Proof-of Concept that an Acute Trophic Factors Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin-Expressing Progenitors and Regeneration.

Trophic factor treatment has been shown to improve the recovery of brain and spinal cord injury (SCI). In this study, we examined the effects of TSC1 (a combination of insulin-like growth factor 1 and transferrin) 4 and 8 h after SCI at the thoracic segment level (T12) in nestin-GFP transgenic mice. TSC1 treatment for 4 and 8 h increased the number of nestin-expressing cells around the lesion site and prevented Wallerian degeneration. Treatment with TSC1 for 4 h significantly increased heat shock protein (HSP)-32 and HSP-70 expression 1 and 2 mm from lesion site (both, caudal and rostral). Conversely, the number of HSP-32 positive cells decreased after an 8-h TSC1 treatment, although it was still higher than in both, non-treated SCI and intact spinal cord animals. Furthermore, TSC1 increased NG2 expressing cell numbers and preserved most axons intact, facilitating remyelination and repair. These results support our hypothesis that TSC1 is an effective treatment for cell and tissue neuroprotection after SCI. An early intervention is crucial to prevent secondary damage of the injured SC and, in particular, to prevent Wallerian degeneration.

Induced pluripotency enables differentiation of human nullipotent embryonal carcinoma cells N2102Ep.

Embryonal carcinoma (EC) cells, which are considered to be malignant counterparts of embryonic stem cells, comprise the pluripotent stem cell component of teratocarcinomas, a form of testicular germ cell tumors (GCTs). Nevertheless, many established human EC cell lines are nullipotent with limited or no capacity to differentiate under normal circumstances. In this study, we tested whether an over-expression of Yamanaka's reprogramming factors OCT4, SOX2, c-MYC and KLF4 might enable differentiation of the human nullipotent EC cells N2102Ep. Using OCT4 knockdown differentiated N2102Ep cells, we are able to derive reprogrammed N2102Ep cell lines. The induced pluripotency of N2102Ep allows the cells to differentiate toward neural lineage by retinoic acid; the expression of SSEA3 and SSEA4 is down-regulated, whereas that of neural surface markers is up-regulated. Consistent with the up-regulation of neural surface markers, the expression of the master neuroectodermal transcription factor PAX6 is also induced in reprogrammed N2102Ep. We next investigated whether PAX6 might induce spontaneous differentiation of nullipotent stem cells N2102Ep. However, while an ectopic expression of PAX6 promotes differentiation of NTERA2, it induces cell death in N2102Ep. We nevertheless find that upon induction of retinoic acid, the reprogrammed N2102Ep cells form mature neuronal morphology similar to differentiated pluripotent stem cells NTERA2 as determined by TUJ1 expression, which is absent in N2102Ep parental cells. Altogether, we conclude that the nullipotent state of human EC cells can be reprogrammed to acquire a more relaxed state of differentiation potential by Yamanaka's factors.

Effectiveness of neurobic exercise program on memory performance in community-dwelling older adults with mild cognitive impairment: A randomized controlled crossover trial.

Background: Mild cognitive impairment (MCI) is an early stage of cognitive decline in individuals who are still able to perform their activities of daily living. They are at increased risk of developing dementia. Improving and maintaining cognitive functions are essential goals for older people with MCI to delay or prevent the transition to dementia. Objective: This study investigated the effect of the neurobic exercise program on memory performance among community-dwelling older adults with MCI. Methods: A single-blind, randomized, controlled, two-period crossover design was used. Thirty-two older adults who met the study criteria were randomly assigned to one of two sequence groups, A (n =16) and B (n = 16). Group A received three weeks of neurobic exercise, followed by a three-week washout period, and then three weeks of the traditional brain exercise program. Group B received the treatments in the reverse order but otherwise in a similar manner. Two aspects of memory performance were evaluated: subjective memory and objective memory. Blinded evaluators measured the outcomes four times at baseline, post-intervention (week 3), follow-up stage (week 7), and the end of the study (week 9). Descriptive statistics, independent t-tests, and repeated measures ANOVA were employed for data analyses. Results: For subjective memory, rmANOVA revealed a significant difference of within-subject (F1.437, 43.113 = 9.324, p <0.05) and interaction effect (time*group) (F1.437, 43.113 = 12.313, p <0.05) and also showed significant differences of within-subject (F1.794,53.811 = 28.931, p < .05) and interaction effect (time*group) (F1.794, 53.811 = 31.190, p <0.05) for objective memory. The study results revealed that the participants in both groups had significantly lower mean scores on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), indicating better or improved subjective memory. They also had significantly higher mean scores on the Common Objects Memory Test (COMT) after receiving the neurobic exercise program, indicating improvement in cognitive performance. Conclusion: The neurobic exercise intervention could improve subjective and objective memory among community-dwelling older adults with MCI more than those who received the traditional brain exercise program. Therefore, the neurobic exercise program can be used by nurses and multidisciplinary teams to enhance memory performance among older adults with MCI. Trial registration: Thai Clinical Trials Registry (TCTR) 20210326003.

The effects of lavender oil inhalation on emotional states, autonomic nervous system, and brain electrical activity.

OBJECTIVE: Investigate the effects of lavender oil on the central nervous system, autonomic nervous system, and mood responses in humans after inhalation. MATERIAL AND METHOD: Twenty healthy volunteers participated in the experiments. The present study assessed autonomic parameters such as blood pressure, heart rate, respiratory rate, and skin temperature to determine the arousal level of the autonomic nervous system. In addition, subjects were asked to estimate their mood responses such as feeling pleasant or unpleasant, uncomfortable, sensuality, relaxation, or refreshing in order to assess subjective behavioral arousal. Finally, electroencephalogram (EEG) was recorded from 31 electrodes on the scalp according to the international 10 to 20 system, and EEG power spectra were calculated by Fast Fourier Transform (FFT). Data was analyzed by comparing the effects of lavender oil on physiological and mood states with sweet almond oil. These assessments were measured before and after using paired t-test statistical procedure. RESULTS: The results revealed that lavender oil caused significant decreases of blood pressure, heart rate, and skin temperature, which indicated a decrease of autonomic arousal. In terms of mood responses, the subjects in the lavender oil group categorized themselves as more active, fresher relaxed than subjects just inhaling base oil. Compared with base oil, lavender oil increased the power of theta (4-8 Hz) and alpha (8-13 Hz) brain activities. The topographic map showed obviously more scattering power in alpha range waves particularly in bilateral temporal and central area. CONCLUSION: The findings provided evidence the relaxing effect of inhaling lavender oil.

Amyloid deposits show complexity and intimate spatial relationship with dendrosomatic plasma membranes: an electron microscopic 3D reconstruction analysis in 3xTg-AD mice and aged canines.

Little is known about how amyloid-beta (Abeta) is deposited in relation to the complex ultrastructure of the brain. Here we combined serial section immunoelectron microscopy with 3D reconstruction to elucidate the spatial relationship between Abeta deposits and ultrastructurally identified cellular compartments. The analysis was performed in a transgenic mouse model with mutant presenilin-1, and mutant amyloid-beta protein precursor (AbetaPP) and tau transgenes (3xTg-AD mice) and in aged dogs that develop Abeta plaques spontaneously. Reconstructions based on serial ultrathin sections of hippocampus (mice) or neocortex (dogs) that had been immunolabeled with Abeta (Abeta(1-42)) antibodies showed that the organization of extracellular Abeta deposits is more complex than anticipated from light microscopic analyses. In both species, deposits were tightly associated with plasma membranes of pyramidal cell bodies and major dendrites. The deposits typically consisted of thin sheets as well as slender tendrils that climbed along the large caliber dendritic stems of pyramidal neurons. No preferential association was observed between Abeta deposits and thin dendritic branches or spines, nor was there any evidence of preferential accumulation of Abeta around synaptic contacts or glial processes. Our data suggest that plaque formation is a precisely orchestrated process that involves specialized domains of dendrosomatic plasma membranes.

Delayed cortical maturation at the centrotemporal brain regions in patients with benign childhood epilepsy with centrotemporal spikes (BCECTS).

Benign childhood epilepsy with centrotemporal spikes (BCECTS) is an epilepsy syndrome commonly found in child and adolescent. Although the prognosis is mostly favorable as long as the seizure is well controlled. However, they are often suffering from the cognitive and behavioral problems which might be the consequences of the initial insults. It is still not clear whether the initial epileptiform discharges has long term impact on the resting-state brain activities at later ages. This study investigated the resting-state brain activities in BCECTS patients with clinical seizure remission stage (n = 16; 11 males) and compared with the non-epileptic, age-matched control subjects. Quantitative electroencephalography (qEEG) revealed a significantly higher absolute power of the theta and alpha waves in BCECTS patients with clinical seizure remission as compared with the non-epileptic control subjects. Interestingly, the differences were observed mainly over the centrotemporal electrodes which are the common sites of the initial epileptiform discharges. The differences were more significant in patients with bilateral epileptiform discharges than those with the unilateral epileptic activities. Typically, the brain wave power continuously decreases with increasing ages. Therefore, higher absolute powers of the brain waves indicate more delayed in cortical maturation compared with the non-epileptic control group. These findings indicated that BCECTS patients have delay cortical maturation at the centrotemporal brain regions even at the clinical seizure remission phase.

Potential effects and molecular mechanisms of melatonin on the dopaminergic neuronal differentiation of human amniotic fluid mesenchymal stem cells.

Melatonin, a highly lipophilic molecule secreted by the pineal gland in the brain, plays a role in various biological functions. Previous studies reported that melatonin exerts its effect on mesenchymal stem cell (MSC) survival and differentiation into osteogenic- and adipogenic-lineage. However, the effect of melatonin in neurogenic differentiation in amniotic fluid (AF)-MSCs remains to be explored, thus we investigated the potential role of melatonin on dopaminergic neuron differentiation in AF-MSCs. The results showed that various concentrations of melatonin did not affect cell viability and proliferative effects of AF-MSCs. Increases in the levels of neuronal protein marker (ßIII-tubulin) and dopaminergic neuronal markers (tyrosine hydroxylase, TH and NURR1), but decrease in the level of glial fibrillary acidic protein (GFAP), were observed in melatonin-treated AF-MSCs. Melatonin induced alteration in differential expression patterns of mesenchymal stem cell antigens by reducing CD29, CD45, CD73, CD90 and CD105, but no changing CD34 expressing cells. AF-MSCs were sequentially induced in neurobasal medium containing standard inducing cocktails (ST: bFGF, SHH, FGF8, BDNF), 1 µM melatonin, or a combination of ST and melatonin. The levels of TUJ1, TH, MAP2, NURR1 and dopamine transporter (DAT) were significantly increased in all treated groups when compared with control-untreated cells. Pretreated AF-MSCs with non-selective MT1/MT2 receptors antagonist, luzindole and selective MT2 receptor antagonist, 4-P-PDOT diminished melatonin-induced increase in dopaminergic neuronal markers and phosphorylated ERK but did not diminish increase in phosphorylated CaMKII by melatonin. Pretreatment with mitogen-activated protein kinase (MEK) inhibitor, PD98059 and CaMKII inhibitor, KN-93 were able to abolish increase in the levels of dopaminergic markers in melatonin-treated AF-MSCs. These findings suggest that melatonin promotes dopaminergic neuronal differentiation of AF-MSCs possibly via the induction in ERK and CaMKII pathways through melatonin receptor-dependent and -independent mechanisms, respectively.

Tiagabine treatment in kainic acid induced cerebellar lesion of dystonia rat model.

Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements. The exaggerated movements have been studied and have implicated basal ganglia as the point of origin. In more recent studies, the cerebellum has also been identified as the possible target of dystonia, in the search for alternative treatments. Tiagabine is a selective GABA transporter inhibitor, which blocks the reuptake and recycling of GABA. The study of GABAergic drugs as an alternative treatment for cerebellar induced dystonia has not been reported. In our study, tiagabine was i.p. injected into kainic acid induced, cerebellar dystonic adult rats, and the effects were compared with non-tiagabine injected and sham-operated groups. Beam walking apparatus, telemetric electromyography (EMG) recording, and histological verification were performed to confirm dystonic symptoms in the rats on post-surgery treatment. Involuntary dystonic spasm was observed with repetitive rigidity, and twisting movements in the rats were also confirmed by a high score on the dystonic scoring and a high amplitude on the EMG data. The rats with tiagabine treatment were scored based on motor amelioration assessed via beam walking. The result of this study suggests and confirms that low dose of kainic acid microinjection is sufficient to induce dystonia from the cerebellar vermis. In addition, from the results of the EMG recording and the behavioral assessment through beam walking, tiagabine is demonstrated as being effective in reducing dystonic spasm and may be a possible alternative therapeutic drug in the treatment of dystonia.

Potential role of N-benzylcinnamide in inducing neuronal differentiation from human amniotic fluid mesenchymal stem cells.

Neurodegenerative disorders are characterized by chronic and progressive loss of neurons in structure and function related to aging, such as Alzheimer's disease, the latter characterized by the degeneration of cholinergic neurons in basal forebrain connected to the cerebral cortex and hippocampus. Amniotic fluid mesenchymal stem cells (AF-MSCs) have been proposed as one of the candidates for stem cell therapy of nervous system disorders. This study demonstrates that incubation of AF-MSCs, obtained from 16 to 20 week pregnant women, with 10ng/ml bone morphogenetic protein (BMP)-9 for 48h in conditioned medium resulted in transdifferentiation to cholinergic neuronal-like cells. This phenomenon could also be obtained with N-benzylcinnamide (PT-3). Pre-treatment for 1h with 10nM PT-3 augmented BMP-9 transdifferentiation effect, elevated ßIII-tubulin cell numbers and fluorescence intensity of immunoreactive ChAT, ameliorated BMP-9-related production of reactive oxygen species and enhanced anti-apoptosis status of the neuronal-like cells. The transdiffirentiation process was accompanied by increased p53 but decreased Notch1 and SIRT1 (p53 deacetylase) levels, and activation of p38, ERK1/2 MAPK, and PI3K/Akt pathways, in concert with inactivation of JNK, all of which were accentuated by PT-3 pre-treatment. These findings suggest that N-benzylcinnamide may provide a useful adjuvant in BMP-9-induced transdifferentiation of AFMSCs into ultimately cholinergic neurons.

Preattentive discrimination of across-category and within-category change in consonant-vowel syllable.

Event-related potentials to infrequently presented spoken deviant syllables /pi/ and /po/ among repetitive standard [see text] syllables were recorded in Thai study participants who ignored these stimuli while reading books of their choices. The vowel across-category and within-category changes elicited a change-specific mismatch negativity response. The across-category and within-category change discrimination of vowels in consonant-vowel syllable was also assessed using the low-resolution electromagnetic tomography. The results of low-resolution electromagnetic tomography mismatch negativity generator analysis suggest that the within-category change perception of vowels is analyzed as the change in physical features of the stimuli, thus predominantly activating the right temporal cortex. In contrast, the left temporal cortex is predominantly activated in the across-category change perception of vowels, emphasizing the role of the left hemisphere in speech processing already at a preattentive processing level also in consonant-vowel syllables. The results support the hypothesis that a part of the superior temporal gyrus contains neurons specialized for speech perception.

Afferent projections from motoneurons innervating extraocular muscles to the cerebellum demonstrated by the retrograde double-labeling technique.

The objective of this study was to investigate the characteristics and distributions of neuronal origin of cerebellar afferents from motor cranial nerve nuclei innervating extraocular muscles by the method of retrograde transport of two fluorescence tracers in rats. Under deep anesthesia and aseptic conditions, 5 microl of 3% solution of Fluoro-Gold (FG) in phosphate buffer solution (PBS) was injected into the bellies of the six extraocular muscles to study the labeling of motoneurons innervating corresponding extraocular muscles. The cerebellum was exposed by craniotomy, and 0.3 microl of 10% solution of Dextran Tetramethyl Rhodamine Biotin (Micro Ruby: or MR) in PBS was injected into many regions of the anterior vermis (lobule I, II) and the posterior vermis (lobule VI, VII, IX, X), the flocculus, the paraflocculus and the deep cerebellar nuclei. Multiple injections were made to cover the entire cerebellum in order to obtain a near maximum labeling of cerebellar afferent neurons. In other cases, only small single or a few injections were made in specific areas of the cerebellum to study specific distributions and topographic organization. In one group of rats, injections were made both in the extraocular muscles with FG and in the cerebellum with MR to study the double labeling of neurons, which project their axons to both the extraocular muscle and the cerebellum. Another group of rats were injected in both sites with only PBS and served as the control for auto-fluorescence background. After 3 days postoperative survival time, all animals were deeply reanesthetized and perfused with heparinized normal saline solution, followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, and 30% sucrose solution in PBS. The brainstem and the cerebellum were removed immediately, and stored in sucrose solution in PBS at 4 degrees C. Serial transverse sections of the brainstem and sagittal sections of the cerebellum were obtained by a freezing microtome at 40 microm thickness, collected on uncoated glass slides, and immediately dried. All sections were examined under an epifluorescence or confocal microscope equipped with filter systems for FG and MR. The presence of both single and double retrograde labeled neurons in the Oculomotor (CN 3), Trochlear (CN 4) and Abducens (CN 6) nuclei was recorded, photographed, stored as computer images files and printed out as hard copies. The labeling neurons in the vicinity of the CN 3, 4, 6 from all sections were plotted onto diagrams and counted Neurons labeled only with MR retrogradely transported from injection sites in the cerebellum were found bilaterally and scattered throughout in the Oculomotor, Trochlear and Abducens nuclei. These neurons labeled only with MR were small and medium-sized interneurons and represented only a small proportion of the entire population. Neurons labeled only with FG retrogradely transported from injection sites in the extraocular muscles were the most numerous, and distributed almost throughout the entire population of small, medium-sized and large motoneurons, which innervate the extraocular muscles. A smaller proportion of small and medium-sized FG labeled neurons within these nuclei were also double labeled with MR, indicating that they project their axon collaterals to both extraocular muscles and the cerebellum. In conclusion, the present findings provide clear anatomical evidence that a small population of motoneurons in the Oculomotor, Trochlear and Abducens nuclei of the rat project their axon collaterals directly to the cerebellum and the extraocular muscle, in addition to the cerebellar afferents from other interneurons within these nuclei. The findings also indicate that cerebellar neuronal circuits play more direct roles in monitoring and controlling eye movements than previously known.

Protective role of taurine in developing offspring affected by maternal alcohol consumption.

Maternal alcohol consumption is known to affect offspring growth and development, including growth deficits, physical anomalies, impaired brain functions and behavioral disturbances. Taurine, a sulfur-containing amino acid, is essential during development, and continually found to be protective against neurotoxicity and various tissue damages including those from alcohol exposure. However, it is still unknown whether taurine can exert its protection during development of central nervous system and whether it can reverse alcohol damages on developed brain later in life. This study aims to investigate protective roles of taurine against maternal alcohol consumption on growth and development of offspring. The experimental protocol was conducted using ICR-outbred pregnant mice given 10 % alcohol, with or without maternal taurine supplementation during gestation and lactation. Pregnancy outcomes, offspring mortality and successive bodyweight until adult were monitored. Adult offspring is supplemented taurine to verify its ability to reverse damages on learning and memory through a water maze task performance. Our results demonstrate that offspring of maternal alcohol exposure, together with maternal taurine supplementation show conserved learning and memory, while that of offspring treated taurine later in life are disturbed. Taurine provides neuroprotective effects and preserves learning and memory processes when given together with maternal alcohol consumption, but not shown such effects when given exclusively in offspring.

Hypothalamic and zona incerta neurons in sheep, initially only responding to the sight of food, also respond to the sight of water after intracerebroventricular injection of hypertonic saline or angiotensin II.

Extracellular single-unit recordings were made from neurons in the lateral hypothalamus (LH) or zona incerta (ZI) of conscious sheep. A small population of neurons (12/83) were found which responded with increased firing rate when the animal looked at food but did not respond when the sheep looked at water. The effects of rapidly inducing intense thirst by the intracerebroventricular (i.c.v.) injection of hypertonic (0.85 M) saline or 200 ng of angiotensin II, or a mixture of the two dipsogenic stimuli, on the response of neurons initially responding only to the sight of food were investigated. Following i.c.v. injection of the dipsogenic stimuli the neurons began to respond strongly to the sight of water. The results demonstrated that changing the animal's motivational state alters the response of some neurons in the LH and ZI and suggests that the neuronal response is influenced by the animal's dominant need at the time of testing.

Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup.

Physical activities for a few days can increase brain-derived neurotrophic factor (BDNF) mRNA in rat hippocampus. To investigate the influence of maternal exercise during pregnancy on rat pup hippocampal BDNF mRNA, we studied its expression by a semi-quantitative RT-PCR method after young pregnant rats were exercised on a motor driven treadmill. Pups of exercised mothers had significantly increased hippocampal BDNF mRNA expression compared to the control rat pups at birth (on postnatal day 0) (P<0.001). In contrast, hippocampal BDNF mRNA expression in pups of exercised mothers decreased significantly on postnatal day 28 (P<0.002). Spatial learning of rat pups was examined by multiple T maze training for 7 consecutive days between postnatal days 40 and 47. Pups of exercised mothers showed a significant increase in spatial learning ability as demonstrated by significant decreases in total time from starting to target and total number of errors as compared to age-matched control pups during the first 4 days of 7 consecutive days on multiple T maze training (P<0.05). Thus, physical exercise during gestation in pregnant mothers can increase hippocampal BDNF mRNA expression of postnatal pups and result in an improvement in spatial learning in pups from exercised dams.

Enriched environment attenuates changes in water-maze performance and BDNF level caused by prenatal alcohol exposure.

Prenatal exposure to alcohol can result in fetal alcohol syndrome (FAS), characterized by significant changes in the physiology, structural plasticity of hippocampal function, including long-term deficits in learning and memory. Environmental enrichment has long been known to improve motor and cognitive function levels, causes several neurochemical and morphological alterations in the brain. Therefore, the effects of environmental enrichment on the neurobehavioral and neurotrophic changes in mice exposed prenatally to alcohol were investigated in this study. The pregnant dams were given 25 % ethanol (w/v) or isocaloric sucrose by liquid diet from gestation day 7 to 20. After weaning on postnatal day 28, offspring were exposed to standard cage (CC, CFAS) or enriched living conditions (CE, EFAS) for 8 weeks. Neurobehavioral studies both on hippocampus-dependent spatial learning and place and cue learning strategy, a striatum-dependent test, were measured by the Morris water maze task. Moreover, the reverse-transcriptase polymerase chain reaction (RT-PCR) technique was also used in order to study the expression of brain-derived neurotrophic factor (BDNF) level in both the hippocampus and striatum of mice. Neurobehavioral studies show that animals exposed prenatally to alcohol were impaired as shown in both hippocampal-dependent spatial/place and striatal-dependent response/cue learning tests. Moreover, the levels of BDNF expression both in the hippocampus and striatum of mice were also decreased. Interestingly, environmental enrichment can ameliorate the effects of prenatal alcohol exposure both on the neurobehavioral and neurotrophic levels. These observations indicated that enriched environment attenuated memory impairment of prenatal alcohol exposure both in hippocampal and striatal circuitry.

Effects of inhaled rosemary oil on subjective feelings and activities of the nervous system.

Rosemary oil is one of the more famous essential oils widely used in aroma-therapy. However, the effects of rosemary oil on the human body, in particular the nervous system, have not been sufficiently studied. This study investigates the effects of the inhalation of rosemary oil on test subjects' feelings, as well as its effects on various physiological parameters of the nervous system. Twenty healthy volunteers participated in the experiment. All subjects underwent autonomic nervous system (ANS) recording. This consisted of measurements of skin temperature; heart rate; respiratory rate; blood pressure; evaluations of the subjects' mood states; and electroencephalography (EEG) recordings in the pre-, during treatment, and post-rosemary inhalation periods as compared with control conditions. Our results showed significant increases in blood pressure, heart rate, and respiratory rate after rosemary oil inhalation. After the inhalation treatments, subjects were found to have become more active and stated that they felt "fresher". The analysis of EEGs showed a reduction in the power of alpha1 (8-10.99 Hz) and alpha2 (11-12.99 Hz) waves. Moreover, an increment in the beta wave (13-30 Hz) power was observed in the anterior region of the brain. These results confirm the stimulatory effects of rosemary oil and provide supporting evidence that brain wave activity, autonomic nervous system activity, as well as mood states are all affected by the inhalation of the rosemary oil.

Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse.

Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R(-/-)). The human disease most commonly presents, however, as haploinsufficiency of the MC4R. This study validates the MC4R(+/-) mouse as a model of the human disease in that, like the MC4R(-/-), the MC4R(+/-) mouse also exhibits a sustained hyperphagic response to dietary fat. Furthermore, both saturated and monounsaturated fats elicit this response. N-acylphosphatidylethanolamine (NAPE) is a signaling lipid induced after several hours of high-fat feeding, that, if dysregulated, might explain the feeding behavior in melanocortin obesity syndrome. Remarkably, however, MC4R(-/-) mice produce elevated levels of NAPE and are fully responsive to the anorexigenic activity of NAPE and oleoylethanolamide. Interestingly, additional differences in N-acylethanolamine (NAE) biochemistry were seen in MC4R(-/-) animals, including reduced plasma NAE levels and elevated hypothalamic levels of fatty acid amide hydrolase expression. Thus, while reduced expression of NAPE or NAE does not explain the high-fat hyperphagia in the melanocortin obesity syndrome, alterations in this family of signaling lipids are evident. Analysis of the microstructure of feeding behavior in response to dietary fat in the MC4R(-/-) and MC4R(+/-) mice indicates that the high-fat hyperphagia involves defective satiation and an increased rate of food intake, suggesting defective satiety signaling and enhanced reward value of dietary fat.

Epidemiology of sleep-related complaints associated with sleep-disordered breathing in Bangkok, Thailand.

BACKGROUND: This study assesses the prevalence of and risk factors for sleep-related complaints in Bangkok, Thailand. METHODS: A representative sample of the Bangkok population was selected based on results of the 2000 Census. A total of 4680 participants underwent face-to-face interview with a 49-question sleep inventory. RESULTS: Four percent of the total sampled (5.3% of men and 3.5% of women) complained of habitual snoring (>3 nights/week) and excessive daytime sleepiness (>3 days/week) for at least 3 months. These subjects were significantly (p<0.0001) older (41.4 vs. 36.7 years), had greater BMI (26.0 vs. 22.8 kg/m(2)), neck size (34.7 vs. 32.5 cms), and waist circumference (88.0 vs. 78.7 cms). They reported significantly shorter nocturnal sleep time, greater frequency of sleep disturbances and awakenings, unrefreshing sleep, choking during sleep, night sweats, nocturia, and bruxism. There was also a greater prevalence of cardiovascular and endocrine diseases. Multivariate analysis showed that male gender; BMI; waist size; and reports of witnessed apneas, unrefreshing sleep and night sweats were significant predictors of snoring and daytime sleepiness. CONCLUSION: This is the first epidemiologic study investigating sleep-related complaints and associated health morbidities in the Thai population.