged on the day of surgery when all SOPs were followed and 46% where they were not. High rates of day-case ACLR with excellent patient satisfaction can be achieved with the use of a specialised patient pathway with SOPs.

Illness intrusiveness in myalgic encephalomyelitis: an exploratory study.

This study assessed the relationship between illness intrusiveness, symptoms, disability and depression in patients with myalgic encephalomyelitis (ME). Participants were 16 patients with ME and eight patients with ME plus co-morbid disorders. The patients with co-morbid disorders reported greater illness intrusiveness than the patients with ME alone, but there were no differences between the groups on the other variables. Significant correlations were found between illness intrusiveness on the one hand, and fatigue, cognitive dysfunction, disability and depression, on the other. We conclude that ME is a disabling illness, which has a major impact on various life domains.

Nicotine, alcohol and drug dependence, and psychiatric comorbidity--results of a national household survey.

There is a well-recognized relationship between substance use disorders and other psychiatric disorders. This relationship has been well documented in a range of population-based studies. This study aims to report on consumption patterns of and dependence on nicotine, alcohol, and non-prescribed drugs and to report on the levels of psychiatric morbidity in these groups. A national household study of psychiatric morbidity was conducted in England and Wales. Psychiatric assessment was based on the Clinical Interview Schedule-Revised (CIS-R). Measures of nicotine, alcohol and drug use and dependence were obtained. This paper compares the levels of psychiatric morbidity in the non-dependent and the nicotine-, alcohol- and drug-dependent cases. Twelve per cent of the non-dependent population were assessed as having any psychiatric disorder compared with 22% of the nicotine-dependent, 30% of the alcohol-dependent, and 45% of the drug-dependent population. There is a clear relationship between dependence on nicotine, alcohol, and drugs and other psychiatric morbidity.

Substance misuse and psychiatric comorbidity: an overview of the OPCS National Psychiatric Morbidity Survey.

There have been a number of national surveys of psychiatric morbidity, which have included questions on drugs, alcohol, and tobacco. These surveys have helped delineate the overlap between substance use and dependence and other psychological morbidity. There is a strong association reported between high substance consumption and other measures of psychological problems. This article provides an overview of a national household survey, a survey of institutional residents with psychiatric disorders, and a national survey of a homeless population. All three surveys used comprehensive and complex sampling strategies and lay interviewers to conduct structured diagnostic interviews. The household survey included over 10,000 households, the institutional survey interviewed 755 individuals, and the homeless survey of hostels, night shelters, day centres, and private sector leased accommodation interviewed 1,061 individuals. This overview looks at patterns of nicotine, alcohol, and other drug use in the different samples and examines interactions with other psychiatric morbidity. The survey reports that substance-related disorders are some of the commonest disorders in the community, with 5% of the household sample alcohol dependent, 7% alcohol dependent in the institutional sample and over 21% in the homeless sample recorded as alcohol dependent. Tobacco, alcohol and other drug use and dependence were dramatically higher in the homeless sample than in either of the other two samples. Substance use was significantly associated with higher rates of psychological morbidity as measured by the Clinical Interview Schedule Revised. Future service planning needs to take account of the striking disparity of prevalence of psychiatric disorders in different subsections of the population.

Nicotine, alcohol and drug dependence and psychiatric comorbidity. Results of a national household survey.

BACKGROUND: There is a well-recognised relationship between substance use disorders and other psychiatric disorders. This relationship has been well documented in a range of population-based studies. AIMS: This study aims to report on consumption patterns of and dependence on nicotine, alcohol and non-prescribed drugs and to report on the levels of psychiatric morbidity in these groups. METHOD: A national household study of psychiatric morbidity was conducted in England and Wales. Psychiatric assessment was based on the Clinical Interview Schedule-Revised (CIS-R). Measures of nicotine, alcohol and drug use and dependence were obtained. This paper compares the levels of psychiatric morbidity in the non-dependent and the nicotine-, alcohol- and drug-dependent cases. RESULTS: Twelve per cent of the non-dependent population were assessed as having any psychiatric disorder compared with 22% of the nicotine-dependent, 30% of the alcohol-dependent and 45% of the drug-dependent population. CONCLUSIONS: There is a clear relationship between dependence on nicotine, alcohol and drugs and other psychiatric morbidity.

Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats.

The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS-) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.

Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression.

RATIONALE: Dopamine dysfunction in the nucleus accumbens is thought to underlie the altered propensity of isolation-reared rats to self-administer psychomotor stimulants. OBJECTIVE: To identify specific changes in monoamine and glutamate function in the nucleus accumbens and c-fos induction in the amygdala and striatum which may be correlated with altered cocaine self-administration in isolates. METHODS: In three separate studies, group-reared and isolation-reared rats were trained to self-administer cocaine (0.083. 0.25 or 1.5 mg/kg per IV infusion; FR1), intracerebral microdialysis was used to measure cocaine-induced changes in extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and the expression of the immediate-early gene c-fos was quantified using quantitative immunocytochemistry of its protein product Fos in several amygdala and striatal brain regions following cocaine administration. RESULTS: Isolation-reared rats showed an enhanced sensitivity to self-administer the lowest dose of cocaine but showed retarded acquisition at the highest dose. Isolation rearing produced no effect on basal levels of dopamine, serotonin or glutamate in the nucleus accumbens but potentiated the increase in dopamine efflux, though not serotonin efflux, induced by cocaine. Cocaine increased FOS expression in most amygdala and striatal brain regions examined that were relatively greater in isolation-reared rats in core and shell regions of the nucleus accumbens, medial and lateral regions of the dorsal striatum as well as the central nucleus of the amygdala. CONCLUSION: These data are consistent with the hypothesis that isolation rearing produces enduring changes in the sensitivity of dopamine-mediated functions in amygdala-striatal circuitry that may be directly related to the altered reinforcing properties of cocaine and other psychomotor stimulants.

Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.

Many mammalian viruses have acquired genes from their hosts during their evolution. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Here we describe the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that we have called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W. We find that the major sites of syncytin expression are placental syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts. We show that expression of recombinant syncytin in a wide variety of cell types induces the formation of giant syncytia, and that fusion of a human trophoblastic cell line expressing endogenous syncytin can be inhibited by an anti-syncytin antiserum. Our data indicate that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.

Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens.

The present study investigated the effects of excitotoxic lesions of the prefrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) function in the nucleus accumbens core using in vivo microdialysis in freely moving rats. As a postsynaptic marker of neuronal function, the nuclear levels of the transcriptional factor CREB and its active phosphorylated form, CREB-P, were measured in the ventral tegmental area (VTA), and in the core and shell subregions of the nucleus accumbens of sham and lesioned animals. PFC-lesioned animals exhibited a greater locomotor response to novelty and amphetamine administration (125-500 microg/kg i.v.). No change was observed in extracellular levels of glutamate or saturable d-aspartate binding (a marker for the high-affinity EAA transporter) in the nucleus accumbens of PFC-lesioned animals. Extracellular levels of DA were comparable in sham and lesioned animals under tonic conditions, however, following amphetamine administration, DA efflux was significantly attenuated in lesioned animals. No correlation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Further, no effect of the lesion was found on nuclear CREB protein in saline- and amphetamine-treated rats. The density of CREB-P immunoreactive nuclei, while remaining unchanged in the VTA, increased in the nucleus accumbens shell following amphetamine treatment in lesioned animals. The results show that an important modulatory role of the PFC on the behavioural response to novelty and amphetamine is associated with the level of immediate-early gene regulation rather than levels of extracellular DA and amino acids in the ventral striatum.

Estimating the prevalence of problem drug use in inner London: a discussion of three capture-recapture studies.

AIMS: To provide an evidence base of estimates of the prevalence of problem drug use in inner London. DESIGN: Re-analysis of three capture-recapture studies using subjects aged 15-49 years, that aim to estimate the hidden population from analysing the overlaps between three data sources. SETTING: Newham (1995) Camden and Islington (C&I) (1993/4) and Lambeth, Southwark and Lewisham (LSL) (1992). PARTICIPANTS: Each study collected data from three sources of problem drug users including: the Regional Drug Misuse Database, specialist drug agencies, HIV tests, social services, police arrests and court records. In LSL opiate users were analysed separately. The studies identified 1832 individuals in LSL, 543 in Newham, and 1321 in C&I. MEASUREMENTS: Poisson models were fitted to the data testing different interactions between the data sources representing potential dependencies. The simplest model was selected on the basis of its AIC score and log-likelihood ratio tests. FINDINGS: The number of hidden problem drug users were estimated to be 12,500 (95% CI 9600-16,100) in LSL with 4400 (3200-6100) opiate users; 7000 (5000-10,000) in C&I and 3800 (2000-7200) in Newham. The prevalence of problem drug use in those aged 15-49 was estimated to be 3.1% (2.5-3.9%) in LSL with 1.3% (1.0-1.6%) opiate users; and 3.6% (2.7-4.9%) and 3.3% (1.9-5.7%) in C&I and Newham, respectively. CONCLUSIONS: Despite the inherent problems with capture-recapture methods, our three studies establish an evidence base for estimates of problem drug use in London. It is important that a larger study is carried out in London.

Substance misuse and psychiatric comorbidity: an overview of the OPCS National Psychiatric Morbidity Survey.

There have been a number of national surveys of psychiatric morbidity which have included questions on drugs, alcohol and tobacco. These surveys have helped delineate the overlap between substance use and dependence and other psychological morbidity. There is a strong association reported between high substance consumption and other measures of psychological problems. This article provides an overview of a national household survey, a survey of institutional residents with psychiatric disorders and a national survey of a homeless population. All three surveys used comprehensive and complex sampling strategies and lay interviewers to conduct structured diagnostic interviews. The household survey included over 10,000 households, the institutional survey interviewed 755 individuals and the homeless survey of hostels, night-shelters, day centres and private-sector leased accommodation interviewed 1,061 individuals. This overview looks at patterns of nicotine, alcohol and other drug use in the different samples and examines interactions with other psychiatric morbidity. The survey reports that substance-related disorders are some of the commonest disorders in the community, with 5% of the household sample alcohol dependent, 7% alcohol dependent in the institutional sample and over 21% in the homeless sample recorded as alcohol dependent. Tobacco, alcohol and other drug use and dependence were dramatically higher in the homeless sample than in either of the other two samples. Substance use was significantly associated with higher rates of psychological morbidity as measured by the Clinical Interview Schedule Revised. Future service planning needs to take account of the striking disparity of prevalence of psychiatric disorders in different subsections of the population.

Isolated P-selectin glycoprotein ligand-1 dynamic adhesion to P- and E-selectin.

Leukocyte adhesion to vascular endothelium under flow involves an adhesion cascade consisting of multiple receptor pairs that may function in an overlapping fashion. P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin have been implicated in neutrophil adhesion to P- and E-selectin under flow conditions. To study, in isolation, the interaction of PSGL-1 with P- and E-selectin under flow, we developed an in vitro model in which various recombinant regions of extracellular PSGL-1 were coupled to 10-microm-diameter microspheres. In a parallel plate chamber with well defined flow conditions, live time video microscopy analyses revealed that microspheres coated with PSGL-1 attached and rolled on 4-h tumor necrosis factor-alpha-activated endothelial cell monolayers, which express high levels of E-selectin, and CHO monolayers stably expressing E- or P-selectin. Further studies using CHO-E and -P monolayers demonstrate that the first 19 amino acids of PSGL-1 are sufficient for attachment and rolling on both E- and P-selectin and suggest that a sialyl Lewis x-containing glycan at Threonine-16 is critical for this sequence of amino acids to mediate attachment to E- and P-selectin. The data also demonstrate that a sulfated, anionic polypeptide segment within the amino terminus of PSGL-1 is necessary for PSGL-1-mediated attachment to P- but not to E-selectin. In addition, the results suggest that PSGL-1 has more than one binding site for E-selectin: one site located within the first 19 amino acids of PSGL-1 and one or more sites located between amino acids 19 through 148.

Genetic analysis of polyomavirus large T nuclear localization: nuclear localization is required for productive association with pRb family members.

Polyomavirus large T antigen (LT) is a multifunctional nuclear protein. LT has two nuclear localization signals (NLS2), one spanning residues 189 to 195 (NLS1) and another spanning residues 280 to 286 (NLS2). Site-directed mutagenesis showed that each signal contains at least two critical residues. The possibility of connections between NLSs and adjacent phosphorylations has attracted much attention. Cytoplasmic LT (CyT) mutants were underphosphorylated, particularly at sites adjacent to NLS2. However, since a nuclear LT bearing an inactivated NLS2 was phosphorylated normally at adjacent sites, the signal was not directly required for phosphorylation. Conversely, LT could be translocated to the nucleus via NLS2 even when the adjacent phosphorylation sites were deleted. CyT was examined to probe the importance of LT localization. CyT was unable to perform LT functions related to interactions with retinoblastoma susceptibility gene (pRb) family members. Hence, CyT was unable to immortalize primary cells or to transactivate an E2F-responsive promoter. Consistent with these findings, CyT, though capable of binding pRb in vitro, did not cause relocalization of pRb in cells. Assays of transactivation of the simian virus 40 late promoter and of the human c-fos promoter showed that defects of CyT were not limited to functions dependent on pRb interactions.

Analysis of the effects of intra-accumbens SKF-38393 and LY-171555 upon the behavioural satiety sequence.

The outcome of intra-accumbens infusions of the dopamine D1 receptor family agonist SKF-38393 and the D2 receptor family agonist LY-171555 upon measures taken during the behavioural satiety sequence was assessed (0.01 micrograms, 0.1 micrograms, 1.0 micrograms in each case). Each drug was infused either separately, or together as a co-infusion in order to examine the functional relationship between these dopamine receptor subtypes within the nucleus accumbens. Measures of feeding did not change following infusions of SKF-38393 or LY-171555, whether infused separately or together. However, following separate infusion of the lowest dose tested of each drug (0.01 micrograms), the onset of resting was advanced. Moderate to high doses of SKF-38393 and LY-171555 (0.1 micrograms, 1.0 micrograms) infused separately resulted in a marked increase in activity at the expense of resting. Co-infusion of 0.01 micrograms of each drug also resulted in a dramatic increase in activity. Thus, measures of feeding behaviour were unchanged following excitation of D1 and D2 dopamine receptor families within the nucleus accumbens. In marked contrast, locomotor behaviour appeared to be under the potent synergistic control of these receptor families.

Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never "primed" with noncontingent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbens d-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists.

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.