Clinical approach to the diagnosis of acid-base disorders.

An ability to rapidly and effectively diagnose and treat acid-base disorders is essential to the management of seriously ill patients. In this paper an approach to the diagnosis of pure and mixed acid-base disorders is presented that is based upon an understanding of the bicarbonate buffer system and a knowledge of the well defined and predictable compensatory responses that occur in association with each of the primary acid-base disorders. With this approach a number of acid-base problems are presented and solved.     

Adaptation of the Human Body to Simulated Weightlessness: Clinical Studies

Problems of adaptation of functional systems of the human body to conditions of continuous weightlessness are considered (prolonged stay under conditions of antiorthostatic hypokinesia and in an immersion medium). It was revealed that, during adaptation to these conditions, polymorphic clinicofunctional disorders develop, transforming into clinicophysiological syndromes, the most frequently observed being autonomic vascular malfunction, asthenoneurotic syndrome, detraining of the blood circulatory system, trophic and neuromuscular disorders, statokinetic syndrome, pain syndrome, and metabolic and hormonal disorders. The severity of the specified disorders and the duration of the recovery period depend on the duration of hypokinesia and the intensity and regularity of application of preventive measures during hypokinesia. The most probable pathophysiological mechanisms of adverse effects of continuous hypokinesia (maladaptation) on functional systems of the human body are described.     

An immunocytochemical approach to detection of mitochondrial disorders.

Mitochondrial disorders can lead to a confusing array of symptoms, which frequently makes a diagnosis difficult. Traditional approaches to such diagnoses are based on enzyme activity assays, with further characterization provided by genetic analysis. However, these methods require relatively large sample sizes, are time-consuming, labor-intensive, and show variability between laboratories. Here, we report an immunocytochemical test that makes use of monoclonal antibodies to subunits from each of the oxidative phosphorylation complexes and pyruvate dehydrogenase to aid in the detection of mitochondrial disorders. It can be completed and data analyzed in less than 4 hr. We have used this test to study fibroblast cultures from patients with mitochondrial disorders arising from both mitochondrial DNA and nuclear DNA defects. We have also examined cases of Leigh syndrome arising from different genetic causes. We show that patients can be categorized on the basis of which complexes are affected and whether or not the defect being studied shows a mosaic distribution, an indicator of whether the causal mutation(s) is/are in the mitochondrial or nuclear genome. Immunocytochemical analysis as described here should be considered as an initial screen for mitochondrial disorders by which to direct (and limit) the subsequent enzymatic and genetic tests required to make an unambiguous diagnosis.     

Analysis of the molecular pathophysiology of sleep disorders relevant to a disturbed biological clock

Genetic studies have revealed several clock gene variations/mutations involved in the manifestation of sleep disorders or interindividual differences in sleep–wake patterns, but only part of the genetic risk can be explained by the gene variations/mutations identified to date. Recent progress in research into circadian rhythm generation has provided efficient tools for eliciting the molecular basis of clock-relevant sleep disorders, complementing traditional genetic analysis. While the human master clock resides in the suprachiasmatic nucleus of the hypothalamus (central clock), peripheral tissue cells also generate self-sustained circadian oscillations of clock gene expression (peripheral clock), enabling estimation of individual human clock properties through a single collection of skin fibroblasts or venous blood cells. Some of the established cell lines exhibit autonomous circadian oscillations of clock gene expression, and introduction of clock gene variations into these cell lines by gene targeting makes it possible to investigate changes in the circadian phenotype induced by these variations/mutations without the need for generating transgenic animals. Estimation of human clock properties using peripheral tissue cells, in addition to genetic analysis, will facilitate comprehensive explication of the genetic risk of a variety of disorders relevant to biological clock disturbances, including sleep disorders, mood disorders, and metabolic diseases.     

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis.

Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis. Four human disorders of morphogenesis (Smith-Lemli-Opitz syndrome, desmosterolosis, X-linked chondrodysplasia punctata, CHILD syndrome) have recently been shown to be caused by sterol abnormalities resulting from cholesterol biosynthesis enzyme deficiencies. This review summarizes the clinical, biochemical and molecular data in these disorders with an emphasis on understanding the pathophysiology of dysmorphogenesis.     

National efforts to identify research issues related to prevention of work-related musculoskeletal disorders.

Musculoskeletal disorders (MSDs), including low back and upper extremity disorders, represent one of the greatest work-related health concerns facing industrialized nations. Recently, two national groups were charged with developing research agendas aimed at increasing our knowledge of the prevention of these disorders. The first agenda, developed by the National Institute for Occupational Safety and Health's (NIOSH) National Occupational Research Agenda (NORA) MSD team, was based on input from several hundred practitioners and safety and health experts representing industry, labor, and academia. The second agenda, developed by the National Research Council (NRC) and the Institute of Medicine's (IOM) National Panel on Musculoskeletal Disorders and the Workplace, was based on input from leading researchers in the fields of medicine, information science, and ergonomics. This paper summarizes the findings of the two groups and compares the two research agendas.     

Regulation of dopamine system responsivity and its adaptive and pathological response to stress

Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders.     

Lost working years due to mental disorders: an analysis of the norwegian disability pension registry

Objectives

Mental disorders are prevalent diagnoses in disability benefit statistics, with awards often granted at younger age than for other diagnoses. We aimed to compare the number of lost working years following disability benefit award for mental disorders versus other diagnostic groups.

Methods

Data from the complete Norwegian official registry over disability benefit incidence, including primary diagnoses, were analyzed for the period 2001 to 2003 (N = 77,067), a time-period without any reform in the disability benefit scheme. Lost working years due to disability benefit award before scheduled age retirement at age 67 were calculated.

Results

Musculoskeletal disorders were the commonest reason for disability benefit awards (36.3%) with mental disorders in second place (24.0%). However, mental disorders were responsible for the most working years lost (33.8%) compared with musculoskeletal disorders (29.4%). Individuals awarded disability benefit for a mental disorder were on average 8.9 years younger (46.1 years) than individuals awarded for a musculoskeletal disorder (55.0 years), and 6.9 years younger than individuals awarded for any other somatic disorder (53.0 years). Anxiety and depressive disorders were the largest contributors to lost working years within mental disorders.

Conclusion

Age at award is highly relevant when the total burden of different diagnoses on disability benefits is considered. There is great disparity in total number of lost working years due to disability benefit award for different diagnostic groups. The high number of lost working years from mental disorders has serious consequences for both the individual and for the wider society and economy.     

Features of EEG in patients with disorders due to psychoactive substance use during olfactory stimulation

Electroencephalographic (EEG) spectra have been analyzed under baseline conditions and during olfactory stimulation in substance-dependent and healthy subjects. The intergroup differences in the EEG spectra resulting from an increase in the power of cortical bioelectric potentials in patients with disorders due to psychoactive substance use were recorded in the parietal and temporal EEG leads. Interhemispheric differences have been found in the contribution of different frequencies to the spectral characteristics of the EEG. In patients with addictive disorders, in the temporal area of the left hemisphere, in the high-frequency range, a significant increase in the power of bioelectric potentials was recorded under baseline conditions and during olfactory stimulation. An increased power of α activity was typical of the temporal area of the right hemisphere in patients with disorders due to psychoactive substance use compared to the healthy subjects. The neurophysiological patterns found may be related to the psychological and behavioral features of addictive disorders.     

Resistin: A journey from metabolism to cancer

Resistin, a small secretory molecule, has been implicated to play an important role in the development of insulin resistance under obese condition. For the past few decades, it has been linked to various cellular and metabolic functions. It has been associated with diseases like metabolic disorders, cardiovascular diseases and cancers. Numerous clinical studies have indicated an increased serum resistin level in pathological disorders which have been reported to increase mortality rate in comparison to low resistin expressing subjects. Various molecular studies suggest resistin plays a pivotal role in proliferation, metastasis, angiogenesis, inflammation as well as in regulating metabolism in cancer cells. Therefore, understanding the role of resistin and elucidating its’ associated molecular mechanism will give a better insight into the management of these disorders. In this article, we summarize the diverse roles of resistin in pathological disorders based on the available literature, clinicopathological data, and a compiled study from various databases. The article mainly provides comprehensive information of its role as a target in different treatment modalities in pre as well as post-clinical studies.     

Ehlers–Danlos syndrome: A showcase of conditions that lead to understanding matrix biology

The Ehlers–Danlos syndromes (EDS) are genetically and clinically diverse disorders in which affected individuals share a number of physical characteristics, including joint hypermobility, skin extensibility, and tissue friability. Clinical investigations opened the door to identifying the biochemical and molecular etiologies of this diverse but overlapping group of disorders. In this article, we provide an overview of how these disorders inform our understanding of matrix biology, including the role of collagens (types I, III and V), proteoglycans and other proteins.     

Impaired attribution of emotion to facial expressions in anxiety and major depression

Background

Recognition of others'' emotions is an important aspect of interpersonal communication. In major depression, a significant emotion recognition impairment has been reported. It remains unclear whether the ability to recognize emotion from facial expressions is also impaired in anxiety disorders. There is a need to review and integrate the published literature on emotional expression recognition in anxiety disorders and major depression.

Methodology/Principal Findings

A detailed literature search was used to identify studies on explicit emotion recognition in patients with anxiety disorders and major depression compared to healthy participants. Eighteen studies provided sufficient information to be included. The differences on emotion recognition impairment between patients and controls (Cohen''s d) with corresponding confidence intervals were computed for each study. Over all studies, adults with anxiety disorders had a significant impairment in emotion recognition (d = −0.35). In children with anxiety disorders no significant impairment of emotion recognition was found (d = −0.03). Major depression was associated with an even larger impairment in recognition of facial expressions of emotion (d = −0.58).

Conclusions/Significance

Results from the current analysis support the hypothesis that adults with anxiety disorders or major depression both have a deficit in recognizing facial expression of emotions, and that this deficit is more pronounced in major depression than in anxiety.     

An expert system applied to the diagnosis of anemia with special reference to myelodysplastic syndromes

An expert system is described that includes interpretation of the results from a complete blood count as well as data from bone marrow aspiration. The system utilizes Bayes' rule. It has previously been tested on 180 cases of anemia including 20 benign and malignant hematologic disorders. On the data set, the system achieved 84% satisfactory diagnoses. In the present study, patients with myelodysplastic syndromes and with disorders of heme synthesis have been added to the test cases. For support, the expert system requires an IBM Personal Computer or equivalent. The program is available commercially (Coulter Electronics, Hialeah, FL).     

Yeast models of human mitochondrial diseases: from molecular mechanisms to drug screening

Mitochondrial diseases are rare diseases most often linked to energy in the form of ATP-depletion. The high number of nuclear- and mitochondrial-DNA-encoded proteins (>500), required for ATP production and other crucial mitochondrial functions such as NADH re-oxidation, explains the increasing number of reported disorders. In recent years, yeast has revealed to be a powerful model to identify responsible genes, to study primary effects of pathogenic mutations and to determine the molecular mechanisms leading to mitochondrial disorders. However, the clinical management of patients with mitochondrial disorders is still essentially supportive. Here we review some of the most fruitful yeast mitochondrial disorder models and propose to subject these models to highthroughput chemical library screening to prospect new therapeutic drugs against mitochondrial diseases.     

Role of iron metabolism in heart failure: From iron deficiency to iron overload

Iron metabolism is a balancing act, and biological systems have evolved exquisite regulatory mechanisms to maintain iron homeostasis. Iron metabolism disorders are widespread health problems on a global scale and range from iron deficiency to iron-overload. Both types of iron disorders are linked to heart failure. Iron play a fundamental role in mitochondrial function and various enzyme functions and iron deficiency has a particular negative impact on mitochondria function. Given the high-energy demand of the heart, iron deficiency has a particularly negative impact on heart function and exacerbates heart failure. Iron-overload can result from excessive gut absorption of iron or frequent use of blood transfusions and is typically seen in patients with congenital anemias, sickle cell anemia and beta-thalassemia major, or in patients with primary hemochromatosis. This review provides an overview of normal iron metabolism, mechanisms underlying development of iron disorders in relation to heart failure, including iron-overload cardiomyopathy, and clinical perspective on the treatment options for iron metabolism disorders.     

Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders

Psychiatric disorders affect approximately 10% of adults in North-America. The complex nature of these illnesses makes the search for their pathophysiology a challenge. However, studies have consistently shown that mitochondrial dysfunction and oxidative stress are common features across major psychiatric disorders, including bipolar disorder and schizophrenia. Nevertheless, little is known about specific targets of oxidation in the brain. The search for redox sensors (protein targets for oxidation) will offer information about which pathways are regulated by oxidation in psychiatric disorders. Additionally, DNA is also a target for oxidative damage and recently, studies have suggested that oxidation of cytosine and guanosine can serve as an epigenetic modulator by decreasing or preventing further DNA methylation. Therefore, this review aims to discuss how we can use redox-proteomics and epigenomics to help explain the role of oxidative damage in major psychiatric disorders, which may ultimately lead to the identification of targets for development of new medications.     

Focus: Rare Disease: Psychosocial Functioning in Siblings of Children With Rare Disorders Compared to Controls

Siblings of children with chronic disorders are at increased risk of psychosocial problems. The risk may be exacerbated when the chronic disorder is rare and limited medical knowledge is available, due to more uncertainty and feelings of isolation. We examined mental health, parent-child communication, child-parent relationship quality, and social support among 100 children aged 8 to 16 years (M age 11.5 years, SD = 2.2; 50.0% boys, 50.0% girls). Fifty-six were siblings of children with rare disorders, and 44 were controls. The siblings of children with rare disorders (herein, siblings) were recruited from a resource centre for rare disorders and comprised siblings of children with a range of rare disorders including neuromuscular disorders and rare chromosomal disorders with intellectual disability. Controls were recruited from schools. Self-reported child mental health was significantly poorer for siblings compared to controls (effect size difference d = 0.75). Parent-reported child mental health was not significantly different between the groups (d = -0.06 to 0.16). Most child-parent relationships (anxiety/avoidance; mothers/fathers) were significantly poorer for siblings compared to controls (d = 0.47 to 0.91). There was no difference between groups in anxious relation with mother. Parent-child communication was significantly poorer for siblings compared to controls (d = -0.87 to -0.75). Social support was significantly poorer for siblings compared to controls (d = 0.61). We conclude that siblings of children with rare disorders display more psychosocial problems than controls. Interventions are indicated to prevent further maladjustment for siblings.     

Significance of individual resistance to hypoxia for the correction of the brain trauma sequelae

In rats, the individual sensitivity to hypoxia plays an prominent role for recovery of animals after mechanic brain injury. Enthomerzol (25 mg/kg intraperitoneally) for three days after brain injury decreased behavioral disorders in rats with different resistance to acute hypoxia, recovered structure of individual behavior, prevented metabolic disorders in brain. Therefore, antihypoxant ethomerzol is effective as a drug against hypoxia due to brain injury.