Mutations in the John Cunningham virus VP1 gene could predispose to the development of progressive multifocal leukoencephalopathy in multiple sclerosis patients undergoing treatment with natalizumab.

BACKGROUND: Patients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management. OBJECTIVE: To identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index. METHODS: Eighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples. RESULTS: In MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G â†’ C), leading to an amino acid change (Lys â†’ Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection. CONCLUSIONS: . The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN.

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of (-1.0_{-1.1}^{+0.9}) eV^{2}. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation.

[Comparison of neuromyelitis optica spectra according to AQP4 antibody serostatus in a Mexican referral centre]. / Comparacion de los espectros de neuromielitis optica segun el seroestado del anticuerpo AQP4 en un centro de referencia mexicano.

INTRODUCTION: Recent studies report that patients with neuromyelitis optica (NMO) or seropositive NMO spectra disorders display clinical characteristics that are different from those of patients who are seropositive for the aquaporin-4 (AQP4) antibody. AIM: To analyse the clinical and paraclinical characteristics of patients with NMO according to their serum AQP4 status. PATIENTS AND METHODS: We conducted a retrospective study of 100 patients with NMO who fulfilled the Wingerchuk criteria: 70 were positive for the AQP4 antibody and 30 were seronegative. RESULTS: 70% of the subjects met the criteria for NMO, and 30% met criteria for NMO spectra disorders. The seropositive patients presented greater disability in the scores on the American Spinal Injury Association scale (ASIA) and the Expanded Disability Status Scale (p = 0.034 and 0.004, respectively) compared to seronegatives during the follow-up; in this same group there was greater visual involvement (p = 0.02), a higher number of relapses (p = 0.008) and a greater number of spinal segments involved (p = 0.003). CONCLUSION: This study provides an overview of the clinical and paraclinical characteristics of patients with NMO according to the AQP4 antibody serostatus. Patients who are seropositive for the AQP4 antibody present greater clinical and imaging involvement.

TITLE: Comparacion de los espectros de neuromielitis optica segun el seroestado del anticuerpo AQP4 en un centro de referencia mexicano.Introduccion. Estudios recientes describen que los pacientes con neuromielitis optica (NMO) o trastornos del espectro de NMO seronegativos exhiben caracteristicas clinicas diferentes a los pacientes seropositivos al anticuerpo acuaporina-4 (AQP4). Objetivo. Analizar las caracteristicas clinicas y paraclinicas de pacientes con NMO segun el estado serico del anticuerpo AQP4. Pacientes y metodos. Estudio retrospectivo de 100 pacientes con NMO que cumplian los criterios de Wingerchuk: 70 presentaron positividad al anticuerpo AQP4 y 30 fueron seronegativos. Resultados. Un 70% de los sujetos cumplio los criterios para la NMO, y un 30%, para los trastornos del espectro de NMO. Los pacientes seropositivos presentaron mayor discapacidad en las puntuaciones de la escala de la Asociacion Americana de Lesion de la Medula Espinal (ASIA) y la escala ampliada del estado de discapacidad (p = 0,034 y 0,004, respectivamente) comparados con los seronegativos durante el seguimiento; en este mismo grupo hubo mayor afectacion visual (p = 0,02), mayor numero de recaidas (p = 0,008) y mayor numero de segmentos medulares afectados (p = 0,003). Conclusion. Este estudio proporciona una vision general de las caracteristicas clinicas y paraclinicas de los pacientes con NMO segun el seroestado del anticuerpo AQP4. Los pacientes seropositivos al anticuerpo AQP4 presentan mayor afectacion clinica e imaginologica.

[The influence of Spanish neuropsychiatry on the improbable medicine of Ramon Gomez de la Serna]. / Influencia de la neuropsiquiatria española en la medicina inverosimil de Ramon Gomez de la Serna.

INTRODUCTION: El doctor inverosimil (The Improbable Doctor) is a novel by Ramon Gomez de la Serna (1888-1963) in which the reader follows, by means of a series of different clinical cases, the adventures of Doctor Vivar. AIMS: To present and discuss, for the first time, the influence that Spanish neuropsychiatry had on this novel, taking the following short stories as study models: 'Casos cerebrales' ('Brain Cases') and 'La risita' ('The Giggles'). DEVELOPMENT: In these two tales, the improbable doctor embodies the three defining elements of Spanish neuropsychiatry. The repetitions of Alzheimer's disease (or in the way in which progressive general paralysis is referred to) hints at its Germanic orientation. The mixed neuropsychiatric component is exemplified in both his neurological ('La risita') and psychiatric skills ('Casos cerebrales'). Doctor Vivar's affinity to things histopathological is apparent in his wide and timely usage of neurohistological terminology, mainly from Cajal. CONCLUSIONS: It can be deduced that the Spanish neuropsychiatric school had a strong influence on Gomez de la Serna's El doctor inverosimil.

TITLE: Influencia de la neuropsiquiatria española en la medicina inverosimil de Ramon Gomez de la Serna.Introduccion. El doctor inverosimil es una novela de Ramon Gomez de la Serna (1888-1963) donde seguimos, a traves de diversos casos clinicos, las andanzas del doctor Vivar. Objetivo. Presentar y discutir, por primera vez, el influjo que tuvo la neuropsiquiatria española en esta novela, tomando como modelos de estudio los siguientes relatos: 'Casos cerebrales' y 'La risita'. Desarrollo. En este par de relatos, el doctor inverosimil encarna los tres elementos definitorios de la neuropsiquiatria española. En sus repeticiones de la enfermedad de Alzheimer (o en la forma en que se refiere a la paralisis general progresiva) insinua su orientacion germanica. El componente mixto neuropsiquiatrico esta ejemplificado en su destreza tanto neurologica ('La risita') como psiquiatrica ('Casos cerebrales'). La afinidad histopatologica del doctor Vivar es evidente en su amplio y oportuno uso de la terminologia neurohistologica, principalmente la cajaliana. Conclusiones. Es valido deducir que hay una influencia notoria de la escuela neuropsiquiatrica española en El doctor inverosimil de Gomez de la Serna.

Migration of components from cork stoppers to food: challenges in determining inorganic elements in food simulants.

The inorganic elements potentially migrating from cork to a food simulant [a hydroalcoholic solution containing 12 and 20% (v/v) ethanol] have been determined by means of inductively coupled plasma (ICP) with atomic emission and mass spectrometric detection. The experimental instrumental conditions were evaluated in depth, taking into account spectroscopic and nonspectroscopic interference caused by the presence of ethanol and other components in the sample. We report concentrations ranging from 4 µg kg(-1) for Cd to 28000 µg kg(-1) for Al in the food simulant (concentrations given in kilograms of cork). The values found for Ba, Mn, Fe, Cu, and Zn have been compared with the guideline values stated in EU Regulation 10/2011. In all cases, cork met the general safety criteria applicable to food contact material. Finally, we have proposed water as an alternative to the hydroalcoholic solution to simplify quantification of the tested elements using ICP techniques.

The epidemiology of multiple sclerosis in Latin America and the Caribbean: a systematic review.

The incidence and prevalence of multiple sclerosis (MS) varies geographically as shown through extensive epidemiological studies performed mainly in developed countries. Nonetheless, scant data is available in Latin America and the Caribbean (LAC). The objective of this review is to assess epidemiological data of MS in LAC. We conducted a systematic review of published articles and gray literature from January 1995 to May 2011. Twenty-two studies met the inclusion criteria after full-text review. Incidence data were found in only three studies and ranged from 0.3 to 1.9 annual cases per 100,000 person-years. Prevalence was reported in 10 studies and ranged from 0.83 to 21.5 cases per 100,000 inhabitants. The most prevalent subtype of MS was the relapsing-remitting form (48% to 91% of the series). No data about mortality were found. This study showed low frequency for MS in LAC compared with North American and European countries. The role of environmental and genetic factors should be well studied, providing new insights about its etiology.

Relationship between the type and side of motor symptoms with the prevalence of non-motor symptoms in Parkinson's disease.

INTRODUCTION: the relationship between laterality and asymmetry of Parkinson's disease and non-motor dysfunction has been studied mainly from the perspective of cognitive functions, and the few studies that have included other symptoms have mixed reports. The relationship between non-motor symptoms and the type of onset of the disease has not been studied in detail. OBJECTIVE: to analyse the association between the side and type of motor onset and the prevalence of non-motor symptoms. PATIENTS AND METHODS: we included 232 patients diagnosed with Parkinson's disease. Type of onset and the side initially affected were documented. The presence of non-motor symptoms was determined by applying the non-motor symptom questionnaire (NMSQuest). RESULTS: when analysing the side of onset and presence of each non-motor symptom explored, statistically significant differences were found in the frequency of hallucinations (P=0.04) and sleep behaviour disorder (P<0.01) in subjects with right side onset. The motor type of onset differences were not statistically significant. CONCLUSIONS: subjects with right side onset seem to have a higher risk of having hallucinations and sleep behaviour disorders. These symptoms should be intentionally sought in order to provide treatment and improve the patient's quality of life.

Mediterranean and Amerindian MHC class II alleles are associated with multiple sclerosis in Mexicans.

OBJECTIVES: Human leukocyte antigen (HLA)-DRB1, DQA1, DQB1 allele typing was performed in Mexicans Mestizos with multiple sclerosis (MS) to define the HLA class II alleles associated with the disease in this population. METHODS: Patients (n = 51) diagnosed according to the Poser criteria and a group of 173 unrelated healthy subjects were studied. PCR-SSOP and PCR-SSP were used for genotyping. RESULTS: Fifty five percent of the patients were females. The mean age at disease onset was 27 years. A relapsing-remitting disease was the most frequent type of MS (67%). A significant association of DRB1*0403 (OR = 5.68) with MS was shown. DRB1*0802 was also involved in susceptibility (OR = 2.41). An excess of DRB1*0802 homozygotes was observed in patients (P = 0.005), this genotype being in genetic equilibrium in controls. CONCLUSIONS: Two novel class II associations are described in Mexicans with MS: DRB1*0403 and DRB1*0802. Both alleles share with DRB1*1501, valine-86 and negatively charged amino acids, in the DRB1-anchoring motif of pocket 4.

Sleep disturbances, socioeconomic status, and seizure control as main predictors of quality of life in epilepsy.

Improving quality of life is the most important goal for patients with epilepsy. To recognize the factors associated with quality of life in patients with epilepsy in Mexico, we performed a cross-sectional survey using the Quality of Life in Epilepsy 31 (QOLIE-31) inventory to assess the quality of life of 401 adult patients with epilepsy at the National Institute of Neurology and Neurosurgery of Mexico. Clinical and demographical data were collected. Multiple regression was used to determine which factors affected quality of life in our patients. The variables that most strongly predicted a lower QOLIE-31 total score after multiple regression were sleep disorders (P<0.001), socioeconomic status (P<0.001), female gender (P=0.002), and high seizure frequency (P=0.001). In our study, neither depression nor time of evolution of epilepsy had significant influence on QOLIE-31 scores.

Is dementia reversible in patients with neurocysticercosis?

OBJECTIVE: To determine the correlates and outcome of dementia in patients with neurocysticercosis (NCC). METHODS: Ninety consecutive patients with untreated NCC underwent a cognitive assessment (Mini-mental State Examination, Neurobehavioral Cognitive Status Examination, and IQCODE) and were classified as having or not having dementia according to DSM-IV criteria. Imaging and cerebrospinal fluid examination data were recorded. The cognitive measures were repeated six months after treatment with albendazole and steroids. RESULTS: At the initial evaluation 15.5% (n = 14) of the patients were classified as having dementia. Dementia was associated with older age, lower education level, increased number of parasitic lesions in the brain (mostly in the frontal, temporal, and parietal lobes). After six months, 21.5% of the patients from the dementia group continued to have a full dementia disorder and 78.5% no longer fulfilled the DSM-IV criteria for dementia, although some of these patients still showed mild cognitive decline. CONCLUSIONS: The results of this study suggest that dementia occurs frequently in patients with untreated NCC, and it is reversible in most cases.

Calcific neurocysticercosis and epileptogenesis.

Neurocysticercosis is responsible for increased rates of seizures and epilepsy in endemic regions. The most common form of the disease, chronic calcific neurocysticercosis, is the end result of the host's inflammatory response to the larval cysticercus of Taenia solium. There is increasing evidence indicating that calcific cysticercosis is not clinically inactive but a cause of seizures or focal symptoms in this population. Perilesional edema is at times also present around implicated calcified foci. A better understanding of the natural history, frequency, epidemiology, and pathophysiology of calcific cysticercosis and associated disease manifestations is needed to define its importance, treatment, and prevention.

Dimerization-induced activation of soluble insulin/IGF-1 receptor kinases: an alternative mechanism of activation.

To study the role of kinase dimerization in the activation of the insulin receptor (IR) and the insulin-like growth factor receptor-1 (IGF-1R), we have cloned, expressed, and purified monomeric and dimeric forms of the corresponding soluble kinase domains via the baculovirus expression system. Dimerization of the kinases was achieved by fusion of the kinase domains to the homodimeric glutathione S-transferase (GST). Kinetic analyses revealed that kinase dimerization results in substantial increases (10-100-fold) in the phosphotransferase activity in both the auto- and substrate phosphorylation reactions. Furthermore, kinase dimerization rendered the autophosphorylation reaction concentration-independent. However, whereas dimerization was required for the rapid autophosphorylation of the kinases, it was not essential for the enhanced kinase activity in substrate phosphorylation reactions. Comparison of HPLC-phosphopeptide maps of the monomeric and dimeric kinases revealed that dimerization leads to an increased phosphorylation of the regulatory activation loop of the kinases, strongly suggesting that bis- and trisphosphorylation of the activation loop are mediated by transphosphorylation within the kinase dimers. Most strikingly, limited proteolysis revealed that GST-mediated dimerization by itself had a major impact on the conformation of the activation loop by stabilizing a conformation that corresponds to the active, phosphorylated form of the kinase. Thus, in analogy to the insulin/IGF-1-ligated holoreceptors, the dimeric GST-kinases are primed to rapid autophosphorylation by an increase in the local concentration of both phosphoryl donor and phosphoryl acceptor sites and by a dimerization-induced conformational change of the activation loop that leads to an efficient transphosphorylation of the regulatory tyrosine residues.

Regional hypoxia elicits regional changes in chorioallantoic membrane vascular density in alligator but not chicken embryos.

Hypoxic incubation increases vascularization in the chick chorioallantoic membrane (CAM). The effect of regional hypoxia on the vascular density of American alligator (Alligator mississippiensis) and chicken (Gallus gallus) CAMs was studied to determine if hypoxic proliferation of blood vessels is localized or global across the CAM. Eggs were incubated under normoxic conditions with a portion of the eggshell covered with non-toxic beeswax to induce external regional hypoxia. CAMs were examined under a microscope with a 'bulls eye' coverslip and a vascular density index (VDI) was determined. The hypoxic portions of the alligator CAMs were more vascular than the normoxic portions (VDI = 200.9 versus 157. 8, respectively). Presumably this response is maladaptive by causing increased blood flow to the poorly oxygenated portions, i.e. increased 'shunt'. Thus, we hypothesize increased vascularity due to hypoxic incubation is due to local release and subsequent rapid local breakdown or uptake of angiogenic factors. In contrast, the hypoxic and normoxic portions of the chick CAMs exhibited virtually no difference in VDI (VDI= 211.5 versus 217.9, respectively). We suggest the air cell and air space of the chicken eggs allows for circulation of gas in ovo, eliminating the possibility of regional internal hypoxia.

Possible association between Taenia solium cysticercosis and cancer: increased frequency of DNA damage in peripheral lymphocytes from neurocysticercosis patients.

Helminths, particularly some Schistosoma species, have been associated with cancer in humans. Neurocysticercosis, produced by cysticerci of the helminth Taenia solium, has been associated with the emergence of brain tumours and haematological malignancies. Local tumours, such as glioblastoma, could be explained by the induction of DNA damage in cells surrounding the cysticercus and chronically exposed to an inflammatory host response. However, systemic effects such as haematological malignancies are not easy to understand. The present work was conducted in Mexico to find out whether DNA damage arises in peripheral lymphocytes in patients with neurocysticercosis. We utilized a highly sensitive technique to analyse chromosomal aberrations, in-situ hybridization with probes against chromosomes 1, 2 and 4, and in addition the blocked-cytokinesis technique was used to determine the formation of micronuclei, a peculiar form of DNA damage. The study was made in lymphocytes from 8 patients before and after the administration of praziquantel, 1 of the 2 drugs used for neurocysticercosis treatment. The frequencies of chromosome aberrations and micronuclei in peripheral blood lymphocytes were higher in the infected patients as compared to those observed both in healthy donors and in the group of patients after praziquantel therapy. Our results suggest that chromosome aberrations induced in peripheral cells during neurocysticercosis could be associated with the development of haematological neoplasias.

Cardiovascular dysfunction in multiple sclerosis.

Cardiovascular dysfunction (CD) in multiple sclerosis (MS) is related to involvement of reflex pathways in the brainstem. The battery of CD tests was applied to a group of 40 healthy subjects and 40 patients with MS, divided in 2 subgroups according to the expanded disability status scale (EDSS). The tests included: 1) postural blood pressure changes, 2) postural heart rate changes, 3) heart rate changes on inspiration/forced expiration and 4) ECG R-R interval measurement on the Valsalva maneuver. Both groups were subjected to the functional independence scale (FIM). Imaging studies were reviewed and autonomic dysfunction at other levels was explored. The results showed a statistically significant difference (P < 0.05) in all tests when comparing patients to controls. Tests 1 and 4 had the highest significance, with findings of more severe involvement in patients with a higher EDSS and lower FIM. A correlation was also found between CD and brainstem lesions on MRI (P < 0.01). A significant number of MS patients had evidence of CD. Test 1 may be considered a simple marker, in daily clinical practice, to detect subclinical CD. Subclinical CD is a cause of disability in this group of patients.

[Interferon-beta 1a in relapsing-remitting multiple sclerosis. First report of a Mexican population]. / El interferón-beta la en el tratamiento de la esclerosis múltiple con curso remitente-recurrente. Primera descripción en una población mexicana.

OBJECTIVE: We present the results of a prospective and a longitudinal study of IFN-beta 1a (Rebif) in the treatment of Mexican patients with relapsing-remittin multiple sclerosis (MS). PATIENTS AND METHODS: Twenty five patients were included, all of them fulfilled the diagnostic criteria proposed by Poser, had a clinical evolution of at least 2 years, had 2 to 3 acute attacks of MS in the 12 months preceding study entry and an EDSS < 5.5. Six patients were excluded from the trial, one because of anaphylactic shock, 2 progressed to the chronic form and 3 decided not to continue in the study. These patients were considered as treatment failures and represented 24% of the participants entering the trial. The remaining 19 patients (mean age 29.8, 74% females) completed 2-year follow-up. The mean time of disease duration was 48.8 months. Six million units of IFN-beta 1a were applied thrice weekly, in 8 patients (42%) dosage reduction to 6 millions units twice a week was necessary because of leukopenia or elevation in liver enzymes. RESULTS: In the year before treatment with IFN-beta 1a patients had 2.7 +/- 0.93 acute attacks, after treatment the mean number of acute attacks per year was reduced to 1.94 +/- 2.39 (28.9% reduction). When analyzed by gender there was a 62.9% reduction in acute episodes per year in women and a 27.7% reduction in men (p < 0.05). The most frequent side effects were fatigue, headache, local skin reactions, depressed mood, myalgia, weight variations and somnolence. A few patients developed leukopenia, anemia or elevated liver enzymes. In 31.25% of the patients there was an increase in the number of lesions on MRI, in 31.25% there was a reduction in the number of lesions and in 37.5% no change was noted. CONCLUSION: The best-tolerated dose of IFN-beta 1a was 12 million units/week in women and 18 million units/week in men.