Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases.

Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.

Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSß0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0-31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5-54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0-15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76-0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2-64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery.

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.

Human pluripotent stem cell-derived models and drug screening in CNS precision medicine.

Development of effective therapeutics for neurological disorders has historically been challenging partly because of lack of accurate model systems in which to investigate disease etiology and test new therapeutics at the preclinical stage. Human stem cells, particularly patient-derived induced pluripotent stem cells (iPSCs) upon differentiation, have the ability to recapitulate aspects of disease pathophysiology and are increasingly recognized as robust scalable systems for drug discovery. We review advances in deriving cellular models of human central nervous system (CNS) disorders using iPSCs along with strategies for investigating disease-relevant phenotypes, translatable biomarkers, and therapeutic targets. Given their potential to identify novel therapeutic targets and leads, we focus on phenotype-based, small-molecule screens employing human stem cell-derived models. Integrated efforts to assemble patient iPSC-derived cell models with deeply annotated clinicopathological data, along with molecular and drug-response signatures, may aid in the stratification of patients, diagnostics, and clinical trial success, shifting translational science and precision medicine approaches. A number of remaining challenges, including the optimization of cost-effective, large-scale culture of iPSC-derived cell types, incorporation of aging into neuronal models, as well as robustness and automation of phenotypic assays to support quantitative drug efficacy, toxicity, and metabolism testing workflows, are covered. Continued advancement of the field is expected to help fully humanize the process of CNS drug discovery.

A review for the pharmacological effect of lycopene in central nervous system disorders.

Lycopene is an aliphatic hydrocarbon carotenoid extracted from plants like tomatoes, papayas, and watermelons. Previous studies have shown that lycopene can exert prophylactic and/or therapeutic effects in different disorders, such as heart failure and neoplasm via anti-oxidative, anti-inflammatory, and anti-proliferative activities. In the central nervous system (CNS), lycopene also has prophylactic and/or therapeutic effects in different type of disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), cerebral ischemia, epilepsy, and depression. Lycopene also improves cognition and memory ability of rodents in different pathological conditions, such as diabetes, colchicine exposure, high-fat diet (HFD), and aging. Further, lycopene can prevent neuro-toxicities induced by monosodium glutamate (MSG), trimethyltin (TMT), methylmercury (MeHg), tert-butyl hydroperoxide (t-BHP), and cadmium (Cd). In some special conditions such as ethanol addiction and haloperidol-induced orofacial dyskinesia, lycopene administration displays special therapeutic effects. Mechanisms including inhibition of oxidative stress and neuroinflammation, inhibition of neuronal apoptosis, and restoration of mitochondrial function have been shown to mediate the neuroprotective effects of lycopene. Other mechanisms, such as inhibition of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), activation of the nuclear factor erythroid 2-related factor (Nrf2) and brain-derived neurotrophic factor (BDNF) signaling, and restoration of intracellular Ca2+ homeostasis, may be also involved in the neuroprotective effect of lycopene. In hope of get a clear impression about the role of lycopene in the CNS, we summarize and discuss the pharmacological effects of lycopene as well as its possible mechanisms in CNS disorder prevention and/or therapy.

Advances in Discovery of PDE10A Inhibitors for CNS-Related Disorders. Part 1: Overview of the Chemical and Biological Research.

Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.

Melatonin, a calpain inhibitor in the central nervous system: Current status and future perspectives.

Dysregulation of neuronal Ca2+ and oxidative stress plays an important role in the activation of cysteine proteases including calpains and caspases that contribute to neuronal death. In neurodegenerative diseases, traumatic brain injury, stroke, and neuropathic pain calpain activities are markedly increased. Melatonin is a beneficial supplement in the treatment of central nervous system (CNS) disorders. Melatonin is a potent antioxidant and works as a free-radical scavenger to regulate a large number of molecular pathways, including oxidative stress, inflammation, apoptosis, and cell death under different pathological conditions. However, limited studies have evaluated the inhibitory effect of melatonin on calpains. This review summarizes the current knowledge related to the effects of melatonin on calpains in some of the common CNS disorders.

Survival and medical utilization of children and adolescents with prolonged ventilator-dependent and associated factors.

Over the course of a year, more than 20,000 patients in Taiwan require prolonged mechanical ventilation (PMV). Data from the National Health Insurance Research Database for patients between 2005 and 2011 were used to conduct a retrospective analysis on ventilator dependence. The study subjects were PMV patients aged <17 years in Taiwan. A multiple regression model employing general estimating equations was applied to investigate the factors affecting the use of medical resources by children and adolescent PMV patients. A Cox proportional hazard model was incorporated to explore the factors affecting the survival of these patients. Data were collected for a total of 1,019 children and adolescent PMV patients in Taiwan. The results revealed that the average number of outpatient visits per subject was 32.1 times per year, whereas emergency treatments averaged 1.56 times per year per subject and hospitalizations averaged 160.8 days per year per subject. Regarding average annual medical costs, hospitalizations accounted for the largest portion at NT$821,703 per year per subject, followed by outpatient care at NT$123,136 per year per subject and emergency care at NT$3,806 per year per subject. The demographic results indicated that the patients were predominately male (61.24%), with those under 1 year of age accounting for the highest percentage (36.38%). According to the Kaplan-Meier curve, the 1-year and 5-year mortality rates of the patients were approximately 32% and 47%, respectively. The following factors affecting the survival rate were considered: age, the Charlson Comorbidity Index (CCI), diagnosis type necessitating ventilator use, and whether an invasive ventilator was used. This study investigated the use of medical resources and the survival rates of children and adolescent PMV patients. The findings of this study can serve as a reference for the National Health Insurance Administration in promoting its future integrated pilot projects on ventilator dependency.

Neuroprotective potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action.

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as ß-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.

Does long term supplementation of vitamin E cause detrimental effects on the central nervous system? Morphological and histological study in experimental male Wistar rats.

AIM: Aging is attributed to neuronal loss associated with increased oxidative stress. Vitamin E, and in particular, tocotrienol are potent antioxidants, which have been shown to be neuroprotective. The main aim of the present study was to observe the effect of long term intake of vitamin E in the form of tocotrienol rich fraction (TRF) and refined, bleached, deodorized palm olein (RBDPO) on the brain of experimental rats. MATERIALS AND METHODS: Thirty male Wistar rats aged 3 months were either supplemented with TRF (dose of 200 mg/kg body weight), RBDPO (dose of 1 ml/kg body weight) or distilled water, continuously for 8 months. The animals were then examined in vivo for clinical magnetic resonance imaging (MRI) studies before being sacrificed. The brain was extracted, measured and studied for histological changes. RESULTS: The magnetic resonance imaging (MRI) scan of the lateral ventricle, cortical thickness of cingulate gyrus and hippocampus size did not show any significant changes in all three groups. The brain weight, length and width as well as histological sections of the brain showed no significant changes between the groups. CONCLUSION: It is thereby concluded that chronic consumption of vitamin E was not detrimental to the central nervous system.

Stem cell therapy: from evidence-based medicine to emotion-based medicine? The long Italian way for a scientific regulation.

On 23 May 2013, the Italian health minister decided to endorse a law regarding controversial stem cell-based therapies in 32 young terminally ill patients, shocking many scientists. According to the international scientific community, these therapies could be dangerous because they were not rigorously tested in humans. This decision was made after many days of media and judiciary pressure. Several lawsuits regarding stem cell-based therapies were brought before the judiciary districts of different Italian regions. We analyzed the Italian legal context regarding the field of pharmaceutical and medical devices, including the European Union trend. A national database - commonly used to manage legal materials for professional or educational purposes or both - was used to find relevant legal cases involving stem cell-based therapies. Stem cell-based therapies endorsed by the new Italian law have been the subject of an important discussion not only in the scientific community but also in various courts. We found several legal actions filed by parents in order to make stem cells available to their young children, who had serious neurodegenerative diseases. The majority of the analyzed legal disputes were settled in favor of the applicants, whereas only two decisions (Courts of Justice of Rome and Florence) rejected the complaint because of the absence of sufficient scientific data regarding stem cell-based therapies. The present Italian situation is influencing the destiny of future young patients and strongly impacting public and institutional opinion. It is a practical example of the complexity of the decision of not providing unapproved scientific stem cell-based therapies when medicine does not have any other alternative therapies.

Triptolide with potential medicinal value for diseases of the central nervous system.

Tripterygium wilfordii Hook.f. (TWHF) has a long history as a Traditional Chinese Medicine (TCM) herb that aids in treating inflammatory and autoimmune diseases. The major bioactive component of TWHF is triptolide, which has been recognized to possess a broad spectrum of biological profiles including antiinflammatory, immunosuppressive, antifertility, and antitumor activities, as well as neurotrophic and neuroprotective effects. Limitation of triptolide, such as poor water solubility and severe systemic toxicity, has postponed clinical development and trials; however, the wide range of medicinal value of triptolide has been drawing intensive worldwide attention. In particular, triptolide has been shown to have significant effects on central nervous system (CNS) diseases, such as Parkinson's disease, Alzheimer's disease, spinal cord and brain injury, and multiple sclerosis. This review focuses on the potential therapeutic role of triptolide on CNS diseases, and discusses the structural features, potential modifications, and the other pharmacological activities of triptolide.

Concurrent ivermectin and Solanum spp. toxicosis in a herd of horses.

BACKGROUND: Representatives from a herd of horses with acute onset of neurologic signs after administration of ivermectin presented for evaluation and treatment. OBJECTIVES: Describe clinical signs of horses intoxicated by ingestion of Solanum sp. and administered ivermectin. ANIMALS: Six of 11 affected unrelated horses presented for evaluation and treatment. The remaining 5 affected horses were treated at the farm. Four additional horses, housed separately, were unaffected. METHODS: Case series is presented. Serum ivermectin concentrations were evaluated in the 6 hospitalized horses. The remnants of the tubes of ivermectin paste were analyzed for ivermectin concentration. The hay fed to the affected horses was analyzed for the presence of toxic plants. RESULTS: Serum ivermectin concentrations were higher than expected, given the dosage of ivermectin administered. The ivermectin concentration remaining in the administration tubes did not exceed specifications. The hay was heavily contaminated by 2 Solanum species. All horses returned to normal neurologic function with supportive care. CONCLUSIONS AND CLINICAL IMPORTANCE: Horses might exhibit signs of ivermectin toxicity after appropriate dosing of the drug if they concurrently consume toxic plants of the Solanum family.

Nervous system disruption and concomitant behavioral abnormality in early hatched pufferfish larvae exposed to heavy oil.

BACKGROUND AND OBJECTIVE: Spills of heavy oil (HO) over the oceans have been proven to have an adverse effect on marine life. It has been hypothesized that exposure of early larvae of sinking eggs to HO leads largely to normal morphology, whereas abnormal organization of the developing neural scaffold is likely to be found. HO-induced disruption of the nervous system, which controls animal behavior, may in turn cause abnormalities in the swimming behavior of hatched larvae. To clarify the toxicological effects of HO, we performed exposure experiments and morphological and behavioral analyses in pufferfish (Takifugu rubripes) larvae. EXPERIMENTAL PROCEDURE: Fertilized eggs of pufferfish were exposed to 50 mg/L of HO for 8 days and transferred to fresh seawater before hatching. The hatched larvae were observed for their swimming behavior, morphological appearance, and construction of muscles and nervous system. RESULTS AND DISCUSSION: In HO-exposed larvae, we did not detect any anomaly of body morphology. However, they showed an abnormal swimming pattern and disorganized midbrain, a higher center controlling movement. Our results suggest that HO-exposed fishes suffer developmental disorder of the brain that triggers an abnormal swimming behavior and that HO may be selectively toxic to the brain and cause physical disability throughout the life span of these fishes.

Does functional electrical stimulation for foot drop strengthen corticospinal connections?

BACKGROUND: Long-term use of a foot-drop stimulator applying functional electrical stimulation (FES) to the common peroneal nerve improves walking performance even when the stimulator is off. This "therapeutic" effect might result from neuroplastic changes. OBJECTIVE: To determine the effect of long-term use of a foot-drop stimulator on residual corticospinal connections in people with central nervous system disorders. METHODS: Ten people with nonprogressive disorders (eg, stroke) and 26 with progressive disorders (eg, multiple sclerosis) used a foot-drop stimulator for 3 to 12 months while walking in the community. Walking performance and electrophysiological variables were measured before and after FES use. From the surface electromyogram of the tibialis anterior muscle, we measured the following: (1) motor-evoked potential (MEP) from transcranial magnetic stimulation over the motor cortex, (2) maximum voluntary contraction (MVC), and (3) maximum motor wave (M(max)) from stimulating the common peroneal nerve. RESULTS: After using FES, MEP and MVC increased significantly by comparable amounts, 50% and 48%, respectively, in the nonprogressive group and 27% and 17% in the progressive group; the changes were positively correlated (R(2) = .35; P < .001). Walking speed increased with the stimulator off (therapeutic effect) by 24% (P = .008) and 7% (P = .014) in the nonprogressive and progressive groups, respectively. The changes in M(max) were small and not correlated with changes in MEP. CONCLUSIONS: The large increases in MVC and MEP suggest that regular use of a foot-drop stimulator strengthens activation of motor cortical areas and their residual descending connections, which may explain the therapeutic effect on walking speed.

Matrix metalloproteinases (MMPs) in health and disease: an overview.

Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion in their active site for catalytic activity. MMPs are critical for maintaining tissue allostasis. MMPs are active at neutral pH and can therefore catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as the interstitial and basement membrane collagens, proteoglycans such as aggrecan, decorin, biglycan, fibromodulin and versican as well as accessory ECM proteins such as fibronectin. Members of the MMP family include the "classical" MMPs, the membrane-bound MMPs (MT-MMPs) the ADAMs (a disintegrin and metalloproteinase; adamlysins) and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif). There are more than 20 members in the MMP and ADAMTS family including the collagenases, gelatinases, stromelysins, some elastases and aggrecanases. Adamlysins are membrane-bound MMPs that also degrade aggrecan, but more importantly, one ADAM family member (i.e.ADAM-17) is a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) that activates pro-TNF-alpha. Most of the MMPs are synthesized as inactive latent enzymes. Conversion to the active enzyme is generally mediated by activator systems that include plasminogen activator or the pro-hormone convertase, furin. MMP activity is regulated by a group of endogenous proteins, called, tissue inhibitor of metalloproteinases (TIMPs) that bind to active and alternative sites of the activated MMP. Significant advances have occurred in the understanding of the regulation of MMPs, ADAMs and ADAMTSs gene expression. In addition, development of MMP inhibitors to study MMP structure/function relationships spawned many studies to determine the effectiveness of MMP inhibitors in regulating abnormal connective tissue turnover. In addition, development of MMP null mice carrying specific MMP deletions has provided an opportunity to explore the role of MMPs in normal development as well as in such diverse conditions and diseases as skeletal dysplasias, coronary artery and heart disease, arthritis, cancer, and brain disorders.

Hyperbaric oxygen reduces delayed immune-mediated neuropathology in experimental carbon monoxide toxicity.

The goal of this investigation was to determine whether exposure to hyperbaric oxygen (HBO(2)) would ameliorate biochemical and functional brain abnormalities in an animal model of carbon monoxide (CO) poisoning. In this model, CO-mediated oxidative stress causes chemical alterations in myelin basic protein (MBP), which initiates an adaptive immunological response that leads to a functional deficit. CO-exposed rats do not show improvements in task performance in a radial maze. We found that HBO(2) given after CO poisoning will prevent this deficit, but not eliminate all of the CO-mediated biochemical alterations in MBP. MBP from HBO(2) treated CO-exposed rats is recognized normally by a battery of antibodies, but exhibits an abnormal charge pattern. Lymphocytes from HBO(2)-treated and control rats do not become activated when incubated with MBP, immunohistological evidence of microglial activation is not apparent, and functional deficits did not occur, unlike untreated CO-exposed rats. The results indicate that HBO(2) prevents immune-mediated delayed neurological dysfunction following CO poisoning.

Chronic arsenic toxicity in Bangladesh and West Bengal, India--a review and commentary.

Fifty districts of Bangladesh and 9 districts in West Bengal, India have arsenic levels in groundwater above the World Health Organization's maximum permissible limit of 50 microg/L. The area and population of 50 districts of Bangladesh and 9 districts in West Bengal are 118,849 km2 and 104.9 million and 38,865 km2 and 42.7 million, respectively. Our current data show arsenic levels above 50 microg/ L in 2000 villages, 178 police stations of 50 affected districts in Bangladesh and 2600 villages, 74 police stations/blocks of 9 affected districts in West Bengal. We have so far analyzed 34,000 and 101,934 hand tube-well water samples from Bangladesh and West Bengal respectively by FI-HG-AAS of which 56% and 52%, respectively, contained arsenic above 10 microg/L and 37% and 25% arsenic above 50 microg/L. In our preliminary study 18,000 persons in Bangladesh and 86,000 persons in West Bengal were clinically examined in arsenic-affected districts. Of them, 3695 (20.6% including 6.11% children) in Bangladesh and 8500 (9.8% including 1.7% children) in West Bengal had arsenical dermatological features. Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. The time of onset depends on the concentration of arsenic in the drinking water, volume of intake, and the health and nutritional status of individuals. Major dermatological signs are diffuse or spotted melanosis, leucomelanosis, and keratosis. Chronic arsenicosis is a multisystem disorder. Apart from generalized weakness, appetite and weight loss, and anemia, our patients had symptoms relating to involvement of the lungs, gastrointestinal system, liver, spleen, genitourinary system, hemopoietic system, eyes, nervous system, and cardiovascular system. We found evidence of arsenic neuropathy in 37.3% (154 of 413 cases) in one group and 86.8% (33 of 38 cases) in another. Most of these cases had mild and predominantly sensory neuropathy. Central nervous system involvement was evident with and without neuropathy. Electrodiagnostic studies proved helpful for the diagnosis of neurological involvement. Advanced neglected cases with many years of exposure presented with cancer of skin and of the lung, liver, kidney, and bladder. The diagnosis of subclinical arsenicosis was made in 83%, 93%, and 95% of hair, nail and urine samples, respectively, in Bangladesh; and 57%, 83%, and 89% of hair, nail, and urine samples, respectively in West Bengal. Approximately 90% of children below 11 years of age living in the affected areas show hair and nail arsenic above the normal level. Children appear to have a higher body burden than adults despite fewer dermatological manifestations. Limited trials of 4 arsenic chelators in the treatment of chronic arsenic toxicity in West Bengal over the last 2 decades do not provide any clinical, biochemical, or histopathological benefit except for the accompanying preliminary report of clinical benefit with dimercaptopropanesulfonate therapy. Extensive efforts are needed in both countries to combat the arsenic crisis including control of tube-wells, watershed management with effective use of the prodigious supplies of surface water, traditional water management, public awareness programs, and education concerning the apparent benefits of optimal nutrition.

Proton magnetic resonance spectroscopy ((1)H-MRS) of the brain following high-dose methotrexate treatment for childhood cancer.

BACKGROUND: To avoid the late sequelae associated with cranial radiation therapy in childhood, intermediate- or high-dose intravenous methotrexate (HDMTX) has found increasing application as a means of preventing the development of overt central nervous system disease in childhood acute leukaemia. However, acute and chronic neurotoxicity has been described following HDMTX therapy, and the long-term intellectual outcome in children treated in this way is inadequately documented. Proton magnetic resonance spectroscopy ((1)H-MRS) of the brain is a noninvasive, quantitative way of assessing aspects of cerebral metabolism, which has not previously been applied to the study of children undergoing central nervous system directed therapy. PROCEDURE: To evaluate the potential role of (1)H-MRS in the investigation of related neurotoxicity, 11 children who had received HDMTX (cumulative dose 6-96 g/m(2)) underwent localised (1)H-MRS, magnetic resonance imaging. Neuropsychological assessments were performed on the children who had more than 1 year of follow-up time since last methotrexate treatment. Control (1)H-MRS studies on 11 adult and 6 young volunteers were undertaken. Eight patients had spectra of adequate quality. Comparisons between (1)H-MRS metabolite ratios and normal controls were made. RESULTS: Patients had a low choline/water ratio compared to controls (P < 0.01). No differences between patient and control NAA/water, Cr/water, Naa/Cr, and Cho/Cr ratios were seen. Overall, 3 patients had abnormal white matter changes on MRI. The mean IQ of the patients (104.1) was in the normal range. CONCLUSIONS: It is postulated that choline depletion in the brains of these patients may reflect subclinical disturbances of myelin metabolism as a result of methotrexate therapy and may represent a possible avenue of treatment in patients with clinical chronic methotrexate-related neurotoxicity.