Planning sleep-related animal and translational research

With the aim of improving human health, scientists have been using an approach referred to as translational research, in which they aim to convey their laboratory discoveries into clinical applications to help prevent and cure disease. Such discoveries often arise from cellular, molecular, and physiological studies that progress to the clinical level. Most of the translational work is done using animal models that share common genes, molecular pathways, or phenotypes with humans. In this article, we discuss how translational work is carried out in various animal models and illustrate its relevance for human sleep research and sleep-related disorders.

Sleep patterns and sleep-related complaints of Brazilian interstate bus drivers

Sleep-related complaints have become a highlight for physicians as well as public health administrators. Studies of sleep patterns and sleep-related complaints of shift workers have been useful in minimizing reduction in the quality of life due to the warping of the sleep-wake cycle. The objective of the present study was to assess patterns of sleep, sleep-related complaints as well as physical activity and scoring rates for depression and anxiety in interstate bus drivers. Data were obtained with a sleep questionnaire, with the Beck inventory for depression, and the State-Trait Anxiety Inventory (STAI). A total of 400 interstate bus drivers from the northern, southern, central-western and south-eastern regions of Brazil were interviewed. Sixty percent of the subjects interviewed presented at least one sleep-related complaint, 16% admitted to have dozed at the wheel while on duty, and 41% stated that they exercised on a regular basis. Other sleep disturbance complaints reported were: sleep latency 29'17"; physical fatigue, 59.8%; mental fatigue, 45.4%; sleepiness, 25.8%; irritability, 20.6%; insomnia, 37.5%, respiratory disturbances, 19.25% and snoring, 20.75%. Scores for anxiety and depression were not in the pathological range. The present data reinforce the view that bus drivers are generally discontent with shift work and its effects on sleep. Consequently, it is very important to establish an appropriate work schedule for drivers, besides implementing photo-therapy and physical activities in order to minimize sleepiness when driving.

Longitudinal evaluation of sleep-related breathing disorders in an orthodontic population

Introduction: Les troubles respiratoires du sommeil (TRS), qui représentent une préoccupation croissante pour la santé, ont des effets significatifs sur la santé, le comportement et la performance académique chez l’enfant. Les malformations craniofaciales, l’hypertrophie adéno-amygdalienne et l'obésité, représentent des facteurs de risque importants dans le développement de cette condition. Les symptômes des TRS ont été étudiés dans une étude prospective chez les enfants et adolescents durant leur traitement orthodontique dans un milieu universitaire. Cette étude a cherché à décrire la prévalence et les facteurs de risque principaux des TRS, ainsi que l'impact des différentes interventions orthodontiques sur les symptômes TRS. Matériel et méthodes: dans une étude cohorte prospective, un groupe de 168 sujets âgés de 12 à 21 ans ont été soumis, quatre ans après la prise de données initiale, à un examen craniofacial en plus d'être administré des questionnaires qui ont recueilli des données sur la situation socio-démographique, le bruxisme et les troubles d’ATM, le sommeil et le comportement diurne, et les facteurs neuropsychologiques. Résultats: l'indice de masse corporelle a été augmenté mais est demeurée dans la même catégorie aux deux moments de l'enquête. Il ya eu une augmentation du serrement des dents et des symptômes de l'ATM, une diminution de la taille des amygdales, et une augmentation de la somnolence diurne. La prévalence des TRS n'a pas changé entre l’étude initiale et l’étude de suivi. Aucune intervention orthodontique s'est avérée avoir un effet cliniquement significatif sur les voies aériennes supérieures. Conclusions: la prévalence des symptômes TRS était constante par rapport aux valeurs de base pour la population étudiée, mais a augmenté si rapportée à la population générale. Les traitements orthodontiques ne montrent aucun effet sur les TRS. Mots-clés : apnée du sommeil, craniofacial, prévalence, ronflement, traitement orthodontique, voies aériennes supérieures

Definition and diagnostic criteria of sleep-related hypermotor epilepsy

The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic. The etiology may be genetic or due to structural pathology, but in most cases remains unknown. Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE. The main research gaps involve epidemiology, pathophysiology, treatment, and prognosis.

Ambulatory EEG monitoring in the diagnosis and treatment of epilepsy and related disorders

Ambulatory EEG recording enables patients with epilepsy and related disorders to be monitored in an unrestricted environment for prolonged periods. Attacks can therefore be recorded and EEG changes at the time can aid diagnosis. The relevant Iiterature is reviewed and a study made of' 250 clinical investigations. A study was also made of the artefacts,encountered during ambulatory recording. Three quarters of referrals were for distinguishing between epileptic and non-epileptic attacks. Over 60% of patients showed no abnormality during attacks. In comparison with the basic EEG the ambulatory EEG provided about ten times as much information. A preliminary follow-up study showed that results, of ambulatory monitoring agreed with the final diagnosis in 8 of 12 patients studied. Of 10 patients referred, for monitoring the occurrence of absence seizures, 8 showed abnormality during the baslcJ EEG .and 10 during the ambulatory EEG. Other patients. were referred: for sleep recording and to clarify the seizure type. An investigation into once daily (OD) versus twice daily administration of sodium valproate in patients with absence seizures showed that an OD regime was equally as effective as a BD regime. Circadian variations in spike and wave activity in patients on and off treatment were also examined. There was significant agreement between subjects on the time of occurrence of abnormality during sleep only, This pattern was not ,affected with treatment nor was there any difference in the daily pattern of occurrence of abnormality between the two regimes. Overall findings suggested that ambulatory monitoring was a valuable tool in the diagnosis and treatment of epilepsy which with careful planning and patient selection could be used in any EEG department and would benefit a:wide range of patients.

Androgen Therapy Reverses Injuries Caused By Ethanol Consumption In The Prostate: Testosterone As A Possible Target To Ethanol-related Disorders.

Chronic ethanol consumption leads to reproductive damages, since it can act directly in the tissues or indirectly, causing a hormonal imbalance. Prostate is a hormone-dependent gland and, consequently, susceptible to ethanol. The potential of testosterone therapy in the ethanol-related disorders was investigated in the prostate microenvironment. UChB rats aged 90 days were divided into 2 experimental groups (n=20): C: drinking water only and EtOH: drinking 10% (v/v) ethanol at >2 g/kg body weight/day+water. At 150 days old, 10 rats from each group received subcutaneous injections of testosterone cypionate (5 mg/kg body weight) diluted in corn oil every other day for 4 weeks, constituting T and EtOH+T, while the remaining animals received corn oil as vehicle. Animals were euthanized at 180 days old, by decapitation. Blood was collected to obtain hormone concentrations and ventral prostate was dissected and processed for light microscope and molecular analyses. Ventral prostate weight, plasma testosterone and DHT and intraprostatic testosterone concentrations were increased after testosterone treatment. Plasma estradiol level was reduced in the EtOH+T. Inflammatory foci, metaplasia and epithelial atrophy were constantly found in the prostate of EtOH and were not observed after hormonal therapy. No differences were found in the expression of AR, ERβ and DACH-1. Additionally, testosterone treatment down-regulated ERα and increased the e-cadherin and α-actinin immunoreactivities. Testosterone was able to reverse damages caused by ethanol consumption in the prostate microenvironment and becomes a possible target to be investigated to ethanol-related disorders.

Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders

Background: The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority. This paper presents CPGs for schizophrenia and related disorders. Over the past decade schizophrenia has become more treatable than ever before. A new generation of drug therapies, a renaissance of psychological and psychosocial interventions and a first generation of reform within the specialist mental health system have combined to create an evidence-based climate of realistic optimism. Progressive neuroscientific advances hold out the strong possibility of more definitive biological treatments in the near future. However, this improved potential for better outcomes and quality of life for people with schizophrenia has not been translated into reality in Australia. The efficacy-effectiveness gap is wider for schizophrenia than any other serious medical disorder. Therapeutic nihilism, under-resourcing of services and a stalling of the service reform process, poor morale within specialist mental health services, a lack of broad-based recovery and life support programs, and a climate of tenacious stigma and consequent lack of concern for people with schizophrenia are the contributory causes for this failure to effectively treat. These guidelines therefore tackle only one element in the endeavour to reduce the impact of schizophrenia. They distil the current evidence-base and make recommendations based on the best available knowledge. Method: A comprehensive literature review (1990-2003) was conducted, including all Cochrane schizophrenia reviews and all relevant meta-analyses, and a number of recent international clinical practice guidelines were consulted. A series of drafts were refined by the expert committee and enhanced through a bi-national consultation process. Treatment recommendations: This guideline provides evidence-based recommendations for the management of schizophrenia by treatment type and by phase of illness. The essential features of the guidelines are: (i) Early detection and comprehensive treatment of first episode cases is a priority since the psychosocial and possibly the biological impact of illness can be minimized and outcome improved. An optimistic attitude on the part of health professionals is an essential ingredient from the outset and across all phases of illness. (ii) Comprehensive and sustained intervention should be assured during the initial 3-5 years following diagnosis since course of illness is strongly influenced by what occurs in this 'critical period'. Patients should not have to 'prove chronicity' before they gain consistent access and tenure to specialist mental health services. (iii) Antipsychotic medication is the cornerstone of treatment. These medicines have improved in quality and tolerability, yet should be used cautiously and in a more targeted manner than in the past. The treatment of choice for most patients is now the novel antipsychotic medications because of their superior tolerability and, in particular, the reduced risk of tardive dyskinesia. This is particularly so for the first episode patient where, due to superior tolerability, novel agents are the first, second and third line choice. These novel agents are nevertheless associated with potentially serious medium to long-term side-effects of their own for which patients must be carefully monitored. Conventional antipsychotic medications in low dosage may still have a role in a small proportion of patients, where there has been full remission and good tolerability; however, the indications are shrinking progressively. These principles are now accepted in most developed countries. (vi) Clozapine should be used early in the course, as soon as treatment resistance to at least two antipsychotics has been demonstrated. This usually means incomplete remission of positive symptomatology, but clozapine may also be considered where there are pervasive negative symptoms or significant or persistent suicidal risk is present. (v) Comprehensive psychosocial interventions should be routinely available to all patients and their families, and provided by appropriately trained mental health professionals with time to devote to the task. This includes family interventions, cognitive-behaviour therapy, vocational rehabilitation and other forms of therapy, especially for comorbid conditions, such as substance abuse, depression and anxiety. (vi) The social and cultural environment of people with schizophrenia is an essential arena for intervention. Adequate shelter, financial security, access to meaningful social roles and availability of social support are essential components of recovery and quality of life. (vii) Interventions should be carefully tailored to phase and stage of illness, and to gender and cultural background. (viii) Genuine involvement of consumers and relatives in service development and provision should be standard. (ix) Maintenance of good physical health and prevention and early treatment of serious medical illness has been seriously neglected in the management of schizophrenia, and results in premature death and widespread morbidity. Quality of medical care for people with schizophrenia should be equivalent to the general community standard. (x) General practitioners (GPs)s should always be closely involved in the care of people with schizophrenia. However, this should be truly shared care, and sole care by a GP with minimal or no special Optimal treatment of schizophrenia requires a multidisciplinary team approach with a consultant psychiatrist centrally involved.

Sleep-related changes in hemodynamic and autonomic regulation in human hypertension

Objectives The present study investigates the hemodynamic and autonomic regulation during sleep-awake transitions and across different sleep cycles in patients with essential hypertension. Methods Nineteen individuals free of sleep apnea (10 normotensive and nine hypertensive matched for age, sex, and body mass index) underwent a standard polysomnography, with simultaneous electrocardiography and beat-to-beat blood pressure monitoring (Portapres). All measurements were determined while awake (before and after sleep), as well as in the beginning and at end of the sleep cycle (first/last cycle of nonrapid and rapid eye movement stages). Results Systolic blood pressure was higher in hypertensives and exhibited a similar reduction to the normotensives ones in initial nonrapid eye movement sleep. This reduction was because of different mechanisms: a significant fall in cardiac output in normotensives, whereas in hypertensives was also dependent of a decrease in peripheral vascular resistance. Hypertensive patients presented lower heart rate variation and attenuated baroreflex sensitivity during sleep but not immediately before and after sleep. Spectral analysis suggested a higher sympathetic activity in the sleep stages in hypertension. Additionally, a progressive sympathetic predominance (final rapid eye movement> initial rapid eye movement and awake period postsleep> awake period presleep) was observed in both groups. Conclusion Hypertension is associated with depressed baroreflex sensitivity and increased sympathetic activation during sleep. The greater sympathetic predominance at the end of night (preceding the morning surge of sympathetic activity) could be implicated in the occurrence of cardiovascular events. J Hypertens 27: 1655-1663 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Immunological abnormalities of acquired immunodeficiency syndrome and related disorders in patients from Rio de Janeiro, Brazil

The immunoloical profile of acquired immunodeficiency syndrome (AIDS) and chronic lymphadenopathy syndrome (CLAS) in 15 and 11 Brazilian patients, respectively, was studied. The AIDS patients showed reduced percentage of total T (CD3) and T-helper-inducer (CD4) lymphocytes, relative increase in numbers of T-suppressor-cytotoxic (CD8) cells and a marked inversion of T-helper-inducer/suppressor-cytotoxic (CD4/CD8) ratio. Lymphoproliferative responses to PHA, ConA, PPD and PWM were diminished. Hypergamaglobulinemia and high levels of circulating immune complexes were also found. The CLAS patients also showed important immunological alterations, but not so intense as those with AIDS. These data seems to be similar to those observed in other parts of the world.

T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites.

T-type Ca2+ channels (T channels) underlie rhythmic burst discharges during neuronal oscillations that are typical during sleep. However, the Ca2+-dependent effectors that are selectively regulated by T currents remain unknown. We found that, in dendrites of nucleus reticularis thalami (nRt), intracellular Ca2+ concentration increases were dominated by Ca2+ influx through T channels and shaped rhythmic bursting via competition between Ca2+-dependent small-conductance (SK)-type K+ channels and Ca2+ uptake pumps. Oscillatory bursting was initiated via selective activation of dendritically located SK2 channels, whereas Ca2+ sequestration by sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) and cumulative T channel inactivation dampened oscillations. Sk2-/- (also known as Kcnn2) mice lacked cellular oscillations, showed a greater than threefold reduction in low-frequency rhythms in the electroencephalogram of non-rapid-eye-movement sleep and had disrupted sleep. Thus, the interplay of T channels, SK2 channels and SERCAs in nRt dendrites comprises a specialized Ca2+ signaling triad to regulate oscillatory dynamics related to sleep.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Nicotinamide phosphoribosyltransferase as a target in inflammation- related disorders.

NAD(+) biosynthesis through nicotinamide phosphoribosyltransferase (NAMPT) holds potential as a target for the treatment of inflammatory disorders due to NAD(+)'s role in immune cell signaling and metabolism. In addition to its activity as an enzyme, NAMPT is also secreted in the extracellular space where it acts as a pro-inflammatory and proangiogenic cytokine. NAMPT inhibition with FK866 has anti-inflammatory activity in different models of immune disorders and it prevents ischemia-reperfusion-induced heart damage by dampening the production of neutrophil chemoattractants. NAMPT blockade with a neutralizing antibody has beneficial effects in an acute lung injury model. Last, but not least, the anticancer activity of NAMPT inhibitors may also reflect, at least in part, their ability to modify the cancer microenvironment through their anti-inflammatory properties. Overall, NAMPT inhibition holds potential for the treatment of inflammation-related disorders and the development of effective and safe NAMPT inhibitors remains an area of strong interest in pharmaceutical research.

Prevalence and correlates of DSM-5 bipolar and related disorders and hyperthymic personality in the community.

BACKGROUND: To 1) establish the lifetime and 12-month prevalence of DSM-5 bipolar and related disorders including the new algorithmically defined conditions grouped within Other Specified Bipolar and Related Disorders (OSBARD) as well as hyperthymic personality in a randomly selected community sample, and 2) determine the clinical relevance of the OSBARD category in terms of sociodemographic characteristics, course, comorbidity and treatment patterns by comparing the subjects of this category to those with bipolar-I (BP-I), bipolar-II (BP-II), major depressive disorder (MDD), and those with no history of mood disorders. METHODS: The semi-structured Diagnostic Interview for Genetic Studies was administered by masterslevel psychologists to a random sample of an urban area (n=3'719). RESULTS: The lifetime prevalence was 1.0% for BP-I, 0.8% for BP-II, 1.0% for OSBARD and 3% for hyperthymic personality. Subjects with OSBARD were more severely affected than subjects without a history of mood disorders regarding almost all clinical correlates. Compared to those with MDD, they also revealed an elevated risk of suicidal attempts, lower global functioning, more treatment seeking and more lifetime comorbidity including anxiety, substance use and impulse-control disorders. However, they did not differ from subjects with BP-II. LIMITATIONS: Small sample sizes for bipolar and related disorders and potential inaccurate recall of symptoms. CONCLUSIONS: The modifications of diagnostic criteria for manic/hypomanic episodes according to the DSM-5 only marginally affect the prevalence estimates for BP-I and BP-II. The new DSM-5 OSBARD category is associated with significant clinical burden, is hardly distinct from BP-II with respect to clinical correlates and deserves similar clinical attention.