Blood Pressure Regulation Evolved from Basic Homeostatic Components.

Blood pressure (BP) is determined by several physiological factors that are regulated by a range of complex neural, endocrine, and paracrine mechanisms. This study examined a collection of 198 human genes related to BP regulation, in the biological processes and functional prisms, as well as gene expression in organs and tissues. This was made in conjunction with an orthology analysis performed in 19 target organisms along the phylogenetic tree. We have demonstrated that transport and signaling, as well as homeostasis in general, are the most prevalent biological processes associated with BP gene orthologs across the examined species. We showed that these genes and their orthologs are expressed primarily in the kidney and adrenals of complex organisms (e.g., high order vertebrates) and in the nervous system of low complexity organisms (e.g., flies, nematodes). Furthermore, we have determined that basic functions such as ion transport are ancient and appear in all organisms, while more complex regulatory functions, such as control of extracellular volume emerged in high order organisms. Thus, we conclude that the complex system of BP regulation evolved from simpler components that were utilized to maintain specific homeostatic functions that play key roles in existence and survival of organisms.

Iatrogenic hypertension: a bioinformatic analysis.

It is well known that a myriad of medications and substances can induce side effects that are related to blood pressure (BP) regulation. This study aims to investigate why certain drugs tend to cause iatrogenic hypertension (HTN) and focus on drug targets that are implicated in these conditions.Databases and resources such as SIDER, DrugBank, and Genomatix were utilized in order to bioinformatically investigate HTN-associated drug target-genes for which HTN is a side effect. A tree-like map was created, representing interactions between 198 human genes that relate to the blood pressure system. 72 HTN indicated drugs and 160 HTN-inducing drugs were investigated. HTN-associated genes affected by these drugs were identified. HTN indicated drugs, which target nearly all branches of the interaction tree, were shown to exert an effect on most functional sub-systems of the BP regulatory system; and specifically, for the adrenergic and dopaminergic receptor pathways. High prevalence (25 genes) of shared targets between the HTN indicated and HTN-inducing drug categories was demonstrated. We focus on six drug families which are not indicated for HTN treatment, yet are reported as a major cause for blood pressure side effects. We show the molecular mechanisms that may lead to this iatrogenic effect. Such an analysis may have clinical implications that could allow for the development of tailored medicine with fewer side effects.

Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative motor neuron disease that involves activation of the immune system and inflammatory response in the nervous system. Reduced level of the immuno-modulatory and anti-inflammatory protein alpha-1-antitrypsin (AAT) is associated with inflammation-related pathologies. The objective of the present is to determine AAT levels and IL-23 in the cerebrospinal fluid (CSF) of ALS patients and control group. FINDINGS: CSF samples from newly diagnosed ALS patients and age-matched controls were analyzed for AAT and IL-23 by ELISA and magnetic luminex screening, respectively. A statistically significant reduction of 45 % in mean AAT levels was observed in the CSF of ALS patients (21.4 µg/ml) as compared to the control group (mean 38.8 µg/ml, p = 0.013). A statistically significant increase of 30.8 % in CSF mean levels of the pro-inflammatory cytokine IL-23 was observed in ALS patients (1647 pg/ml) in comparison to the controls (1259 pg/ml, p = 0.012). A negative correlation coefficient (r = -0.543) was obtained by linear regression analysis of the two measured parameters (p = 0.036). CONCLUSIONS: Reduced AAT and elevated IL-23 CSF levels support the notion of neuroinflammatory process occurring in ALS patients. Increasing AAT levels in the patients' nervous system should be further investigated as a new therapeutic approach and a novel potential tool for ALS treatment.

Selenium neurotoxicity in humans: bridging laboratory and epidemiologic studies.

Selenium is a metalloid of considerable interest in the human from both a toxicological and a nutritional perspective, with a very narrow safe range of intake. Acute selenium intoxication is followed by adverse effects on the nervous system with special clinical relevance, while the neurotoxicity of long-term overexposure is less characterized and recognized. We aimed to address this issue from a public health perspective, focusing on both laboratory studies and the few epidemiologic human studies available, with emphasis on their methodological strengths and limitations. The frequently overlooked differences in toxicity and biological activity of selenium compounds are also outlined. In addition to lethargy, dizziness, motor weakness and paresthesias, an excess risk of amyotrophic lateral sclerosis is the effect on the nervous system which has been more consistently associated with chronic low-level selenium overexposure, particularly to its inorganic compounds. Additional research efforts are needed to better elucidate the neurotoxic effects exerted by selenium overexposure.

Are environmental exposures to selenium, heavy metals, and pesticides risk factors for amyotrophic lateral sclerosis?

The etiology of sporadic amyotrophic lateral sclerosis (ALS), the most common form of this degenerative disease of the motor neurons, is still unknown, despite extensive investigation of several genetic and environmental potential risk factors. We have reviewed laboratory and epidemiological studies assessing the role of exposure to neurotoxic chemicals (metalloid selenium; heavy metals mercury, cadmium, and lead; pesticides) in ALS etiology by summarizing the results of these investigations and examining their strengths and limitations. Despite limitations in the exposure assessment methodologies typically used in human studies, we found suggestive epidemiological evidence and biologic plausibility for an association between ALS and antecedent overexposure to environmental selenium and pesticides. The relation with mercury, cadmium, and lead appears weaker.

Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes.

Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal primary astrocytes. Astrocytes were pretreated for 66 h with 5 µg/ml IIIM1 (4.95 µM) followed by 6 h exposure to MeHg (5 µM). MeHg significantly increased F(2)-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E(2) (PGE(2)), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.

Impact of integrated pest management (IPM) training on reducing pesticide exposure in Illinois childcare centers.

Children, mainly infants, are especially vulnerable to pesticides, as a result of physiological factors which facilitate absorption of chemicals and limit the ability to detoxify and eliminate them. Moreover, children exhibit mouthing activity with pesticide contaminated objects. Therefore, the rapid course of growth and development creates a time-frame of unique vulnerability, where exposed children are prone to develop delayed neurotoxic brain disorders. Parents, childcare workers and staff are generally untrained in using pesticides and may not follow instructions or consider safer alternatives in efforts to provide a sanitary pest-free environment. A survey of 3364 Illinois childcare centers was conducted to assess the direct and indirect impact of a formal integrated pest management (IPM) "Train-the-Trainer" program implemented by a non-governmental organization to childcare centers and supervisory agencies over a 3-year period. This survey determined that the training increased the level of confidence, positive attitudes (easy, controls pests, efficient) and implementation of IPM by childcare providers. Childcare staff was motivated primarily by how IPM protects children's health from exposure to pesticides, in which neurotoxic substances may play a major role.

Exposure and susceptibility: schizophrenia in a young man following prolonged high exposures to organic solvents.

There is an abundant literature on the adverse effects of solvents on the neurobehavioral performance, higher brain functions, and chronic solvent-induced encephalopathy. However, the occurrence of solvent-related schizophrenia is rare, with few reports on the link between solvent exposure and schizophrenia. Here, we report on a patient with schizophrenia, presenting after a sustained period of 6 months of everyday exposure to neurotoxic solvents in an unprotected occupational setting in Haifa, Israel. In light of the similarity of symptoms of schizophrenia and chronic solvent encephalopathy, we call for further epidemiologic studies to examine the potential contribution of solvent exposure to the etiology and evolution of schizophrenia in selected cases. This case study and review of relevant literature underscores the importance of obtaining detailed histories on occupational exposures to search for agents which can trigger psychotic episodes. In the meantime, policies to prevent such exposures at the source can be expected to contribute to the prevention of a non-trivial proportion of neurotoxic diseases, including, possibly, schizophrenia in worker populations.

Peaceful use of disastrous neurotoxicants.

The increasing exposure to environmental neurotoxicants in the last decades caused serious health problems in the world population. Some of the neurotoxic agents are being used in agriculture and household such as insecticides and rodenticides and others are of natural origin like snake and scorpion venoms. Additional group of harmful substances is the chemical warfare agents including nerve and blistering agents that are known for their disastrous effects on neuronal tissues. The present paper presents a combination of epidemiological/clinical and molecular approaches for investigating the effect of certain groups of neurotoxicants on a variety of pathologies. The work of Finkelstein and coworkers describes epidemiological and clinical studies on acute and chronic organophosphate (OP)-induced neurotoxicity in certain populations in Israel. They mainly investigated the neurotoxic effects of low-level long-term exposure to OP in agricultural areas but also dealt with acute exposures as well. A molecular approach to OP mechanism of neuronal injury was described by Milatovic and coworkers. They demonstrated OP-induced oxidative injury in pyramidal neurons in the CA1 hippocampal area and its suppression by antioxidants. Lecht and coworkers described the novel snake venom angioneurins as important mediators of the physiological cross-talk between the cardiovascular and nervous systems. They also showed that under certain conditions these angioneurins may induce pathologies such as tumor development or disruption of the vascular barrier function during envenomation. Additional mechanistic/therapeutic approach was presented by Brodsky, Rosengarten, Proscura, Shapira and Wormser. They developed a novel anti-inflammatory peptide that reduced skin irritation induced by heat and sulfur mustard (SM) stimuli. Since SM causes neuropsychiatric symptoms and alterations in neurological functions this peptide may serve as a potential treatment of neuronal injuries caused by environmental neurotoxicants. These reviews highlight different aspects of neurotoxicity, addressing epidemiology and mechanisms of toxicity; and identifying novel potential therapies.

Differential deposition of manganese in the rat brain following subchronic exposure to manganese: a T1-weighted magnetic resonance imaging study.

BACKGROUND: Manganism is a central nervous system disorder caused by toxic exposure to manganese. Manganism has been related to occupational exposures, liver diseases, prolonged parenteral nutrition, and abuse of illicit drugs. Initially manifested by a reversible neuropsychiatric syndrome (locura manganica), the main symptoms and signs of manganism are emotional lability, compulsive behavior and visual hallucinations. Locura manganica is followed by an irreversible extrapyramidal syndrome, the onset of which occurs years after chronic exposure. OBJECTIVES: To characterize the regional distribution of Mn in the rat brain after subchronic exposure to Mn. This animal model holds special clinical relevance, reflecting the earlier clinical stages of manganism before chronic exposure to Mn exerts its irreversible effects. METHODS: Sprague-Dawley rats were intravenously injected with MnCl2 weekly, for a total of 14 weeks - approximately 1/10 of the lifetime of the rat. T1-weighted magnetic resonance imaging was used to detect the distribution of Mn deposition in brain tissues, as evidenced by areas of T1-weighted hyperintense signals. RESULTS: A consistent region-specific pattern of T1-weighted hyperintensities was observed in the brains of Mn-treated rats. Cortical hyperintensities were prominent in the hippocampus and dentate gyrus. Hyperintensities were also observed in the olfactory bulbs, pituitary gland, optic nerves and chiasma, pons, midbrain tegmentum, habenula, lentiform and caudate nuclei, thalamus, chorioid plexus and cerebellar hemispheres. CONCLUSIONS: Prominent Mn depositions, evidenced by T1-weighted hyperintensities in the hippocampus after subacute exposure to Mn, are compatible with the clinical picture of manganism during its early stages, and may explain its pathophysiology.

Herbal medicine and epilepsy: proconvulsive effects and interactions with antiepileptic drugs.

The use of complementary and alternative medicine is on the rise, including among patients with epilepsy. Herbal medicine, one of the most popular forms of CAM, is considered to be both safe and effective by most consumers. Yet many herbs may increase the risk for seizures, through intrinsic proconvulsant properties or contamination by heavy metals, as well as via effects on the cytochrome P450 enzymes and P-glycoproteins, altering antiepileptic drug (AED) disposition. Herb-drug interactions may be difficult to predict, especially since the quality and quantity of active ingredients are often unknown. Since most patients do not inform their physicians that they are taking herbal medicines, health care professionals must initiate a dialogue in order to prevent complications with the combined regimen. At the same time, further research is required regarding the effect of herbs on seizure activity and interactions with AED treatment.

Modulation of cholinergic systems by manganese.

Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the preferential involvement of the cholinergic systems, initially in the septo-hippocampus and later in the basal ganglia. These observations highlight the importance of studying the role of the CNS cholinergic systems in manganese-mediated neurotoxicity.

Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: an open-label prospective 1 year study.

BACKGROUND: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools. OBJECTIVES: To evaluate the clinical effect of IFNbeta-1b (Betaferon) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS) in MS patients during 1 year of follow-up. METHODS: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin test score at baseline was measured using the paired t-test. RESULTS: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNbeta-1b: from 20.3 +/- 8.3 microv to 13.1 +/- 10.6 microv (P = 0.026) for amplitude, and from 312.9 +/- 15.6 msec to 302.0 +/- 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement--from 20.7 +/- 30.7 to 13.1 +/- 10.6 (P = 0.001) and 96.7 +/- 15.7 to 100.1 +/- 11.1 (P = 0.0025) respectively--after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 +/- 0.5 to 2.8 +/- 1.1. CONCLUSIONS: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNbeta-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Pediatric cinnarizine overdose and toxicokinetics.

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel-blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t(1/2) = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel-blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.

Respiratory failure in a neonate after folk treatment with broom bush (Retama raetam) extract.

OBJECTIVES: To increase the awareness of intoxication by folk herbal remedies in the pediatric population. METHODS: Case report of a 7-day-old baby boy admitted to a pediatric intensive care unit in a university-affiliated hospital. RESULTS: The patient presented with respiratory failure and central nervous system depression. Specific questioning of the parents revealed consumption of folk herbal remedy by the neonate. Mechanical ventilation was used for 24 hours until normal activity level resumed. CONCLUSIONS: The possibility of intoxication in a neonate should not be overlooked. Folk herbal remedies, especially if taken in larger than recommended amounts, may be hazardous. Accessible herbal and folk medicine data bank will contribute to a better treatment of patients having side effects of these remedies.