Recurrent groin hernia surgery after primary open inguinal procedures: a reappraisal of the open preperitoneal (Ugahary) technique.

PURPOSE: There are several methods for repairing recurrent inguinal hernia, depending on the type of initial repair. Our aim was to analyze our long follow-up results on the open preperitoneal repair for patients with recurrent inguinal hernia. METHODS: Our retrospective survey included 135 consecutive recurrent inguinal hernia patients, operated on during 1999-2010, with a mean follow-up time of 8.7 years. RESULTS: During the mean follow-up time of 8.7 years, only four (3%) patients developed a re-recurrence. Two of these patients were asymptomatic, and the two other were operated on. Early postoperative complications occurred in four (3%) patients. The complications comprised one hematoma, one seroma, and two infections. Chronic pain was diagnosed in five (3.7%) patients, but their symptoms disappeared spontaneously within a few years. CONCLUSIONS: We conclude that in competent hands, the open preperitoneal repair (Ugahary) is a good surgical option in operating recurrent inguinal hernias.

Novel concepts in sleep regulation.

Knowledge regarding the cellular mechanisms of sleep regulation is accumulating rapidly. In addition to neurones, also non-neuronal brain cells (astrocytes and microglia) are emerging as potential players. New techniques, particularly optogenetics and designed receptors activated by artificial ligands (DREADD), have provided also sleep research with important additional tools to study the effect of either silencing or activating specific neuronal groups/neuronal networks by opening or shutting ion channels on cells. The advantages of these strategies are the possibility to genetically target specific cell populations and the possibility to either activate or inhibit them with inducing light signal into the brain. Studies probing circuits of NREM and REM sleep regulation, as well as their role in memory consolidation, have been conducted recently. In addition, fundamentally new thoughts and potential mechanisms have been introduced to the field. The role of non-neuronal tissues in the regulation of many brain functions has become evident. These non-neuronal cells, particularly astrocytes, integrate large number of neurones, and it has been suggested that one of their functions is to integrate the (neural) activity in larger brain areas-a feature that is one of the prominent features of also the state of sleep.

Sleep regulatory factors.

The state of sleep consists of different phases that proceed in successive, tightly regulated order through the night forming a physiological program, which for each individual is different but stabile from one night to another. Failure to accomplish this program results in feeling of unrefreshing sleep and tiredness in the morning. The pro- gram core is constructed by genetic factors but regulated by circadian rhythm and duration and intensity of day time brain activity. Many environmental factors modulate sleep, including stress, health status and ingestion of vigilance-affecting nutrients or medicines (e.g. caffeine). Knowledge of the factors that regulate the spontaneous sleep-wake cycle and factors that can affect this regulation forms the basis for diagnosis and treatment of the many common disorders of sleep.

Sleep, its regulation and possible mechanisms of sleep disturbances.

The state of sleep consists of different phases that proceed in successive, tightly regulated order through the night forming a physiological program, which for each individual is different but stabile from one night to another. Failure to accomplish this program results in feeling of unrefreshing sleep and tiredness in the morning. The program core is constructed by genetic factors but regulated by circadian rhythm and duration and intensity of day time brain activity. Many environmental factors modulate sleep, including stress, health status and ingestion of vigilance-affecting nutrients or medicines (e.g. caffeine). Acute sleep loss results in compromised cognitive performance, memory deficits, depressive mood and involuntary sleep episodes during the day. Moreover, prolonged sleep curtailment has many adverse health effects, as evidenced by both epidemiological and experimental studies. These effects include increased risk for depression, type II diabetes, obesity and cardiovascular diseases. In addition to voluntary restriction of sleep, shift work, irregular working hours, jet lag and stress are important factors that induce curtailed or bad quality sleep and/or insomnia. This review covers the current theories on the function of normal sleep and describes current knowledge on the physiologic effects of sleep loss. It provides insights into the basic mechanisms of the regulation of wakefulness and sleep creating a theoretical background for understanding different disturbances of sleep.

TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans.

Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, ß = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, ß = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, ß = 0.063; meta-analysis of both samples P = 8.1(*)10(-6), ß = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6-fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep.

Sleep homeostasis and depression: studies with the rat clomipramine model of depression.

Neonatal treatment of rat pups with clomipramine (CLI) has been shown to cause long-lasting and persistent depression-related behaviors and changes in sleep architecture and in brain-derived neurotrophic factor (BDNF) signaling in adult animals, producing an animal model of depression. However, the molecular mechanisms which mediate these effects of early-life CLI treatment on adult animals remain largely unknown. In order to characterize these further, we investigated in neonatally CLI-treated rats the sleep architecture as well as the extracellular and cellular levels of sleep regulators (nitric oxide, adenosine) and BDNF, respectively, in the basal forebrain (BF), i.e. the brain area which is implicated in sleep and depression. We found that CLI-treated rats exhibited a disturbed sleep architecture (REM sleep fragmentation was increased and NREM periods preceding REM were shorter) and reduced levels of BDNF and adenosine in the BF, whereas the levels of nitric oxide were elevated. Next, we examined sleep deprivation (SD)-induced homeostatic responses on sleep regulation and brain BDNF levels in CLI-treated rats. Compared to control rats, 3h of SD induced a smaller increase in the amount of NREM sleep during sleep recovery. At the molecular level, the normal homeostatic response was dissociated: the rise in the adenosine level was not accompanied by a rise in the nitric oxide concentration. Moreover, while BF BDNF levels decreased during SD in control rats, such a decline was not observed in CLI rats. Taken together, neonatal CLI treatment produces long-lasting functional changes in the sleep architecture and sleep regulation in adult rats, accompanied by dysregulated BDNF signaling in the BF.

Increases in extracellular serotonin and dopamine metabolite levels in the basal forebrain during sleep deprivation.

The basal forebrain (BF) is an important mediator of cortical arousal, which is innervated by all ascending arousal systems. During sleep deprivation (SD) a site-specific accumulation of sleep factors in the BF results in increased sleep pressure (Kalinchuk et al., 2006; Porkka-Heiskanen et al., 1997; Porkka-Heiskanen et al., 2000). However, animals are able to stay awake and even increase their neuronal activity in the BF and cortex during SD, suggesting increased activity of the ascending arousal systems to counteract the effect of sleep pressure. This study used in vivo microdialysis to measure the effect of a 6h SD, by "gentle handling" in freely moving rats, on the extracellular levels of serotonin and dopamine metabolites (5-HIAA, and DOPAC and HVA respectively) in the BF. Additionally, because glucocorticoids can interact with monoaminergic neurotransmission, and SD could be stressful, corticosterone levels were measured. We found an increase in extracellular serotonin and dopamine metabolite levels (n=8, p≤0.05). No interaction between corticosterone and the monoaminergic systems was apparent. Extracellular corticosterone levels showed no increase during the first 3h of SD, and the subsequent increase (n=8, p≤0.05) did not result in values exceeding the normal diurnal maximum, indicating that no substantial stress was induced. The results demonstrate that SD increases extracellular dopamine and serotonin metabolites in the BF, suggesting increased activity of the ascending arousal systems. It remains to be investigated what the specific roles of the dopaminergic and serotonergic ascending arousal systems are in BF-mediated cortical arousal.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients.

Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the µ-opioid receptor. However, its affinity for the µ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent µ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients. The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1. Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0-12h of oxycodone by 19% (-23 to 113%; P = 0.003), and that of noroxycodone by 100% (5-280%; P < 0.0001) but decreased the AUC0-12 h of oxymorphone by 67% (-100 to -22%; P < 0.0001) and that of noroxymorphone by 68% (-100 to -16%; P < 0.0001). Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine. No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine-oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied. The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

Characterization of sleep-wake patterns in a novel transgenic mouse line overexpressing human prepro-orexin/hypocretin.

AIM: Orexin/hypocretin peptides are expressed in the lateral hypothalamus and involved in the regulation of autonomic functions, energy homeostasis and arousal states. The sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and occurrence of sudden rapid eye movement (REM) sleep, is associated with a loss of orexin neurones. Our study investigated the effects of orexins on sleep-wake patterns in a novel transgenic mouse line overexpressing the human prepro-orexin (hPPO) gene under the control of its endogenous promoter. METHODS: Orexin overexpression was investigated by PCR, Southern and Western blotting as well as immunohistochemistry. Polysomnographic recordings were performed for analyses of sleep-wake patterns and for electroencephalographic activity during 24 h baseline and during and after 6 h of sleep deprivation (SD). RESULTS: Transgenic hPPO mice had increased expression of human prepro-orexin (hPPO) and orexin-A in the hypothalamus. Transgene expression decreased endogenous orexin-2 receptors but not orexin-1 receptors in the hypothalamus without affecting orexin receptor levels in the basal forebrain, cortex or hippocampus. Transgenic mice compared with their wild type littermates showed small but significant differences in the amount of waking and slow wave sleep, particularly during the light-dark transition periods, in addition to a slight reduction in REM sleep during baseline and during recovery sleep after SD. CONCLUSION: The hPPO-overexpressing mice show a small reduction in REM sleep, in addition to differences in vigilance state amounts in the light/dark transition periods, but overall the sleep-wake patterns of hPPO-overexpressing mice do not significantly differ from their wild type littermates.

Association of depressive symptoms and metabolic syndrome in men.

OBJECTIVE: To explore the relationship between several indicators of depression and metabolic syndrome (MetS). METHOD: A population-based sample with high (HMS group) or low (LMS group) levels of mental symptoms, including those of depression, in three follow-ups participated in a clinical examination in 2005 (n = 223). MetS was determined according to the NCEP criteria. RESULTS: The prevalence of MetS was 49% in men and 21% in women. Men with MetS had higher rates of major depressive disorder than other men. They also displayed higher Hamilton Rating Scale for Depression (HDRS) scores and more often signs of suicidality. In logistic regression analyses, higher HDRS scores (OR 1.31, 95% CI 1.04-1.64) and belonging to the HMS group (OR 10.1, 95% CI 1.98-51.3) were independent associates for MetS but only in men. CONCLUSION: The results highlight that there is an association between long-term depressive symptoms and the emergence of MetS, especially in men.

Itraconazole, a potent inhibitor of P-glycoprotein, moderately increases plasma concentrations of oral morphine.

BACKGROUND: Individual variation in opioid response is considerable, partly due to pharmacokinetic factors. Transporter proteins are becoming increasingly interesting also in the pharmacokinetics of opioids. The efflux transporter P-glycoprotein can affect gastrointestinal absorption and tissue distribution, particularly brain access of many opioids. The aim of this study was to evaluate whether itraconazole, which is a potent inhibitor of P-glycoprotein and CYP3A4, would change the pharmacokinetics or the pharmacodynamics of oral morphine. METHODS: Twelve healthy male volunteers ingested, in a randomized crossover study, once daily 200 mg itraconazole or placebo for 4 days. On day 4, 1 h after the last pre-treatment dose, the subjects ingested 0.3 mg/kg morphine. Blood samples for the determination of plasma morphine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G) and itraconazole concentrations were drawn up to 48 h after morphine ingestion. Pharmacodynamic effects were evaluated using a questionnaire, visual analogue scales, a reaction time test, the Digit Symbol Substitution Test and the Critical Flicker Fusion Test. RESULTS: Itraconazole increased the mean area under the plasma concentration-time curve [AUC (0-9)] of morphine by 29% (P=0.002), its AUC (0-48) by 22% (P=0.013) and its peak plasma concentration by 28% (P=0.035). Itraconazole did not significantly affect the pharmacokinetic variables of M3G or M6G or the pharmacodynamic effects of morphine. CONCLUSIONS: Itraconazole moderately increases plasma concentrations of oral morphine, probably by enhancing its absorption by inhibiting intestinal wall P-glycoprotein. A possible improvement of morphine penetration to the brain could not be observed.

The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions.

A topic of high current interest and controversy is the basis of the homeostatic sleep response, the increase in non-rapid-eye-movement (NREM) sleep and NREM-delta activity following sleep deprivation (SD). Adenosine, which accumulates in the cholinergic basal forebrain (BF) during SD, has been proposed as one of the important homeostatic sleep factors. It is suggested that sleep-inducing effects of adenosine are mediated by inhibiting the wake-active neurons of the BF, including cholinergic neurons. Here we examined the association between SD-induced adenosine release, the homeostatic sleep response and the survival of cholinergic neurons in the BF after injections of the immunotoxin 192 immunoglobulin G (IgG)-saporin (saporin) in rats. We correlated SD-induced adenosine level in the BF and the homeostatic sleep response with the cholinergic cell loss 2 weeks after local saporin injections into the BF, as well as 2 and 3 weeks after i.c.v. saporin injections. Two weeks after local saporin injection there was an 88% cholinergic cell loss, coupled with nearly complete abolition of the SD-induced adenosine increase in the BF, the homeostatic sleep response, and the sleep-inducing effects of BF adenosine infusion. Two weeks after i.c.v. saporin injection there was a 59% cholinergic cell loss, correlated with significant increase in SD-induced adenosine level in the BF and an intact sleep response. Three weeks after i.c.v. saporin injection there was an 87% cholinergic cell loss, nearly complete abolition of the SD-induced adenosine increase in the BF and the homeostatic response, implying that the time course of i.c.v. saporin lesions is a key variable in interpreting experimental results. Taken together, these results strongly suggest that cholinergic neurons in the BF are important for the SD-induced increase in adenosine as well as for its sleep-inducing effects and play a major, although not exclusive, role in sleep homeostasis.

Glutamatergic stimulation of the basal forebrain elevates extracellular adenosine and increases the subsequent sleep.

A prolonged period of waking accumulates sleep pressure, increasing both the duration and the intensity of the subsequent sleep period. Delta power, which is calculated from the slow range electroencephalographic (EEG) oscillations (0.1-4 Hz), is regarded as the marker of sleep intensity. Recent findings indicate that not only the duration but also the quality of waking, determines the level of increase in the delta activity during the subsequent sleep period. Elevated levels of extracellular adenosine in the basal forebrain (BF) during prolonged waking have been proposed to act as the molecular signal of increased sleep pressure, but the role of BF neuronal activity in elevating adenosine has not been previously explored. We hypothesized that an increase in neuronal discharge in the BF would lead to increase in the extracellular adenosine and contribute to the increase in the subsequent sleep. To experimentally increase neuronal activity in the rat BF, we used 3 h in vivo microdialysis application of glutamate or its receptor agonists N-methyl-D-aspartate (NMDA) or AMPA. Samples for adenosine measurement were collected during the drug application and the EEG was recorded during and after the treatment, altogether for 24 h. All treatments increased the duration of the subsequent sleep following the application. In contrast, delta power was elevated only if both the waking EEG theta (5-9 Hz) power (which can be regarded as a marker of active waking) and the extracellular adenosine in the BF were increased during the application. These results indicate that increased neuronal activity in the BF, and particularly the type of neuronal activity coinciding with active waking, is one of the factors contributing to the buildup of the sleep pressure.

Nitric oxide production in the basal forebrain is required for recovery sleep.

Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. Here, we assessed the role of the intercellular gaseous signaling agent NO in sleep homeostasis. We measured the concentration of nitrite and nitrate, indicative of NO production, in the basal forebrain (BF) of rats during sleep deprivation (SD), and found the level increased by 100 +/- 51%. To test whether an increase in NO production might play a causal role in recovery sleep, we administered compounds into the BF that increase or decrease concentrations of NO. Infusion of either a NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, or a NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), completely abolished non-rapid eye movement (NREM) recovery sleep. Infusion of a NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2diolate (DETA/NO), produced an increase in NREM that closely resembled NREM recovery after prolonged wakefulness. The effects of inhibition of NO synthesis and the pharmacological induction of sleep were effective only in the BF area. Indicators of energy metabolism, adenosine, lactate and pyruvate increased during prolonged wakefulness and DETA/NO infusion, whereas L-NAME infusion during SD prevented the increases. We conclude that an increase in NO production in the BF is a causal event in the induction of recovery sleep.

Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction.

Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. We have previously shown that nitric oxide (NO) generation increases in the basal forebrain (BF) during sleep deprivation (SD). Moreover, both NO synthase (NOS) inhibition and a NO scavenger prevented recovery sleep induction, while administration of a NO donor during the spontaneous sleep-wake cycle increased sleep, indicating that NO is necessary and sufficient for the induction of recovery sleep. Next we wanted to know which NOS isoform is involved in the production of recovery sleep. Using in vivo microdialysis we infused specific inhibitors of NOS into the BF of rats during SD, and found that an inhibitor of inducible NOS (iNOS), 1400W, prevented non-rapid eye movement (NREM) recovery, while an inhibitor of neuronal NOS (nNOS), L-N-propyl-arginine, decreased REM recovery but did not affect NREM recovery. Using immunoblot analysis we found that iNOS was not expressed during the spontaneous sleep-wake cycle, but was induced by prolonged wakefulness (increased by 278%). A known iNOS inducer, lipopolysaccharide, evoked an increase in sleep that closely resembled recovery sleep, and its effects were abolished by 1400W. These results suggest that the elevation of NO produced by induction of iNOS in the BF during prolonged wakefulness is a specific mechanism for producing NREM recovery sleep and that the two NOS isoforms have a complementary role in NREM and REM recovery induction.

Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey.

Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Orexin A and B levels in the hypothalamus of female rats: the effects of the estrous cycle and age.

OBJECTIVE: Orexins have been implicated in the regulation of several physiological functions including reproduction, energy balance and vigilance state. For successful reproduction, the precisely timed hormonal secretions of the estrous cycle must be combined with appropriate nutritional and vigilance states. The steroid- and nutritional state-dependent modulation of LH release by orexins, as well as an increase of vigilance, suggest that orexins may co-ordinate these functions in the course of the estrous cycle. DESIGN: We studied the brain tissue levels of orexins in the course of the estrous cycle in young and middle-aged rats. Young cycling rats (3 months old) and irregularly/non-cycling (7-9 months old) female rats were inspected for vaginal smears and serum hormone levels. METHODS: Tissue concentrations of orexin A and B were measured in the hypothalamus and lateral hypothalamus on different days of the estrous cycle. RESULTS: Orexin A concentration in the hypothalamus of young cycling rats was higher on the day of proestrus 5-6 h after the lights were switched on than on the other days of the estrous cycle at the same circadian time. Orexin B concentration was higher on both the day of proestrus and the day of estrus as compared with the days of diestrus. The hypothalamic concentrations of both orexin A and B in the non-cycling middle-aged rats were lower than those in cycling rats on the days of proestrus and estrus. CONCLUSIONS: We have concluded that the high hypothalamic concentration of orexins on the day of proestrus may contribute to the LH and prolactin surges. High orexin A levels may also contribute to the decreased amount of sleep on the day of proestrus.

Sexual motivation in relation to social rank in pair-housed sows.

The influence of social subordination on sexual motivation during oestrus was studied using 36 sows of which 24 treatment sows were housed in pairs and 12 control sows were housed individually in 12 and 6 m(2) pens, respectively. Video recordings were made from 07:00 h to 19:00 h during the first 2 days after grouping, which took place 3 days after weaning of the piglets. Based on the aggressive interactions between the pair-housed sows, their rank was determined. From day 4 after weaning, a test for sexual proceptive behaviour was carried out twice daily and back-pressure test was carried out four times daily in order to detect standing oestrus. When standing oestrus had occurred, transrectal ultrasonographical scans were also carried out in order to determine if ovulation took place. The proceptivity test took place in a T-maze with a 2 m x 10 m runway ending in two 1.5 m x 1.5 m goal boxes each adjacent to a stimulus compartment. One compartment contained an adult sexually experienced boar and the other was empty. Latency to and duration of time spent close to the boar and time spent presenting were recorded during the 10-min test period. On the first day that standing oestrus had been detected, a test for sexual receptivity was also carried out by introducing the sow to a mature boar in his home pen (9 m(2)). Sexual- and fear-related behaviour of sow and boar were recorded until mating was terminated or the sow had spent 5 min in the pen without mating being initiated. During oestrus the proceptivity test showed a significant increase (P < 0.05) in the time spent standing close to the boar and in presenting for single-housed sows and for pair-housed dominant sows, but not for subordinate sows. During oestrus subordinate sows spent significantly less time standing close to the boar than the dominant sows (P = 0.01) and the same tended to be the case for presenting (P = 0.07). In the receptivity test more subordinate sows than dominant sows fled (40% versus 0%, P = 0.001) and more subordinate sows than dominant sows squealed (58% versus 15%, P = 0.02) as a response to boar stimulation. In both tests, the single-housed sows differed neither from the dominant nor the subordinate sows. There was however no difference between the groups in the weaning to oestrous interval, duration of oestrus and number of piglet born. In addition, all the sows ovulated. The results indicate that social subordination can have significant consequences for sexual motivation in sows. Subordinate sows showed fear-related behaviour in response to boar stimulation even when they were in standing oestrus. Thus, both heat detection and mating may be impaired in subordinate sows. The results emphasise the importance to alleviate the social stress experienced by subordinates as well as the need for stock people to pay special attention to these animals when they are to be mated or inseminated.

Effect of a single-dose of olanzapine on sleep in healthy females and males.

The effect of a single dose of 10 mg olanzapine on healthy volunteers of both sexes was examined using polysomnography and power spectral analysis. The structure and continuity of sleep were unaffected by olanzapine in both sexes. The increase in both actual sleep time and slow wave sleep in females correlated with the increase in theta power, while delta power was not significantly elevated, suggesting that theta power may be a sensitive indicator of changes in sleep. The changes in sleep had the same tendency in men, but they were not significant. The difference between the sexes could not be explained by differences in body mass index. Olanzapine affects sleep probably through 5-HT(2C) receptors. The receptor gene is located on the X-chromosome, inducing an allelic difference between the females and males. This difference may contribute to the different effects of olanzapine on sleep. Olanzapine seems to preserve the normal structure of sleep and increase the amount of slow-wave sleep, which might be of additional benefit in treatment of schizophrenia. The effective clinical dose may be lower for females than males.