All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation.

Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-α (RAR-α) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus-pituitary-adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all-trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback.

Neuropathology of stress.

Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious.

Increased amoeboid microglial density in the olfactory bulb of Parkinson's and Alzheimer's patients.

The olfactory bulb (OB) is affected early in both Parkinson's (PD) and Alzheimer's disease (AD), evidenced by the presence of disease-specific protein aggregates and an early loss of olfaction. Whereas previous studies showed amoeboid microglia in the classically affected brain regions of PD and AD patients, little was known about such changes in the OB. Using a morphometric approach, a significant increase in amoeboid microglia density within the anterior olfactory nucleus (AON) of AD and PD patients was observed.

Experienced continuity of care in patients at risk for depression in primary care.

Background: Existing studies about continuity of care focus on patients with a severe mental illness.

Objectives: Explore the level of experienced continuity of care of patients at risk for depression in primary care, and compare these to those of patients with heart failure.

Methods: Explorative study comparing patients at risk for depression with chronic heart failure patients.

Perinatal programming of adult hippocampal structure and function; emerging roles of stress, nutrition and epigenetics.

Early-life stress lastingly affects adult cognition and increases vulnerability to psychopathology, but the underlying mechanisms remain elusive. In this Opinion article, we propose that early nutritional input together with stress hormones and sensory stimuli from the mother during the perinatal period act synergistically to program the adult brain, possibly via epigenetic mechanisms. We hypothesize that stress during gestation or lactation affects the intake of macro- and micronutrients, including dietary methyl donors, and/or impairs the dam's metabolism, thereby altering nutrient composition and intake by the offspring.

Mindfulness-based cognitive therapy for patients with medically unexplained symptoms: a randomized controlled trial.

Background: Patients with medically unexplained symptoms make heavy demands on the health care system. An offer for psychological treatment is often declined. There is a need for acceptable and effective treatments.

Generalist solutions to complex problems: generating practice-based evidence--the example of managing multi-morbidity.

Background: A growing proportion of people are living with long term conditions. The majority have more than one. Dealing with multi-morbidity is a complex problem for health systems: for those designing and implementing healthcare as well as for those providing the evidence informing practice.

Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function.

Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamine-induced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)).

Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients.

Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis that stimulates glucocorticoid (GC) release from the adrenal. These hormones exert numerous effects in the body and brain and bind to a.o.

Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer's disease.

Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimer's disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we tested whether activity and pharmacological stimulation could prevent memory deficits and modify neurogenesis and/or neuropathology in the 3xTg model backcrossed to the C57Bl/6 strain. We chronically administered the antidepressant fluoxetine to one group of mice, allowed access to a running wheel in another, and combined both treatments in a third cohort.

Depressive disorder in the last phase of life in patients with cardiovascular disease, cancer, and COPD: data from a 20-year follow-up period in general practice.

Background: Depression is assumed to be common in chronically ill patients during their last phase of life and is associated with poorer outcomes. The prevalence of depression is widely varying in previous studies due to the use of different terminology, classification, and assessment methods.

Aim: To explore the reported incidence of depressive disorder, as registered in the last phase of life of patients who died from cardiovascular disease, cancer or COPD, in a sample of primary care patients.

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator.

Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects.

Tolerance to benzodiazepines among long-term users in primary care.

Background: Tolerance towards the effects of benzodiazepines is observed in various animal and human studies. Therefore, it is assumed that patients who use benzodiazepines for a longer period of time need to increase their dose over time to experience the same effect.

Objective: To observe whether long-term benzodiazepine users increase their dose over time.

[Allergy testing in atopic dermatitis: often unnecessary].

Atopic dermatitis (AD) is a chronic inflammatory skin disease from which many children and adults suffer. In the Netherlands, the majority of patients with AD are treated in the primary health care setting. There is no clear consensus about whether or not to conduct allergy testing in patients with AD.

Mindfulness-based cognitive therapy for patients with medically unexplained symptoms: a cost-effectiveness study.

Objective: Our aim was to assess cost-effectiveness of mindfulness-based cognitive therapy (MBCT) compared with enhanced usual care (EUC) in treating patients with persistent medically unexplained symptoms(MUS).

Methods: A full economic evaluation with a one year time horizon was performed from a societal perspective. Costs were assessed by prospective cost diaries.

Prescribing ANtiDepressants Appropriately (PANDA): a cluster randomized controlled trial in primary care.

Background: Inappropriate use of antidepressants (AD), defined as either continuation in the absence of a proper indication or continuation despite the lack of therapeutic efficacy, applies to approximately half of all long term AD users.

Methods/design: We have designed a cluster randomized controlled clinical trial to assess the (cost-) effectiveness of an antidepressant cessation advice in the absence of a proper indication for maintenance treatment with antidepressants in primary care.We will select all patients using antidepressants for over 9 months from 45 general practices.

Glucocorticoid receptor protein expression in human hippocampus; stability with age.

The glucocorticoid receptor (GR) exerts numerous functions in the body and brain. In the brain, it has been implicated, amongst others, in feedback regulation of the hypothalamic-pituitary-adrenal axis, with potential deficits during aging and in depression. GRs are abundantly expressed in the hippocampus of rodent, except for the Ammon's horn (CA) 3 subregion.

[A heart attack: was the patient lucky or unlucky? Circumstances were favourable but outcome ill-fated].

The assessment of signs and symptoms in primary care is an important but difficult task for general practitioners (GPs) who have to decide whether symptoms require immediate action or rather a watchful waiting approach. However, the GP may sometimes just need a bit of luck. This case report describes how the doctor's luck (in taking the initiative to phone the patient shortly after discharge from a hospital where he had undergone surgery on two coronary vessels) and the luck of the patient (a subsequent cardiac arrest at the GP's office) results in an unsuccessful out-of-hospital resuscitation.

Manipulative therapies for infantile colic.

Background: Infantile colic is a common disorder, affecting around one in six families, and in 2001 was reported to cost the UK National Health Service in excess of £65 million per year (Morris 2001). Although it usually remits by six months of age, there is some evidence of longer-term sequelae for both children and parents.Manipulative therapies, such as chiropractic and osteopathy, have been suggested as interventions to reduce the severity of symptoms.

Aberrant stress hormone receptor balance in the human prefrontal cortex and hypothalamic paraventricular nucleus of depressed patients.

The prefrontal cortex (PFC) plays an important role in the regulation of the hypothalamo-pituitary-adrenal (HPA)-axis regarding stress response and possibly also depression. We used quantitative real-time PCR to determine the mRNA levels of 17 stress-related genes in the human postmortem anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) of patients with mood disorder and of well-matched controls. The correlation between the expression of these DLPFC genes and their earlier measured expression in the paraventricular nucleus (PVN) of the same subjects was also determined.

A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation.

Background: Chronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis.

Acute effects of neonatal dexamethasone treatment on proliferation and astrocyte immunoreactivity in hippocampus and corpus callosum: towards a rescue strategy.

Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone.

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration.