Periodic properties of the histaminergic system of the mouse brain

Brain histamine is involved in the regulation of the sleep–wake cycle and alertness. Despite the widespread use of the mouse as an experimental model, the periodic properties of major markers of the mouse histaminergic system have not been comprehensively characterized. We analysed the daily levels of histamine and its first metabolite, 1‐methylhistamine, in different brain structures of C57BL/6J and CBA/J mouse strains, and the mRNA level and activity of histidine decarboxylase and histamine‐N‐methyltransferase in C57BL/6J mice. In the C57BL/6J strain, histamine release, assessed by in vivo microdialysis, underwent prominent periodic changes. The main period was 24 h peaking during the activity period. Additional 8 h periods were also observed. The release was highly positively correlated with active wakefulness, as shown by electroencephalography. In both mouse strains, tissue histamine levels remained steady for 24 h in all structures except for the hypothalamus of CBA/J mice, where 24‐h periodicity was observed. Brain tissue 1‐methylhistamine levels in both strains reached their maxima in the periods of activity. The mRNA level of histidine decarboxylase in the tuberomamillary nucleus and the activities of histidine decarboxylase and histamine‐N‐methyltransferase in the striatum and cortex did not show a 24‐h rhythm, whereas in the hypothalamus the activities of both enzymes had a 12‐h periodicity. These results show that the activities of histamine‐metabolizing enzymes are not under simple direct circadian regulation. The complex and non‐uniform temporal patterns of the histaminergic system of the mouse brain suggest that histamine is strongly involved in the maintenance of active wakefulness.     

Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study

The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.     

Decline in suicidal ideation among patients with MDD is preceded by decline in depression and hopelessness

BACKGROUND: Suicidal ideation is likely to represent a phase preceding suicidal acts among most suicidal patients with major depressive disorder (MDD). Factors predicting reversal of the suicidal process are unknown. Our aim was to test the hypothesis that a decline in suicidal ideation is preceded by a decline in hopelessness among patients with MDD. METHOD: Of the 269 Vantaa Depression Study patients with DSM-IV MDD, 103 patients scored > or = 6 points at baseline on the Scale for Suicidal Ideation (SSI). Seventy of these patients were followed-up weekly either until they scored zero points on the SSI, or up to 26 weeks. RESULTS: The median duration for a decline of suicidal ideation to zero was 2.2 months after baseline. The level of baseline suicidal ideation, depressive symptoms, and the presence of any personality disorder predicted duration of suicidal ideation. A decline in both depression (BDI) and hopelessness (HS) independently predicted a decline in suicidal ideation. LIMITATIONS: Due to study design, we do not know if suicidal ideation relapsed after the first time the patient reached zero score in the SSI. CONCLUSIONS: Among patients with major depressive disorder having suicidal ideation, the decline in suicidal ideation is independently predicted by preceding declines in the levels of both depressive symptoms as well as hopelessness. The findings are consistent with possible causal roles of declines in depression and hopelessness in reversing the suicidal process.     

Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor

Sleep deprivation (SD) increases extracellular adenosine levels in the basal forebrain, and pharmacological manipulations that increase extracellular adenosine in the same area promote sleep. As pharmacological evidence indicates that the effect is mediated through adenosine A1 receptors (A1R), we expected A1R knockout (KO) mice to have reduced rebound sleep after SD. Male homozygous A1R KO mice, wild-type (WT) mice, and heterozygotes (HET) from a mixed 129/C57BL background were implanted during anesthesia with electrodes for electroencephalography (EEG) and electromyography (EMG). After 1 week of recovery, they were allowed to adapt to recording leads for 2 weeks. EEG and EMG were recorded continuously. All genotypes had a pronounced diurnal sleep/wake rhythm after 2 weeks of adaptation. We then analyzed 24 h of baseline recording, 6 h of SD starting at light onset, and 42 h of recovery recording. Neither rapid eye movement sleep (REM sleep) nor non-REM sleep (NREMS) amounts differed significantly between the groups. SD for 6 h induced a strong NREMS rebound in all three groups. NREMS time and accumulated EEG delta power were equal in WT, HET and KO. Systemic administration of the selective A1R antagonist 8-cyclopentyltheophylline (8-CPT) inhibited sleep for 30 min in WT, whereas saline and 8-CPT both inhibited sleep in KO. We conclude that constitutional lack of adenosine A1R does not prevent the homeostatic regulation of sleep.     

Prediction of inspiratory flow shapes during sleep with a mathematic model of upper airway forces

STUDY OBJECTIVES: To predict the airflow dynamics during sleep using a mathematic model that incorporates a number of static and dynamic upper airway forces, and to compare the numerical results to clinical flow data recorded from patients with sleep-disordered breathing on and off various treatment options. DESIGN: Upper airway performance was modeled in virtual subjects characterized by parameter settings that describe common combinations of risk factors predisposing to upper airway collapse during sleep. The treatments effect were induced by relevant changes of the initial parameter values. SETTING: Computer simulations at our website (http://www.utu.fi/ml/sovmat/bio/). PARTICIPANTS: Risk factors considered in the simulation settings were sex, obesity, pharyngeal collapsibility, and decreased phasic activity of pharyngeal muscles. INTERVENTIONS: The effects of weight loss, pharyngeal surgery, nasal continuous positive airway pressure, and respiratory stimulation on the inspiratory flow characteristics were tested with the model. MEASUREMENTS AND RESULTS: Numerical predictions were investigated by means of 3 measurable inspiratory airflow characteristics: initial slope, total volume, and flow shape. The model was able to reproduce the inspiratory flow shape characteristics that have previously been described in the literature. Simulation results also supported the observations that a multitude of factors underlie the pharyngeal collapse and, therefore, certain medical therapies that are effective in some conditions may prove ineffective in others. CONCLUSIONS: A mathematic model integrating the current knowledge of upper airway physiology is able to predict individual treatment responses. The model provides a framework for designing novel and potentially feasible treatment alternatives for sleep-disordered breathing.     

The effects of maternal risk factors during pregnancy on the onset of sleep difficulties in infants at 3 months old

Sleep problems in young children are among the most common concerns reported to paediatricians. Sleep is thought to have important regulatory functions, and sleep difficulties in early childhood are linked to several psychosocial and physiological problems. Moreover, several prenatal factors have been found to influence infants’ sleep. Among them, most of the studies have been focused on maternal prenatal depression and/or anxiety as potential risk factors for sleep problems in childhood, whereas other relevant psychological factors during pregnancy have not received as much attention. Therefore, we aimed to examine the effect of several psychiatric maternal risk factors during pregnancy (i.e. symptoms of anxiety, depression, insomnia, alcohol use, seasonality, attention deficit and hyperactivity disorder and/or stressful life events) on the onset of some sleep problems related to sleep quality and sleep practices in 3‐month‐old infants. We examined 1,221 cases from a population‐based birth cohort, with subjective measures during pregnancy in mothers, and at 3 months after birth in the infants. The findings showed that all the maternal risk factors during pregnancy, except for symptoms of alcoholism and sleepiness, were related to sleep difficulties in infants. Interestingly, attention deficit and hyperactivity disorder symptomatology in mothers during pregnancy was the only variable that predicted more than two sleeping difficulties (i.e. long sleep‐onset latency, co‐sleeping with parents and irregular sleeping routines) at 3 months old. Our results highlight the relevance of maternal risk factors during pregnancy, and not only prenatal depression and/or anxiety, as variables to be considered when examining sleep difficulties in infants.     

Skin contamination by oestradiol gel--a remarkable source of error in plasma oestradiol measurements during percutaneous hormone replacement therapy

Objectives: To study the consequence of skin contamination by oestradiol gel on circulating plasma oestradiol levels. Methods: We studied ten healthy, hysterectomized postmenopausal women who had used percutaneous oestradiol gel for at least 2 years. After wash-out period percutaneous dose of 1.5 mg 17β-oestradiol was administered once a day in the evening. The gel was applied with a bare or gloved hand to an arm or thigh according to the schedule. Blood samples for assay of plasma oestradiol concentrations were collected from both cubital veins 12 h after gel administration, at baseline and every time after using the gel, for 2 weeks. Results: Plasma oestradiol concentrations were significantly higher in the gel-contaminated samples: in the cubital vein of the gel-applying arm and in the cubital vein of the forearm on which the gel had been spread. Conclusions: Skin contamination by topical 17β-oestradiol can distort plasma oestradiol measurements by giving much higher oestradiol concentrations than in reality there are in the systemic circulation. This has an important meaning when tailoring individual oestrogen therapy.     

Gender differences in age and BMI distributions in partial upper airway obstruction during sleep

The obstructive sleep apnea-hypopnea syndrome occurs more frequently and with higher apnea-hypopnea indices in men than in women. To investigate the gender differences we extended our respiratory analyses during sleep to cover not only periodic obstruction (apnea and hypopnea) but also nonperiodic partial upper airway obstruction during sleep and their associations with increasing age or body mass index (BMI). The clinical sleep recordings with the static-charge-sensitive bed (SCSB) and oximeter were reviewed in 233 age and BMI-matched men-women pairs. Periodic obstruction increased with increasing BMI only in men. Nonperiodic partial obstruction increased with moderate to morbid obesity in women and men after the age of 65 years. Our findings suggest that while partial upper airway obstruction increases with increasing age and BMI in both genders, men have a gender specific BMI dependent predisposition for periodic obstruction (obstructive sleep apnea). The apnea-hypopnea index is likely to underestimate the impact of sleep-disordered breathing, particularly in elderly patients.