Madhu Kalia

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.

Dopaminergic Systems in the Brain and Pituitary

It is now 20 years since Swedish scientists described the existence of the nigrostriatal, mesolimbic, and tuberoinfundibular dopaminergic (DA) neurons in the rat brain [4, 8, 13, 17, 24, 50]. Since then new types of DA neuronal systems in the brain have been mapped out and the existence of peptide comodulators in certain subpopulations of DA neuronal systems has been described [27–29]. Of considerable importance in the mapping of new types of DA systems (Tables 1, 2, and 3) has been the development of new sensitive fluorescence methods for the demonstration of DA, based on the same histochemical principles as the classical formaldehyde method, and the biochemical purification of tyrosine hydroxylase (TH) [41] has made it possible to use TH immunocytochemistry in the mapping of the central DA neuronal systems [23, 25, 27, 33, 34, 38]. It is important to emphasize that although the various DA neuronal systems have been described mainly in the rat brain, they also exist in the primate and human brains, although the details of their anatomy remain to be completely worked out [43].

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.

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 Alzheimers 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.

Somatostatin produces apnea and is localized in medullary respiratory nuclei: a possible role in apneic syndromes

Immunocytochemical studies on the nucleus of the tractus solitarius and adjacent areas of the dorsal medulla of the rat demonstrate the existence of somatostatin immunoreactive nerve cell bodies and nerve terminals within the ventrolateral and ventral subnuclei of the nucleus of the tractus solitarius. Injections of somatostatin (6 nmol in 10 microliters) into the cisterna magna of chloralose-anesthetized rats produced an apnea with a latency of 5-7 min. This apnea was preceded by slow deep breathing, a reduction in heart rate and fall of arterial blood pressure. The apnea was usually irreversible leading to death of the animal. These respiratory and cardiovascular effects of somatostatin were not abolished either by bilateral vagotomy or by low decerebration (below the inferior colliculus). It is suggested that activation of somatostatin receptors linked to neurons in medullary respiratory nuclei might be responsible for the inhibition of respiratory neuronal activity and thus may mediate apneic conditions.

Evidence for the existence of putative dopamine-, adrenaline- and noradrenaline-containing vagal motor neurons in the brainstem of the rat

A combined technique utilizing retrograde transport of horseradish peroxidase (HRP) combined with immunocytochemistry using antibodies raised against tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyl transferase (PNMT) has been used to characterize monoaminergic neurons located within the region of the brainstem vagal motor nucleus. TH-immunoreactive (IR) but not DBH-IR and PNMT-IR neurons were double labelled predominantly at the caudal-most pole of the dorsal motor nucleus of the vagus (dmnX), whereas double-labelled PMNT and DBH plus TH-IR neurons extended from levels just rostral to the obex to 1-2 mm rostrally in the medial and lateral poles of the dmnX, respectively. The presence of putative dopamine (DA), noradrenaline (NA) and adrenaline (A) neurons in topographically distinct regions of the dmnX implicates, DA, NA and A in the modulation of cholinergic transmission at the level of parasympathetic ganglia in discrete parts of the thoracic and abdominal viscera.

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.

Reversible, short-lasting, and dose-dependent effect of (+)-fenfluramine on neocortical serotonergic axons

Dextrofenfluramine [+)-fenfluramine) is the dextro-optical isomer of the racemic compound (+/-)-fenfluramine. This compound stimulates the release of serotonin (5-HT) and blocks its re-uptake in serotonergic nerve terminals. (+)-Fenfluramine and its nor metabolite which have been localized in significant amounts in the rat brain are useful anorectic agents in animals. In humans, (+)-fenfluramine is used as an anti-obesity agent when administered orally in doses of 0.25 mg/kg/twice a day. Studies in some animal species (such as the rat and monkey, but not mice) using high doses of (+)-fenfluramine (administered subcutaneously) have shown long-term neurochemical and immunocytochemical effects in selected brain regions. In the present study we used the rat to determine the mechanism underlying the anorectic effect of orally administered (+)-fenfluramine. The rat was selected because long-term effects of (+)-fenfluramine have been previously described in this species. In addition, a variety of other aspects of orally administered (+)-fenfluramine have been addressed in this study. For example, how long does the depletion of 5-HT in the nerve terminals last following cessation of the drug treatment? i.e. is the effect reversible? Is this depletion of 5-HT and the resultant abnormal morphology of 5-HT-immunoreactive nerve terminals seen at high doses dose-dependent? Since some of these questions relate to morphological evaluation of this drug in brain 5-HT systems, we have examined this system as part of our ongoing effort to examine brain monoaminergic systems under perturbed conditions. We have used a morphological (immunocytochemical) approach to answer these questions. The primary function of this study was to evaluate the effects of short-term exposure (4 days) to varying doses of orally administered (+)-fenfluramine on 5-HT-immunoreactive nerve terminals in the frontal cortex of the rat. The frontal cortex was selected because it contains a homogeneous population of nerve fibers and terminals unlike other cortical regions, the hippocampus, striatum and the hypothalamus where a mixed population of coarse and fine fibers has been described. Since the previously reported effect of fenfluramine on 5-HT nerve terminals was the appearance of coarse fibers, the region of cortex selected for this study showed no coarse fibers in the pair-fed control. This essential feature of control regions has not been used in previous studies on this subject. The present study demonstrates that (+)-fenfluramine produces a dose-dependent reduction in 5-HT immunoreactivity of 5-HT nerve terminals in the neocortex of adult rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Ganglioside-induced regeneration and reestablishment of axonal continuity in spinal cord-transected rats

In this study we examined the effect of chronic GM-1 ganglioside treatment on the reestablishment of axonal continuity and functional recovery in spinal cord-transected rats. Previous studies have shown that chronic treatment with GM-1 ganglioside is effective in producing regeneration of lesioned mesostriatal dopaminergic neurons in the central nervous system [1, 2]. In addition, GM-1 ganglioside advances peripheral nerve regeneration following nerve crush injury [12]. Axonal continuity was determined by the ability of the spinal cord to transport horseradish peroxidase across the region of transection. Comparisons between ganglioside-treated and saline-treated controls showed that ganglioside treatment resulted in the reestablishment of axonal continuity between the spinal cord distal to the level of the transection and the brainstem. Saline-treated controls showed little evidence of axonal continuity between these two regions. Thus gangliosides induce reestablishment of axonal continuity and thereby could advance functional recovery in rats following spinal cord transection.

Maturation of Brain Stem Neurons Involved in Respiratory Rhythmogenesis: Biochemical, Bioelectrical and Morphological Properties

Neonatal and adult respiratory-related functions of brain stem were compared using in vivo or in vitro approaches. The control of inspiratory off-switch by glutamate-like neurotransmitters was found active at birth. However, neurons from the nucleus tractus solitarius (NTS) are immature at birth because they present growth cones and the transient potassium current appears progressively during the first week of life in association with modification of the dendritic tree. These data support the hypothesis that the mechanisms of respiratory rhythmogenesis are different at birth and in the adult.