Biomarkers of psychiatric diseases: current status and future prospects.

Abnormal behavior and disturbed cognition, often assumed to represent psychiatric illness, may actually result from some form of occult organic brain disease that can be detected by means of one or more biomarkers. This truth was discovered more than a century ago by Aloysius Alzheimer, a German psychiatrist and neuropathologist. As a psychiatrist, he described the behavioral manifestations of "senile dementia" in a 51-year-old female; as a neuropathologist, he was the first to recognize the significance of the senile plaques and neurofibrillary tangles found in her brain after her death at age 55 years. It was Alzheimer who made the connection between these "biomarkers" and the symptoms of the increasingly prevalent disease that now bears his name. In recent years, the search for psychiatry-relevant biomarkers of major depression, schizophrenia, bipolar disease, and other important psychiatric/neuropsychiatric disorders has intensified. Biomarkers in psychiatry and neuropsychiatry have the potential of clarifying the etiology of an ambiguous clinical presentation-making it possible, for example, to detect underlying differences between psychological maladies that have confusingly similar symptoms. In addition, attempts are now being made to classify mental disorders on the basis of biomarkers. Biomarkers may also disclose the presence of a previously unsuspected physical explanation for behavior(s) originally presumed to be "psychiatric" in origin. Although clinically usable biomarkers in the diagnosis and treatment of mental illness await validation, candidate genomic biomarkers and protein profiling of candidate biomarkers in psychiatry are rapidly gaining ground as areas of interest, with considerable future potential. This review considers biomarker-related issues germane to psychiatry and neuropsychiatry in the context of new data that can be used to tailor therapies to the individual psychiatric patient.

Biomarkers for personalized oncology: recent advances and future challenges.

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells and oncology is a branch of medicine that deals with tumors. The last decade has seen significant advances in the development of biomarkers in oncology that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as we begin to understand the complex mechanisms that transform a normal cell into an abnormal one. These discoveries have fueled the development of novel drug targets and new treatment strategies. The standard of care for patients with advanced-stage cancers has shifted away from an empirical treatment strategy based on the clinical-pathological profile to one where a biomarker driven treatment algorithm based on the molecular profile of the tumor is used. Recent advances in multiplex genotyping technologies and high-throughput genomic profiling by next-generation sequencing make possible the rapid and comprehensive analysis of the cancer genome of individual patients even from very little tumor biopsy material. Predictive (diagnostic) biomarkers are helpful in matching targeted therapies with patients and in preventing toxicity of standard (systemic) therapies. Prognostic biomarkers identify somatic germ line mutations, changes in DNA methylation, elevated levels of microRNA (miRNA) and circulating tumor cells (CTC) in blood. Predictive biomarkers using molecular diagnostics are currently in use in clinical practice of personalized oncotherapy for the treatment of five diseases: chronic myeloid leukemia, colon, breast, lung cancer and melanoma and these biomarkers are being used successfully to evaluate benefits that can be achieved through targeted therapy. Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and gastrointestinal tumors; anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALk fusion; HER2/neu blockage in HER2/neu-positive breast cancer; and epidermal growth factor receptors (EGFR) inhibition in EGFR-mutated lung cancer. This review presents the current state of our knowledge of biomarkers in five selected cancers: chronic myeloid leukemia, colorectal cancer, breast cancer, non-small cell lung cancer and melanoma.

Personalized oncology: recent advances and future challenges.

Personalized oncology is evidence-based, individualized medicine that delivers the right care to the right cancer patient at the right time and results in measurable improvements in outcomes and a reduction on health care costs. Evolving topics in personalized oncology such as genomic analysis, targeted drugs, cancer therapeutics and molecular diagnostics will be discussed in this review. Biomarkers and molecular individualized medicine are replacing the traditional "one size fits all" medicine. In the next decade the treatment of cancer will move from a reactive to a proactive discipline. The essence of personalized oncology lies in the use of biomarkers. These biomarkers can be from tissue, serum, urine or imaging and must be validated. Personalized oncology based on biomarkers is already having a remarkable impact. Three different types of biomarkers are of particular importance: predictive, prognostic and early response biomarkers. Tools for implementing preemptive medicine based on genetic and molecular diagnostic and interventions will improve cancer prevention. Imaging technologies such as Computed Tomography (CT) and Positron Emitted Tomography (PET) are already influencing the early detection and management of the cancer patient. Future advances in imaging are expected to be in the field of molecular imaging, integrated diagnostics, biology driven interventional radiology and theranostics. Molecular diagnostics identify individual cancer patients who are more likely to respond positively to targeted chemotherapies. Molecular diagnostics include testing for genes, gene expression, proteins and metabolites. The use of companion molecular diagnostics is expected to grow significantly in the future and will be integrated into new cancer therapies a single (bundled) package which will provide greater efficiency, value and cost savings. This approach represents a unique opportunity for integration, increased value in personalized oncology.

The role of corticosteroids and stress in chronic pain conditions.

The relationship between corticosteroids (endogenous and exogenous) and stress is well known, as is the use of steroids as concomitant treatment in pain management during acute inflammation. In the past, steroids have not been considered the first line of treatment in pain management. In this review, we examine new scientific and clinical evidence that demonstrates the direct role that steroids play in the generation and clinical management of chronic pain. We will discuss the new findings demonstrating the fact that steroids and related mediators produce paradoxical effects on pain such as analgesia, hyperalgesia, and even placebo analgesia. In addition, we will examine the physiologic effect of stress, high allostatic load, and idiopathic disease states such as chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and burnout. The recently observed positive relationship between glutaminergic activity in the insula and clinical pain will be examined in the context of understanding the central role of steroids in chronic pain. The complex role of the hypothalamic-pituitary-adrenal axis in pain will be discussed as well as other heterogeneous forms of chronic pain that involve many components of the central nervous system. Components of the hypothalamic-pituitary-adrenal axis have paradoxical effects on certain types of pain that are dependent on dose and on site (whether peripheral or central) and mode of application. Recent studies on glia have shown that they prolong a state of neuronal hypersensitization in the dorsal root ganglia by releasing growth factors and other substances that act on the immune system. We will discuss the implication of these new findings directly linking pain to steroids, stress, and key higher brain regions in the context of future therapeutic targets.

Brain development: anatomy, connectivity, adaptive plasticity, and toxicity.

The developing brain is inherently more vulnerable to injury than the adult brain because brain development is extraordinarily complex, with periods of unique susceptibility. When brain developmental processes are suspended or delayed by any external influence, virtually no potential exists for subsequent regeneration and repair. This inevitably leads to long-lasting or permanent consequences. Recent genetic studies have contributed to a better understanding of the dynamic adaptive changes that occur in the developing brain as a consequence of genetic and environmental processes. Many industrial and environmental chemicals such as lead, methyl-mercury, polychlorinated biphenyls, arsenic, and toluene are recognized causes of neurodevelopmental disorders that lead to clinical or subclinical brain dysfunction. A number of these developmental disabilities arise from interactions between environmental factors and individual gene susceptibility. In addition, neurodevelopmental disorders of unknown origin, such as mental retardation, attention deficit disorder, cerebral palsy, and autism are becoming increasingly prevalent, with costly consequences for the family and society. The aim of this review is examine brain developmental anatomy, connectivity, adaptive plasticity, and toxicity in the context of current knowledge and future trends.

Neurobiology of sleep.

The central nervous system undergoes several dynamic changes during sleep, which are coordinated by the pons, basal forebrain areas, and other subcortical structures and are mediated by three major neurotransmitters-norepinephrine, serotonin, and acetylcholine. The neuronal populations that produce these neuromodulators constitute the central representation of the sympathetic and parasympathetic subdivisions of the autonomic nervous system. The locus coeruleus (noradrenergic) and the raphe nucleus (serotoninergic) are most active during waking and become progressively less active in the transition from non-rapid eye movement (non-REM) to rapid eye movement (REM) sleep. On the other hand, the cholinergic neurons in the dorsolateral tegmental and pedunculopontine nuclei area are active both during waking and REM sleep. Over the past decade, a number of studies have provided interesting new evidence supporting the role of sleep in sleep-dependent memory processing. These studies have been directed specifically towards the role of sleep in memory encoding, memory consolidation, brain plasticity and memory reconsolidation, and have confirmed the hypothesis that sleep contributes importantly to processes of memory and brain plasticity. It has been shown in humans that sleep triggers overnight learning on a motor-sequence memory task, while equivalent waking periods produce no such improvement. These findings have important implications for acquiring real-life skills and in clinical rehabilitation following brain trauma and stroke.

Neurobiological basis of depression: an update.

The past 5 years have seen unprecedented advances in our knowledge about the neurobiology of depression. Significant breakthroughs have been made in genomics, imaging, and the identification of key neural systems involved in cognition, emotion, and behavior. In addition, novel targets have been identified for the development of new pharmacological and behavioral treatments. Genetic variations associated with most mental disorders are being identified, and reliable tests for early detection of risk and disease are now on the horizon. New neurobiological concepts have emerged, as they relate to these advances in mental health research such as the serotonin transporter receptor, a genetic variant of which doubles the risk of depression. Brain neurochemicals, including neurotropic factors (implicated in several mental disorders), and anatomical studies involving imaging of the amygdala and the hippocampus and prefrontal cortex are now at the forefront. Several brain neurotransmitters systems: glutamate, gamma -aminobutyric acid, serotonin, norepinephrine, and dopamine have been implicated in depression and mania. These transmitter systems, as well as other neurochemical systems such as membrane-bound signal transduction systems and intracellular signaling systems that modulate gene transcription and protein synthesis, play an important role in the etiology of depression. This new knowledge is expected to provide important clues for the development of selective pharmacological interventions. Neuroimaging studies of depressed patients have shown several abnormalities of regional cerebral blood flow and glucose metabolism--a surrogate of neuronal function--in various brain regions, including the limbic cortex, the prefrontal cortex, the hippocampus, the amygdala, and the anterior cingulate cortex. At this time, a considerable amount of new information is converging--derived from animal models of mood disorders, genetics, basic behavioral research, and neuroscience. It is inevitable that the next step in this progression will be the integration of these basic advances in clinical management and the application of this new information in the context of the depressed patient.

Dysphagia and aspiration pneumonia in patients with Alzheimer's disease.

Dysphagia and aspiration pneumonia are the 2 most serious medical conditions seen in late-stage Alzheimer's disease (AD) patients. Pseudobulbar dysphagia is associated with weight loss, which is not always prevented by optimizing the management of the dysphagia. Failure of basic homeostatic mechanisms appears to play an important role in the nutritional status of these patients. Aspiration pneumonia is the most common cause of death in end-stage AD. The primary problems that predispose to aspiration pneumonia include a reduced level of consciousness, dysphagia, loss of the gag reflex, periodontal disease, and the mechanical effects of inserting various tubes into the respiratory and gastrointestinal tracts. The bacterial flora involved include the indigenous oral flora (among which aerobes predominate) and, in the hospital or nursing home setting, nosocomially acquired pathogens such as Staphylococcus aureus and various aerobic and facultative gram-negative bacilli that may colonize in patients. In addition to treatment with antibiotics, adequate symptomatic treatment of AD patients with pneumonia is a priority in order to relieve suffering.

Assessing the economic impact of stress--the modern day hidden epidemic.

This article examines the economic effects of all forms of stress-work-related stress, home stress, and post-traumatic stress disorder (PTSD)-as health hazards. Such an approach inherently broadens the analysis from a few well-defined, quantitative variables, such as those most commonly studied by economists who traditionally examine job stress alone. It also enables us to draw conclusions regarding the socioeconomic factors and the psychology of stress and helps in understanding the larger question of the economic cost of stress in today's global environment. Stress and its related comorbid diseases are responsible for a large proportion of disability worldwide. The World Health Organization (WHO) Global Burden of Disease Survey estimates that mental disease, including stress-related disorders, will be the second leading cause of disabilities by the year 2020. Although the term "stress" is used in a wide variety of contexts, it has consistently been demonstrated that individuals with stress and related disorders experience impaired physical and mental functioning, more work days lost, increased impairment at work, and a high use of health care services. The disability caused by stress is just as great as the disability caused by workplace accidents or other common medical conditions such as hypertension, diabetes, and arthritis. We present evidence that calls for early recognition of workplace stress and for businesses to allocate more resources to stress management in the workplace.