Cerebrospinal and blood levels of amino acids as potential biomarkers for Parkinson's disease: review and meta-analysis.

BACKGROUND AND PURPOSE: The present systematic review and meta-analysis aims to establish the possible value of cerebrospinal fluid (CSF) and serum/plasma levels of amino acids as markers of Parkinson's disease (PD). METHODS: This is a review of four databases (PubMed, Embase, MEDLINE and Web of Science - Core Collection) from 1966 to 14 March 2020, with identification of references of interest for the topic. The meta-analysis of eligible studies was done using R software package meta, following the PRISMA and MOOSE guidelines. RESULTS: Compared with age- and sex-matched controls, PD patients showed decreased CSF levels of glutamate and taurine and increased CSF levels of tyrosine; decreased serum/plasma levels of aspartate, serine, tryptophan and lysine, and increased serum/plasma proline and homocysteine levels. CONCLUSION: Despite the limitations of this study due to the important variability of results between different series, our findings suggest the value of CSF or serum/plasma levels of several amino acids in the discrimination of PD patients from healthy subjects, related to the levels of some amino acids.

Fungal infection in cerebrospinal fluid from some patients with multiple sclerosis.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system and spinal cord, leading to axonal demyelination of neurons. Recently, we have found a correlation between fungal infection and MS in peripheral blood of patients. The present work provides evidence of fungal infection in the cerebrospinal fluid (CSF) of some MS patients. Thus, fungal antigens can be demonstrated in CSF, as well as antibodies reacting against several Candida species. Comparison was made between CSF and blood serum for the presence of fungal antigens (proteins) and antibodies against different Candida spp. Analyses of both CSF and serum are complementary and serve to better evaluate for the presence of disseminated fungal infection. In addition, PCR analyses indicate the presence of DNA from different fungal species in CSF, depending on the patient analyzed. Overall, these findings support the notion that fungal infection can be demonstrated in CSF from some MS patients. This may constitute a risk factor in this disease and could also help in understanding the pathogenesis of MS.

Update on genetics of essential tremor.

Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case-control association studies, and exome sequencing in familial ET.

Spontaneous intracranial hypotension syndrome treated with a double epidural blood patch.

Spontaneous intracranial hypotension (SIH) is considered to be a very rare disease. It is characterised by an orthostatic headache in the absence of a past history of a trauma or a dural puncture. SIH is caused by a spontaneous spinal cerebrospinal fluid (CSF) leakage demonstrated by neuroradiological studies in most of the patients. Conservative treatment usually includes bed rest, hydration and administration of caffeine or steroids. However, when the patient is refractory to the conservative treatment, an epidural blood patch (EBP) is performed. We report a 34-year-old woman with SIH and no neuroradiologically demonstrable clear point of CSF leakage, who was treated with a double EBP at two different levels (lumbar and thoracic) in the same procedure. The patient was successfully managed, and she was still asymptomatic at the 18 months follow-up. After review of literature, we observed that execution of a double EBP at the same time is not a common procedure for treatment of SIH. We consider that simultaneous use of two EBP could be useful as a novel treatment in those cases of SIH without demonstration of CSF leakage.

[Cadmium polyneuropathy: a rare, but not less important, cause of peripheral neuropathy]. / Polineuropatía por cadmio: una causa infrecuente, pero no menos importante, de neuropatía periférica.

INTRODUCTION: Cadmium is an important heavy metal in neurobiology, with potential neurotoxic effects, often in the form of polyneuropathy (PNP). CASE REPORT: We present an exceptional case of PNP due to cadmium of toxic-occupational origin, specifically a 47-year-old man, aeronautical mechanic, with a 5-year clinical picture, consisting of a tingling sensation having a 'glove and stocking' distribution of symptoms and bimanual manipulative clumsiness. The neurological examination revealed bilateral achilles hyporeflexia and protopathic-thermal-algesic exteroceptive hypoesthesia in hands and feet. The following complementary rests were requested: toxic-metabolic-infectious-vitamin profile, full craniospinal MRI, electroneurographic-electromyographic study (ENG-EMG) of the upper and lower limbs, PET-CT body and 24-hour video-electroencephalogram. The results were consistent with an axonal, distal, symmetric sensory-motor PNP, of moderate intensity, chronic evolution, with active denervation, of toxic-occupational origin due to cadmium. The patient continued on sick leave to cease exposure to cadmium, initiating intensive multimodal neurorehabilitation program, with serial analytical determinations of toxins and new ENG-EMG studies every 6 months. With normalization of the altered values ??and complete clinical restitution at one-year follow-up. CONCLUSIONS: This case highlights the importance of including the toxicological determination of cadmium in case of suspicion of a PNP of toxic-occupational origin, once ruled out other etiologies, in order to early interrupt occupational exposure, as it is a potentially reversible cause of peripheral neuropathy. Currently there is no specific pharmacological treatment against cadmium tested in humans. Randomized clinical trials carried out in these patients are warranted to develop an anti-cadmium drug in refractory cases despite the end of exposure.

TITLE: Polineuropatía por cadmio: una causa infrecuente, pero no menos importante, de neuropatía periférica.Introducción. El cadmio es un metal pesado importante en neurobiología, con potenciales efectos neurotóxicos, frecuentemente en forma de polineuropatía. Caso clínico. Presentamos un caso excepcional de polineuropatía por cadmio de origen tóxico-ocupacional, en concreto, un varón de 47 años, mecánico aeronáutico, con un cuadro de cinco años de evolución, consistente en sensación de hormigueo 'en guante y calcetín' y torpeza manipulativa bimanual. En la exploración destacaba una hiporreflexia aquílea bilateral, y una hipoestesia exteroceptiva protopático-térmico-algésica en las manos y los pies. Se solicitó analítica general completa con perfil tóxico-metabólico-infeccioso-vitamínico, resonancia magnética craneomedular completa, estudio electroneurográfico-electromiográfico de los miembros superiores e inferiores, tomografía por emisión de positrones-tomografía axial computarizada body y videoelectroencefalograma de 24 horas. Los resultados fueron compatibles con una polineuropatía sensitivomotora axonal, distal, simétrica, de intensidad moderada, de evolución crónica y desnervación activa, de origen tóxico-ocupacional por cadmio. El paciente prosiguió la baja laboral para cesar la exposición al cadmio, iniciando neurorrehabilitación intensiva multimodal, y determinaciones analíticas seriadas de tóxicos y nuevos estudios electroneurográficos-electromiográficos cada seis meses, con normalización de los valores alterados y restitución clínica ad integrum al año. Conclusiones. Este caso enfatiza la importancia de incluir la determinación toxicológica del cadmio ante la sospecha de una polineuropatía de origen tóxico-ocupacional, descartadas otras etiologías, para interrumpir precozmente dicha exposición laboral, al ser una causa potencialmente reversible de neuropatía periférica. Actualmente no existe un tratamiento farmacológico específico frente al cadmio demostrado en seres humanos. Urgen ensayos clínicos aleatorizados en estos pacientes, para desarrollar un fármaco frente al cadmio en casos refractarios pese a finalizar la exposición.

Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor.

BACKGROUND: Essential tremor (ET) is a frequent movement disorder with a substantial family aggregation. A genome-wide association study has recently shown that LINGO1 gene variants are associated with increased risk of ET. METHODS: We intended to replicate these findings by genotyping rs9652490 and rs11856808 in a series of 226 familial ET subjects and 1117 healthy controls from referral movement disorder clinics in Spain. RESULTS: We were unable to replicate the association between LINGO1 variants and familial ET. CONCLUSIONS: Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.

[Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): cardiac patient]. / Recomendaciones para el soporte nutricional y metabólico especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: paciente cardíaco.

Patients with cardiac disease can develop two types of malnutrition: cardiac cachexia, which appears in chronic congestive heart failure, and malnutrition due to the complications of cardiac surgery or any other type of surgery in patients with heart disease. Early enteral nutrition should be attempted if the oral route cannot be used. When cardiac function is severely compromised, enteral nutrition is feasible, but supplementation with parenteral nutrition is sometimes required. Sustained hyperglycemia in the first 24 hours in patients admitted for acute coronary syndrome, whether diabetic or not, is a poor prognostic factor for 30-day mortality. In critically-ill cardiac patients with stable hemodynamic failure, nutritional support of 20-25 kcal/kg/day is effective in maintaining adequate nutritional status. Protein intake should be 1.2*-1.5 g/kg/day. Routine polymeric or high protein formulae should be used, according to the patient's prior nutritional status, with sodium and volume restriction according to the patient's clinical situation. The major energy source for myocytes is glutamine, through conversion to glutamate, which also protects the myocardial cell from ischemia in critical situations. Administration of 1 g/ day of omega-3 (EPA+DHA) in the form of fish oil can prevent sudden death in the treatment of acute coronary syndrome and can also help to reduce hospital admission for cardiovascular events in patients with chronic heart failure.

[Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): acute renal failure]. / Recomendaciones para el soporte nutricional y metabólico especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: insuficiencia renal aguda.

Nutritional support in acute renal failure must take into account the patient's catabolism and the treatment of the renal failure. Hypermetabolic failure is common in these patients, requiring continuous renal replacement therapy or daily hemodialysis. In patients with normal catabolism (urea nitrogen below 10 g/day) and preserved diuresis, conservative treatment can be attempted. In these patients, relatively hypoproteic nutritional support is essential, using proteins with high biological value and limiting fluid and electrolyte intake according to the patient's individual requirements. Micronutrient intake should be adjusted, the only buffering agent used being bicarbonate. Limitations on fluid, electrolyte and nitrogen intake no longer apply when extrarenal clearance techniques are used but intake of these substances should be modified according to the type of clearance. Depending on their hemofiltration flow, continuous renal replacement systems require high daily nitrogen intake, which can sometimes reach 2.5 g protein/kg. The amount of volume replacement can induce energy overload and therefore the use of glucose-free replacement fluids and glucose-free dialysis or a glucose concentration of 1 g/L, with bicarbonate as a buffer, is recommended. Monitoring of electrolyte levels (especially those of phosphorus, potassium and magnesium) and of micronutrients is essential and administration of these substances should be individually-tailored.

Dopamine receptor 3 (DRD3) polymorphism and risk for migraine.

BACKGROUND/OBJECTIVES: Dopamine has been implicated in the pathogenesis of migraine. We investigated the possible association between the polymorphism 312G>A (rs6280) in the DRD3 gene(essential tremor 1-ETM1- locus, chromosome 3q13) and the risk for migraine and for triggering migraine attacks by alcohol. METHODS: We studied the frequency of the DRD3 genotypes and allelic variants in 197 patients with migraine and 282 healthy controls using a polymerase chain reaction and MlsI-restriction fragment length polymorphisms method. RESULTS: The frequencies of the DRD3 genotypes and DRD3Gly9 were similar in patients with migraine and controls and were unrelated to the age of onset of migraine, gender, family history of migraine and triggering of migraine attacks by alcohol. The frequency of the genotype DRD3Gly9Gly9 was significantly higher in patients with migraine with aura when compared with patients with migraine without aura, but not with controls. CONCLUSION: DRD3 genotype and allelic variants were not related to the risk for migraine in Caucasian Spanish people.

Impairment of rapid repetitive finger movements and visual reaction time in patients with essential tremor.

BACKGROUND AND PURPOSE: The question whether patients with essential tremor (ET) have slowed movements as part of their clinical manifestations is still a matter of controversy. We analyzed basic motor function in patients with ET and in healthy matched controls. METHODS: We studied 61 patients with ET and 122 age- and sex-matched controls. Evaluation included four timed tests (pronation-supination, finger tapping and movement between two points, all with both hands, and walking test); and three tests performed on a personal computer (speed for pressing repetitively a key - frequency, visual reaction time and movement time, all with both hands). RESULTS: Essential tremor patients showed higher mean values for right and left finger tapping, left movement between two points; and with right and left frequency and reaction time. In the logistic regression study, ET patients showed significantly higher values than controls for right and left finger tapping; mean, SD, maximum and rank values of right and left frequency; and mean, SD, minimum, maximum and rank values of right and left visual reaction time. Tremor severity was not correlated with the altered values. CONCLUSIONS: Patients with ET showed impaired motor performance, at least in some tasks, such as rapid repetitive finger movements (finger tapping and frequency) and visual reaction time (impairment was not related with tremor severity). This probably means that patients with ET have some degree of bradykinesia.

Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis.

BACKGROUND: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine (a mediator of inflammation implicated in the pathogenesis of multiple sclerosis-MS) in the CNS. We have investigated the possible association between a single nucleotide polymorphism of the HNMT (chromosome 2q22.1), that causes the amino acid substitution Thr105Ile (decreasing enzyme activity) and the risk for MS. METHODS: We studied the frequency of the HNMT genotypes and allelic variants in 228 MS patients and 295 healthy controls using a PCR-RLFP method. RESULTS: The frequencies of the HNMT genotypes and allelic variants did not differ significantly between MS patients and controls, and were unrelated with the age of onset of MS, gender, and course of MS. CONCLUSION: The HNMT polymorphism is not related with the risk for MS.

Paraoxonase 1 (PON1) polymorphisms and risk for essential tremor.

BACKGROUND: The polymorphic enzyme human serum paraoxonase 1 (PON1), encoded by the gene PON1 (chromosome 7q21.3), plays a major role in the metabolism of organophosphorus compounds. We investigated the possible association between the PON1 genotype and allelic variants of the polymorphisms Leu55Met and Glu192Arg, and the risk for essential tremor (ET). METHODS: We studied the frequency of the PON1 genotypes and allelic variants in 201 patients with ET and 220 healthy controls using a PCR-RLFP method. RESULTS: The frequencies of the PON1 genotypes and allelic variants of the polymorphisms Leu55Met and Gln192Arg did not differ significantly between patients with ET and controls. These polymorphisms were unrelated with the age of onset of ET. CONCLUSIONS: PON1 polymorphisms are not related with the risk for ET.

Glutathione-S-transferase P1 polymorphism and risk for essential tremor.

Glutathione-S-transferases (GST) are polymorphic enzymes that participate in the metabolism of carcinogens (including those of tobacco smoke) and pesticides. We investigated the possible association between the GSTP1 genotype and allelic variants and the risk for essential tremor (ET). We studied the frequency of the GSTP1 genotypes and allelic variants in 200 patients with ET and 220 healthy controls using PCR-RFLP method. The association between GSTP1 polymorphism and the exposure to some environmental factors (agricultural work, pesticides, well-water and smoking-cigarettes habit) was also studied in a subgroup of patients. The frequencies of the GSTP1 genotypes and allelic variants did not differ significantly between patients with ET and controls or between patients with ET exposed to agricultural work, well water and cigarette smoking versus those non-exposed. Mutated allelic variants were significantly more frequent in patients with ET exposed to pesticides versus those non-exposed. GSTP1 polymorphism was unrelated with the age of onset of ET. GSTP1 genotypes and allelic variants were not related with the risk for ET with the possible exception of those patients exposed to pesticides.

[Oxidative stress and Alzheimer's disease]. / Estrés oxidativo y enfermedad de Alzheimer.

INTRODUCTION: According to the oxidative stress hypothesis, the pathogenesis of several diseases should be related with an excessive production of prooxidant substances (free radicals, transition metals), the deficiency of antioxidant defensive mechanisms, or both. Oxidative stress has been implicated in the pathogenesis of aging of the brain and several neurological diseases, including Alzheimer's disease (AD). DEVELOPMENT: In recent years there are many data suggesting a possible role of oxidative stress in the pathogenesis of AD. These include the demonstration of increased oxidation of lipids, proteins and deoxyribonucleic acid, alterations in mitochondrial function and the possible role of amyloid beta and its precursor protein in the oxidative reactions in experimental models (cortical neuronal cultures and transgenic animals). CONCLUSIONS: Many studies show increased oxidative stress in the brain of patients with AD, although its possible role con the pathogenesis of this disease are controversial.

[The neurochemistry and neuropharmacology of diffuse Lewy body disease]. / Neuroquímica y neurofarmacología de la enfermedad difusa de cuerpos de Lewy.

INTRODUCTION AND DEVELOPMENT: The main neurochemical alteration in diffuse Lewy body disease (DLBD) is the cholinergic deficit in the cerebral cortex, which involves mainly cholin-acetyl-transferase. There have been also described dopamine deficiency and alterations affecting other neurotransmitters and neuromodulators, such as serotonin, noradrenaline, neuropeptides, etc. Cerebral perfusion and glucose metabolism studies usually show diffuse hypoperfusion or hypometabolism, with higher alteration of associative cortex, including occipital involvement. Several studies have shown increased markers of oxidative stress in brain and other tissues, suggesting its possible role in the pathogenesis of DLBD. CONCLUSIONS: Acetylcholinesterase inhibitors seem to improve cognitive and conductual symptoms, although their usefulness according evidence-based medicine criteria is weak. Some patients need atypical neuroleptics at low doses to get the symptomatic control of conductual alterations.

[The neurochemistry and neuropharmacology of frontotemporal dementia]. / Neuroquimica y neurofarmacologia de la demencia frontotemporal.

AIM: To review the neurochemical features and therapeutic options for frontotemporal dementia (FTD). DEVELOPMENT: The main neurochemical alterations in FTD are the serotoninergic and dopamine depletion. In contrast with Alzheimer's and diffuse Lewy bodies disease, there are not significant alterations of the cholinergic system. Cerebral perfusion and glucose metabolism studies usually show hypoperfusion or hypometabolism, with predominant involvement of temporal and frontal cortices. There have been described some alterations related with oxidative stress and apoptosis, although its pathogenetic role in FTD is not well known. Treatment of FTD is not well established, because there are only a few studies with some drugs. The most studied drugs are serotonin reuptake inhibitors, however, despite the well-known serotoninergic deficiency described in FTD, the results are not conclusive. CONCLUSIONS: The main neurochemical alterations of FTD are serotoninergic and dopaminergic deficiencies. The treatment is not well established, although it should be theoretically ideal to use drugs which modulate these neurotransmitter systems.

[Neurotoxic effects induced by the topical administration of cycloplegics. A case report and review of the literature]. / Efectos neurotóxicos inducidos por administración tópica de ciclopléjicos. Caso clínico y revisión de la bibliografía.

INTRODUCTION: We report a patient who developed an acute confusional state with hallucinations after exposure to cycloplejic eye drops, and review the current literature regarding neurotoxicity due to this type of eye drops. CASE REPORT: A 61 year-old man who developed in two occasions confusion, disorientation and vivid visual hallucinations following exposure to a cyclopejic eye drop containing atropine 2%, scopolamine 0.5% and phenylephrine 4%. We performed a literature search regarding neurological complications of cycloplegic eye drops using the PubMed Database and the services of the Virtual Library 'Agencia Lain Entralgo'. The clinical features of all reports in which the original document was obtained are analyzed and summarized. We have summarized the clinical features of 29 patients with neurotoxicity due to cyclopentolate, 19 to atropine, 18 to scopolamine, 7 to homatropine, and 2 to tropicamide. Our patient should be the fourth reported in Spain, being the offending drug in the four cases the same eye drop. The most commonly reported symptoms are visual hallucinations, behavioral disorders/acute psychosis, alterations of consciousness/confusion, restlessness/hyperactivity, ataxia and speech disorders. Many of the patients reported are children and elder. There have been reported some fatal cases, specially related with atropine. CONCLUSIONS: Neurotoxicity related with anticholinergic effects of cycloplegic agents is not infrequent, although it is not well known in our setting; and can cause death in some cases. Exposure to these drugs should be taken in account in the differential diagnosis of acute confusional syndromes.

Acinetobacter baumannii ventilator-associated pneumonia: epidemiological and clinical findings.

OBJECTIVE: To investigate prognostic factors and predictors of Acinetobacter baumannii isolation in ventilator-associated pneumonia (VAP). We specifically analyzed these issues for imipenem-resistant episodes. DESIGN AND SETTING: All episodes of VAP are prospectively included in a database. Information about risk factors was retrieved retrospectively. PATIENTS: Eighty-one patients exhibiting microbiologically documented VAP: 41 by A. baumannii (26 by imipenem-resistant) and 40 by other pathogens. MEASUREMENTS AND RESULTS: The following variables were noted: underlying diseases, severity of illness, duration of mechanical ventilation and of hospitalization before VAP, prior episode of sepsis, previous antibiotic, corticosteroid use, type of nutrition, renal replacement therapy, reintubation, transportation out of the ICU, micro-organisms involved in VAP, concomitant bacteremia, clinical presentation, Sequential Organ Failure Assessment (SOFA) scale on the day of diagnosis, and adequacy of empirical antibiotic therapy. Prior antibiotic use was found to be associated with development of VAP by A. baumannii (OR 14). Prior imipenem exposure was associated with the isolation of imipenem-resistant strains (OR 4). SOFA score on the day of diagnosis was the only predictor of in-hospital mortality (OR 1.22); adequacy of empirical antibiotic therapy was a protective factor (OR 0.067). CONCLUSIONS: Our results confirm that prior exposure to antimicrobials is an independent predictor for the development of A. baumannii VAP, the prognosis of which is similar to that of infections caused by other pathogens. This study highlights the importance of initial antibiotic choice in VAP or whatever cause.