Challenges in the diagnosis and management of disorders of sex development

Disorders of sex development (DSD) represent a spectrum of uncommon but very complex disorders with medical, psychosexual, and family implications for those affected by them. The diagnosis and management of these disorders requires a coordinated team of multiple specialists. Following an international conference in Chicago in 2005, a consensus statement was created and presented, which has resulted in a new paradigm in the nomenclature, classification, and management of DSDs. Since that time, many improvements have been forthcoming, most notably in the area of molecular genetic technologies. These developments have advanced our understanding of the specific etiologies underlying many of these conditions. In this article, we present an overview of the physiology of sex development, a few clinical vignettes highlighting specific pathologic conditions, discussions regarding the evaluation and management of these disorders, and some thoughts on future directions in this field. Birth Defects Research (Part C) 108:293–308, 2016. © 2016 Wiley Periodicals, Inc.     

Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization's World Mental Health Survey Initiative

Data are presented on the lifetime prevalence, projected lifetime risk, and age-of-onset distributions of mental disorders in the World Health Organization (WHO)''s World Mental Health (WMH) Surveys. Face-to-face community surveys were conducted in seventeen countries in Africa, Asia, the Americas, Europe, and the Middle East. The combined numbers of respondents were 85,052. Lifetime prevalence, projected lifetime risk, and age of onset of DSM-IV disorders were assessed with the WHO Composite International Diagnostic Interview (CIDI), a fully-structured lay administered diagnostic interview. Survival analysis was used to estimate lifetime risk. Median and inter-quartile range (IQR) of age of onset is very early for some anxiety disorders (7-14, IQR: 8-11) and impulse control disorders (7-15, IQR: 11-12). The age-of-onset distribution is later for mood disorders (29-43, IQR: 35-40), other anxiety disorders (24-50, IQR: 31-41), and substance use disorders (18-29, IQR: 21-26). Median and IQR lifetime prevalence estimates are: anxiety disorders 4.8-31.0% (IQR: 9.9-16.7%), mood disorders 3.3-21.4% (IQR: 9.8-15.8%), impulse control disorders 0.3-25.0% (IQR: 3.1-5.7%), substance use disorders 1.3-15.0% (IQR: 4.8-9.6%), and any disorder 12.0-47.4% (IQR: 18.1-36.1%). Projected lifetime risk is proportionally between 17% and 69% higher than estimated lifetime prevalence (IQR: 28-44%), with the highest ratios in countries exposed to sectarian violence (Israel, Nigeria, and South Africa), and a general tendency for projected risk to be highest in recent cohorts in all countries. These results document clearly that mental disorders are commonly occurring. As many mental disorders begin in childhood or adolescents, interventions aimed at early detection and treatment might help reduce the persistence or severity of primary disorders and prevent the subsequent onset of secondary disorders.     

Muscarinic receptors: do they have a role in the pathology and treatment of schizophrenia?

The high affinity of antipsychotic drugs for the dopamine D2 receptor focused attention onto the role of these receptors in the genesis of psychoses and the pathology of schizophrenia. However, psychotic symptoms are only one aspect of the complex symptom profile associated with schizophrenia. Therefore, research continues into other neurochemical systems and their potential roles in key features associated with schizophrenia. Modulating the cholinergic system in attempts to treat schizophrenia predates specific neurochemical hypotheses of the disorder. Cholinergic modulation has progressed from the use of coma therapy, through the use of anti-cholinergic drugs to control side-effects of older (typical) antipsychotic medications, to the development of drugs designed to specifically activate selected muscarinic receptors. This review presents data implicating a decrease in muscarinic receptors, particularly the M1 receptor, in the pathology of schizophrenia and explores the potential physiological consequences of such a change, drawing on data available from muscarinic receptor knockout mice as well as clinical and pre-clinical pharmacology. The body of evidence presented suggests that deficits in muscarinic receptors are associated with some forms of schizophrenia and that targeting these receptors could prove to be of therapeutic benefit to patients with the disorder.     

Stereotactic model of the electrical distribution within the internal globus pallidus during deep brain stimulation

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established surgical technique for the treatment of movement disorders. The objective of this study was to propose a computational stereotactic model of the electrical distribution around the electrode within the targeted GPi in order to optimize parameter adjustment in clinical practice. The outline of the GPi can be defined precisely by using stereotactic magnetic resonance imaging (MRI) and from this it is possible to model its three-dimensional structure. The electrode and the distribution of the patient-specific parameters can then be co-registered with the GPi volume. By using this methodology, it is possible to visualize and measure the relationship between the electrical distribution of patient-specific parameters and the morphology of the GPi. The model could be applied in clinical practice to help determine the threshold for achieving a therapeutic effect and consequently may aid in optimizing parameter settings for individual patients.     

BMP-7: Therapeutic target for ocular fibrotic disorders

Scarring of cornea, glaucoma, after-cataract and also proliferative vitreoretinopathy(PVR) related tractional retina detachment, age related macular degeneration and diabetic retinopathy etc., which are the major and seriously impair vision diseases in eyes, with various appearance and different therapy method, but maybe they have the similar pathogenesis—fibrosis, and all the above ocular diseases can be regarded as fibrotic disorders. Thus inhibition of the fibrotic process may provide a potentially novel therapeutic approach to the treatment of these ocular diseases mentioned above. Now numerous studies have proved that BMP-7 significantly reversed renal, hepatic, pulmonary fibrosis, including inhibition of Transforming growth factor-β (TGF-β) production, suppression of epithelial-to-mesenchymal transition (EMT), and repair of severely damaged epithelial cells. So it is reasonable to refer that BMP-7 may have the same preventive effect in these ocular fibrotic disorders. A potential clinical therapy can be developed by using the anti-fibrosis effect of BMP-7.     

Stabilization of inhomogeneous patterns in a diffusion-reaction system under structural and parametric uncertainties

Many phenomena such as neuron firing in the brain, the travelling waves which produce the heartbeat, arrythmia and fibrillation in the heart, catalytic reactions or cellular organization activities, among others, can be described by a unifying paradigm based on a class of nonlinear reaction-diffusion mechanisms. The FitzHugh-Nagumo (FHN) model is a simplified version of such class which is known to capture most of the qualitative dynamic features found in the spatiotemporal signals. In this paper, we take advantage of the dissipative nature of diffusion-reaction systems and results in finite dimensional nonlinear control theory to develop a class of nonlinear feedback controllers which is able to ensure stabilization of moving fronts for the FHN system, despite structural or parametric uncertainty. In the context of heart or neuron activity, this class of control laws is expected to prevent cardiac or neurological disorders connected with spatiotemporal wave disruptions. In the same way, biochemical or cellular organization related with certain functional aspects of life could also be influenced or controlled by the same feedback logic. The stability and robustness properties of the controller will be proved theoretically and illustrated on simulation experiments.     

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.