Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4-, 8-, and 13-fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1-, 1.5-, and 1.7-fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2-fold).

Sleep and wake disturbances following traumatic brain injury.

Traumatic brain injury (TBI) is a major health concern in industrialised countries. Sleep and wake disturbances are among the most persistent and disabling sequelae after TBI. Yet, despite the widespread complaints of post-TBI sleep and wake disturbances, studies on their etiology, pathophysiology, and treatments remain inconclusive. This narrative review aims to summarise the current state of knowledge regarding the nature of sleep and wake disturbances following TBI, both subjective and objective, spanning all levels of severity and phases post-injury. A second goal is to outline the various causes of post-TBI sleep-wake disturbances. Globally, although sleep-wake complaints are reported in all studies and across all levels of severity, consensus regarding the objective nature of these disturbances is not unanimous and varies widely across studies. In order to optimise recovery in TBI survivors, further studies are required to shed light on the complexity and heterogeneity of post-TBI sleep and wake disturbances, and to fully grasp the best timing and approach for intervention.

Cognitive impairment in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterised by repetitive cessation or reduction of airflow due to upper airway obstructions. These respiratory events lead to chronic sleep fragmentation and intermittent hypoxemia. Several studies have shown that OSA is associated with daytime sleepiness and cognitive dysfunctions, characterized by impairments of attention, episodic memory, working memory, and executive functions. This paper reviews the cognitive profile of adults with OSA and discusses the relative role of altered sleep and hypoxemia in the aetiology of these cognitive deficits. Markers of cognitive dysfunctions such as those measured with waking electroencephalography and neuroimaging are also presented. The effects of continuous positive airway pressure (CPAP) on cognitive functioning and the possibility of permanent brain damage associated with OSA are also discussed. Finally, this paper reviews the evidence suggesting that OSA is a risk factor for developing mild cognitive impairment and dementia in the aging population and stresses the importance of its early diagnosis and treatment.

Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients.

BACKGROUND AND PURPOSE: Patients with obstructive sleep apnea syndrome (OSAS) present cognitive deficits similar to those observed with aging. The aim of the study was to assess the effects of age on cognitive functions in OSAS patients. It was hypothesized that older OSAS patients will exhibit significant cognitive dysfunction relative to younger OSAS patients and controls. PATIENTS AND METHODS: Younger and older OSAS patients were compared to younger and older control subjects (age cut-off set at 50 yrs). Participants underwent a polysomnographic (PSG) and neuropsychological evaluation. Variables were analyzed by two-way analyses of variance (ANOVAs) with two factors: Group (control and OSAS) and Age (younger and older). Additionally, we evaluated the contribution of attentional deficits to cognitive dysfunction for each subgroup of patients by using Spearman correlation coefficients. RESULTS: No Group-by-Age interaction was found for any neuropsychological variables (p<0.05). However, main Group and Age effects were found. Correlations indicated that attentional deficits contributed importantly to a poorer cognitive performance in younger OSAS patients only (p<0.01). CONCLUSIONS: Our results are in agreement with those of the literature for both OSAS-related and aging-related cognitive deficits but did not demonstrate that age interacts with the effects of the OSAS condition to make those cognitive deficits worse.

Effect of an integrated reality orientation programme in acute care on post-traumatic amnesia in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To assess the effect of an integrated reality orientation programme (North Star Project) in acute care on the duration of post-traumatic amnesia (PTA) of patients suffering from traumatic brain injury (TBI). It was hypothesized that those patients having participated in this programme would show a shorter PTA than those patients that did not. METHOD: Duration of PTA for 12 patients with TBI who were part of the North Star Project was compared with that of 26 patients matched for initial GCS and age for whom this approach was not available (control group). RESULTS: Length of PTA was shorter by 5 days for the North Star patients. This result was not statistically significant (p = 0.19) but is clinically relevant. No between-group difference was found for Glasgow Coma Scale. CONCLUSIONS: Consequences of shorter PTA would include increased and more appropriate patient interaction and earlier transfer to rehabilitation. The North Star project also allows the family to become more actively involved in the treatment of their loved one. Further study is required to evaluate this intervention strategy to improve orientation for the patient with TBI.

Effect of acute hyperoxia during exercise on quadriceps electrical activity in active COPD patients.

AIMS: This study investigated whether acute hyperoxia improves electrical muscle activity in active chronic obstructive pulmonary disease (COPD) patients with mild hypoxemia (rest PaO(2) = 9.1 +/- 0.4 kPa). METHODS: Two identical incremental exercise tests were performed by nine patients while breathing either air or 30% oxygen. Pulmonary gas exchanges, venous concentrations of lactate and pyruvate, and the electromyographic signal of the quadriceps muscle (vastus lateralis and vastus medialis) were sampled each minute. RESULTS: Peak working capacity increased significantly in hyperoxia (94.4 +/- 5.2W) compared with normoxia (85.4 +/- 5.8W, P < 0.01). During hyperoxic exercise and for a given work load, oxygen uptake was increased (P < 0.001) and ventilation decreased (P < 0.05). Lactate concentration was significantly decreased (P < 0.01) at isowork level and during recovery (respectively - 26% and at least - 15%). In the quadriceps muscle, M-wave amplitude (P < 0.05), root mean square (P < 0.01) and root mean square/oxygen uptake ratio (P < 0.001) were significantly increased during hyperoxic exercise compared with room air. Although median frequency values did not differ between conditions, the median frequency was significantly decreased for higher exercise intensity in hyperoxic condition. These modifications reflected better aerobic metabolism, later emergence of muscle fatigue, and greater muscle excitability and activation for the same level of exercise under hyperoxic condition. CONCLUSION: These data suggest that the acute addition of oxygen in active COPD patients improves their muscle electrical activity during dynamic exercise. Hypoxemia-induced skeletal muscle dysfunction most probably acts through mechanisms based on oxygen availability.

[Exercise effort training for COPD: physiological basis and results]. / Le réentraînement à l'effort des BPCO: bases physiologiques et résultats.

INTRODUCTION: In the last decade pulmonary rehabilitation has become a well accepted treatment for patients with chronic obstructive pulmonary disease (COPD) suffering from persistent dyspnea and fatigue, despite appropriate medical treatment. STATE OF ART: Patients with COPD frequently have muscular dysfunction that can be corrected by appropriate exercise training programmes. Muscle function as measured by strength and endurance tests exercise capacity and also the health status and quality of life are improved by exercise and endurance training. However, integration of exercise training in a multidisciplinary management programme is necessary to take account of all aspects of the illness. PERSPECTIVES: Methods of exercise training need to be adapted for patients with severe COPD who are unable to undertake endurance training and for patients who obtain little benefit. CONCLUSIONS: Pulmonary rehabilitation, thanks to its multidisciplinary nature, seems to be an effective modality of management for patients with COPD. However, the improvements in physical ability, quality of life and general health require an exercise training programme that is adapted for the individual patient.

Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndrome.

OBJECTIVE: Periodic leg movements during sleep (PLMS) are often associated with electroencephalographic (EEG) changes, such as microarousals (MA), and with heart rate (HR) variations. The aim of the present study was to evaluate the effects of age and gender on HR changes associated with PLMS in restless legs syndrome (RLS) patients. METHODS: Forty-two RLS patients underwent one night of polysomnographic recordings. They were divided into 3 groups of 14 subjects (7 women and 7 men) according to age, i.e. young (25-40 years), middle-aged (41-55 years) and elderly (56-71 years) patients. The RR interval was calculated for 5 intervals before and 15 intervals after the onset of 50 PLMS in each patient. RESULTS: PLMS were associated with HR changes characterized by a tachycardia followed by a bradycardia. However, a reduction in the tachycardia and the bradycardia was observed with age. Moreover, women showed a higher amplitude in the bradycardia than men. No age or gender difference was found for MA index and duration. CONCLUSIONS: This study showed age and gender differences in the magnitude of the HR changes associated with PLMS. The knowledge of HR variations during sleep, including rapid HR changes associated with sleep events such as PLMS or MA, may be helpful in understanding the potential mechanisms involved in the increased cardiac risk observed in elderly.

Periodic leg movements in REM sleep behavior disorder and related autonomic and EEG activation.

OBJECTIVE: To assess the frequency of periodic leg movements (PLM) in idiopathic REM sleep behavior disorder (RBD) and to analyze their polysomnographic characteristics and associated autonomic and cortical activation. BACKGROUND: PLM during sleep (PLMS) and wakefulness (PLMW) are typical features of restless legs syndrome (RLS), but are also frequently observed in patients with RBD. METHODS: Forty patients with idiopathic RBD underwent one night of polysomnographic recording to assess PLMS frequency. PLM features, PLMS-related cardiac activation during stage 2 sleep, and EEG changes were analyzed in 15 of these patients with RBD. Results were compared with similar data obtained in 15 sex- and age-matched patients with primary RLS. RESULTS: Twenty-eight (70%) of 40 patients with RBD showed a PLMS index greater than 10. No between-group differences were found in sleep architecture or indexes of PLMW and PLMS during non-REM sleep, but a trend for a higher PLMS index during REM sleep was found in patients with RBD. PLM mean duration and interval in the two conditions were similar. A transient tachycardia followed by a bradycardia was observed in close association with every PLMS in both groups, but the amplitude of the cardiac activation was significantly reduced in patients with RBD. In addition, significantly fewer PLMS were associated with microarousal in this condition. CONCLUSIONS: Periodic leg movements are very common in idiopathic RBD, occurring in all stages of sleep, especially during REM sleep. In idiopathic RBD, the reduction of cardiac and EEG activation associated with PLMS suggests the presence of an impaired autonomic and cortical reactivity to internal stimuli.

Age difference in heart rate changes associated with micro-arousals in humans.

OBJECTIVES: Heart rate (HR) is known to change in association to micro-arousals (MA) during sleep. The aim of the present study was to evaluate the effect of age on HR variations associated with MA. METHODS: Thirty-two healthy subjects underwent one night of polysomnographic recording. They were divided into two groups of 16 subjects according to age i.e. young (20-35 years) and middle-aged (50-65 years). The R-R intervals were calculated for 11 heart beats (10 intervals) before and 15 heart beats after the onset of MA. RESULTS: HR changes associated with MA were characterized by a tachycardia followed by a bradycardia in both young- and middle-aged subjects. However, middle-aged subjects showed a significant reduction in the amplitude of both tachycardia and bradycardia as compared to young subjects. CONCLUSIONS: This study revealed an age-related reduction in the amplitude of the HR changes associated with MA. These results may reflect a decline in parasympathetic functions and a higher risk of cardiovascular diseases with advancing age.

Performance of patients with schizophrenia on the Wisconsin Card Sorting Test (WCST).

OBJECTIVE: To directly compare the performance of patients with schizophrenia and control subjects on the Wisconsin Card Sorting Test (WCST). Specifically, we sought to verify if there are significant differences on the "classical" WCST measurements (perseverative errors and number of categories), as well as on more rarely reported scores, and assess the extent to which patients with schizophrenia can improve their performance with card-by-card instructions and continuous verbal reinforcement. DESIGN: Prospective cross-sectional study. SETTING: Psychiatry department in a university-affiliated hospital. PARTICIPANTS: 30 patients with schizophrenia, diagnosed according to DSM-IV criteria, and 30 control subjects, matched to patients according to age and education. INTERVENTION: The WCST was administered according to the criteria of Heaton, and a subgroup of the patients with schizophrenia was given a retest after an explanation of the WCST and verbal reinforcements. RESULTS: Patients with schizophrenia succeeded on fewer categories (t = 23.3, p < 0.001), committed more perseverative errors (t = 15.6, p < 0.001), made more perseverative responses (t = 14.6, p < 0.001), needed more trials to succeed at the first category (t = 9.2, p < 0.003) and gave significantly lower conceptual level responses (t = 14.1, p < 0.001) than the controls. However, on retest, patients with schizophrenia committed significantly fewer perseverative errors (t = 5.1, p < 0.001) and showed higher conceptual level responses (t = -3.45, p < 0.003). CONCLUSION: Consistent with a hypothesis of frontal dysfunction in schizophrenia, patients with schizophrenia tend to show a perseverative deficit; however, some are able to partially overcome this deficit when given verbal reinforcement.

A developmental study of the affective value of tempo and mode in music.

Do children use the same properties as adults in determining whether music sounds happy or sad? We addressed this question with a set of 32 excerpts (16 happy and 16 sad) taken from pre-existing music. The tempo (i.e. the number of beats per minute) and the mode (i.e. the specific subset of pitches used to write a given musical excerpt) of these excerpts were modified independently and jointly in order to measure their effects on happy-sad judgments. Adults and children from 3 to 8 years old were required to judge whether the excerpts were happy or sad. The results show that as adults, 6--8-year-old children are affected by mode and tempo manipulations. In contrast, 5-year-olds' responses are only affected by a change of tempo. The youngest children (3--4-year-olds) failed to distinguish the happy from the sad tone of the music above chance. The results indicate that tempo is mastered earlier than mode to infer the emotional tone conveyed by music.

Decreased LH pulsatility during initiation of gonadotropin superovulation treatment in the cow: evidence for negative feedback other than estradiol and progesterone.

LH pulse secretion is suppressed during superovulation of cattle. The objective of this study was to determine how soon after initiation of superovulation treatments this suppressive effect occurs, and to test the hypothesis that decreased LH pulsatility is not related to changes in circulating estradiol or progesterone. Heifers (n = 7/group) were injected with eCG (FOLLIGON: a single injection of 2,500 IU) or twice daily injections of decreasing doses of FOLLTROPIN-V (total equivalent of 280 mg of NIH-FSH-P1) or F.S.H.-P (total equivalent of 28 mg of Armour standard) or saline (time controls), starting on Day 10 (Day 0 = estrus). Blood samples were taken every 10 min for 12 h intervals on the day prior to first injection, at 8 to 20 h and 32 to 44 h after initiation of gonadotropin treatment, and also during prostaglandin (PG)-induced luteolysis. A simple method based on robust statistics and on graphical representations of time series was developed to characterize LH pulses. There was a significant interaction between time and treatment for mean LH, estradiol and progesterone when control and treated groups were analyzed together, and no interaction when only the gonadotropin groups were analyzed together. When compared to pretreatment values, pulse frequency of LH was significantly reduced (P<0.05) in each treatment group, 8 to 20 h and 32 to 44 h following initiation of gonadotropin treatment. Mean LH concentrations were also reduced 32 to 44 h following initiation of treatments (P<0.05). Mean estradiol concentrations increased two to threefold at 8 to 20 h following initiation of superovulation treatments (P<0.05). Progesterone concentrations also increased by 20 or 44 h. There was no significant correlation between estradiol or progesterone and LH pulse frequency, amplitude and mean concentrations at any time in control or superovulated animals. This study demonstrates that superovulation treatment in the cow causes a rapid decrease in pulsatile release of LH and suggests that this effect is not mediated through the negative feedback actions of estradiol and progesterone.

[Deficit in suppression of interference in visual information processing by schizophrenic subjects]. / Déficit dans la suppression de l'interférence au niveau du traitement de l'information visuelle chez des patients schizophr nes.

Although many studies have indicated information processing deficits in schizophrenic patients, the precise nature and underlying causes of these deficits remain largely uncertain. One prominent hypothesis is that these patients show insufficient attentional inhibition. This deficit to inhibition has been linked to certain cognitive disorders in schizophrenic patients, including attention deficits, as well as to some clinical symptoms, especially those involving delusional thought, hallucinations,and poor contact with reality. The hypothesis of deficient attentional inhibition, although attractive in some ways, is difficult to work with, because it is not easy to directly measure "attentional inhibition". Several studies involving normal subjects have linked attentional inhibition with performance on a task demanding the suppression of distracting information: the presumption is that efficient attentional inhibition will permit rapid responses because the distracting information will be quickly suppressed, allowing undistracted processing of the target information. The present study measures schizophrenic patients' performance on a task demanding suppression of rapidly-presented visual information. An important methodological feature of this study is that performance is measured in terms of "percent correct responses" rather than the reaction time measures typically used in tasks demanding distractor suppression, such as Stroop-like selective attention tasks. Since reaction times are not considered, the results cannot be interpreted in terms of deficient response organization and execution. Schizophrenic (18) and normal (18) subjects underwent trials in which a visual target was the second of two stimuli presented in rapid succession. Interference produced by a non-target significantly impaired perception of the target for schizophrenic patients. This effect persisted longer in the schizophrenic subjects possibly because of deficient attentional inhibition.

Effects of superovulation on endogenous LH secretion in cattle, and consequences for embryo production.

Stimulation of follicular growth during superovulation is achieved by the injection of FSH or compounds with high FSH-bioactivities. However, some LH-activity is required for follicle maturation. It is of relevance to evaluate, therefore, the effect of superovulatory treatments on endogenous LH secretion. Luteinizing hormone is secreted in discrete pulses, and the pattern of pulsatile LH secretion during superovulation is reviewed. Four of five published studies have shown that LH pulse frequency is significantly reduced by injection of eCG or FSH preparations. This suppression appears within 8 h of treatment Effects of superovulation on LH pulse amplitude are less consistent. The reasons for the decrease in pulse frequency have been investigated, and although the answer is not definitive, it would seem that increased follicular estradiol, acting perhaps in synergism with progesterone, may play a role. Changes in plasma progesterone concentrations are not related to changes in LH pulse frequency. What is the significance of decreased LH pulse frequency? We attempted to investigate this by inducing LH pulses during superovulation, but the result was a major reduction in ovulation rate. More research is required to determine if modification of endogenous LH secretion can improve superovulatory responses.