Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis in Mexican Patients: A Prospective Study.

BACKGROUND: Clinically Isolated Syndrome (CIS) is the first clinical episode suggestive of Clinical Definite Multiple Sclerosis (CDMS). There are no reports on possible predictors of conversion to CDMS in Mexican mestizo patients. AIM OF THE STUDY: To investigate immunological markers, clinical and paraclinical findings, and the presence of herpesvirus DNA to predict the transition from CIS to CDMS in Mexican patients. METHODS: A single-center prospective cohort study was conducted with newly diagnosed patients with CIS in Mexico between 2006 and 2010. Clinical information, immunophenotype, serum cytokines, anti-myelin protein immunoglobulins, and herpes viral DNA were determined at the time of diagnosis. RESULTS: 273 patients diagnosed with CIS met the enrolment criteria; after 10 years of follow-up, 46% met the 2010 McDonald criteria for CDMS. Baseline parameters associated with conversion to CDMS were motor symptoms, multifocal syndromes, and alterations of somatosensory evoked potentials. The presence of at least one lesion on magnetic resonance imaging was the main factor associated with an increased risk of conversion to CDMS (RR 15.52, 95% CI 3.96-60.79, p = 0.000). Patients who converted to CDMS showed a significantly lower percentage of circulating regulatory T cells, cytotoxic T cells, and B cells, and the conversion to CDMS was associated with the presence of varicella-zoster virus and herpes simplex virus 1 DNA in cerebrospinal fluid and blood. CONCLUSION: There is scarce evidence in Mexico regarding the demographic and clinical aspects of CIS and CDMS. This study shows several predictors of conversion to CDMS to be considered in Mexican patients with CIS.

Melatonin in Combination with Albendazole or Albendazole Sulfoxide Produces a Synergistic Cytotoxicity against Malignant Glioma Cells through Autophagy and Apoptosis.

Glioblastoma is the most aggressive and lethal brain tumor in adults, presenting diffuse brain infiltration, necrosis, and drug resistance. Although new drugs have been approved for recurrent patients, the median survival rate is two years; therefore, new alternatives to treat these patients are required. Previous studies have reported the anticancer activity of albendazole, its active metabolite albendazole sulfoxide, and melatonin; therefore, the present study was performed to evaluate if the combination of melatonin with albendazole or with albendazole sulfoxide induces an additive or synergistic cytotoxic effect on C6 and RG2 rat glioma cells, as well as on U87 human glioblastoma cells. Drug interaction was determined by the Chou-Talalay method. We evaluated the mechanism of cell death by flow cytometry, immunofluorescence, and crystal violet staining. The cytotoxicity of the combinations was mainly synergistic. The combined treatments induced significantly more apoptotic and autophagic cell death on the glioma cell lines. Additionally, albendazole and albendazole sulfoxide inhibited proliferation independently of melatonin. Our data justify continuing with the evaluation of this proposal since the combinations could be a potential strategy to aid in the treatment of glioblastoma.

Abscopal Effect, Extracellular Vesicles and Their Immunotherapeutic Potential in Cancer Treatment.

The communication between tumor cells and the microenvironment plays a fundamental role in the development, growth and further immune escape of the tumor. This communication is partially regulated by extracellular vesicles which can direct the behavior of surrounding cells. In recent years, it has been proposed that this feature could be applied as a potential treatment against cancer, since several studies have shown that tumors treated with radiotherapy can elicit a strong enough immune response to eliminate distant metastasis; this phenomenon is called the abscopal effect. The mechanism behind this effect may include the release of extracellular vesicles loaded with damage-associated molecular patterns and tumor-derived antigens which activates an antigen-specific immune response. This review will focus on the recent discoveries in cancer cell communications via extracellular vesicles and their implication in tumor development, as well as their potential use as an immunotherapeutic treatment against cancer.

Lactate-Loaded Nanoparticles Induce Glioma Cytotoxicity and Increase the Survival of Rats Bearing Malignant Glioma Brain Tumor.

A glioblastoma is an aggressive form of a malignant glial-derived tumor with a poor prognosis despite multimodal therapy approaches. Lactate has a preponderant role in the tumor microenvironment, playing an immunoregulatory role as well as being a carbon source for tumor growth. Lactate homeostasis depends on the proper functioning of intracellular lactate regulation systems, such as transporters and enzymes involved in its synthesis and degradation, with evidence that an intracellular lactate overload generates metabolic stress on tumor cells and tumor cell death. We propose that the delivery of a lactate overload carried in nanoparticles, allowing the intracellular release of lactate, would compromise the survival of tumor cells. We synthesized and characterized silica and titania nanoparticles loaded with lactate to evaluate the cellular uptake, metabolic activity, pH modification, and cytotoxicity on C6 cells under normoxia and chemical hypoxia, and, finally, determined the survival of an orthotopic malignant glioma model after in situ administration. A dose-dependent reduction in metabolic activity of treated cells under normoxia was found, but not under hypoxia, independent of glucose concentration. Lactated-loaded silica nanoparticles were highly cytotoxic (58.1% of dead cells) and generated significant supernatant acidification. In vivo, lactate-loaded silica nanoparticles significantly increased the median survival time of malignant glioma-bearing rats (p = 0.005) when administered in situ. These findings indicate that lactate-loaded silica nanoparticles are cytotoxic on glioma cells in vitro and in vivo.

Potential Use of Nitrogen-Doped Carbon Nanotube Sponges as Payload Carriers Against Malignant Glioma.

Glioblastoma is the most aggressive brain tumor with a low median survival of 14 months. The only Food and Drug Administration (FDA)-approved treatment for topical delivery of the cancer drug carmustine is Gliadel. However, its use has been associated with several side-effects, mainly provoked by a mass effect. Nitrogen-doped carbon nanotube sponges (N-CNSs) are a new type of nanomaterial exhibiting high biocompatibility, and they are able to load large amounts of hydrophobic drugs, reducing the amount of carriers. This study evaluated the use of N-CNSs as potential carmustine carriers using malignant glioma cell lines. N-CNSs were characterized by nanoparticle tracking analysis and transmission electron microscopy. The biocompatibility of N-CNSs was determined in glioma cell lines and in primary astrocytes. Afterward, N-CNSs were loaded with carmustine (1:10 w/w), and the drug and liberation efficiency, as well as cytotoxicity induction, were determined. N-CNSs presented a homogeneous size distribution formed by round nanotubes, without induced cytotoxicity, at concentrations below 40 µg/mL. The N-CNSs loaded with carmustine exhibited a continuous kinetic release of carmustine with a maximum release after 72 h. The cytotoxic effect of N-CNSs loaded with carmustine was similar to that of carmustine alone. The results demonstrated that N-CNSs are a biocompatible nanostructure that could be used as carriers for the tumoral load of large amounts of chemotherapeutic agents.

Herpesvirus encephalitis diagnosed by polymerase chain reaction at the National Institute of Neurology of Mexico.

The frequency of central nervous system infections due to herpesvirus have been studied in various populations; however, studies in Mexican mestizo patients are scant. This paper documents the frequency of herpesvirus encephalitis in Mexican mestizo patients from the National Institute of Neurology and Neurosurgery (NINN) of Mexico. To study the frequency of herpetic viral encephalitis at the NINN in the period from 2004 to 2009. We reviewed clinical records from patients with clinically suspected encephalitis; polymerase chain reaction assays were done for detection of herpesviruses in cerebrospinal fluid (CSF) samples. The total number of patients studied was 502; in 59 (12%), the diagnosis of herpetic encephalitis was confirmed by PCR-based testing of CSF. Of them, 21 (36%) were positive for herpes simplex virus type 1, 15 (25%) for Epstein-Barr virus, 10 (17%) for varicella zoster virus, 8 (14%) for cytomegalovirus, 3 (5%) for human herpesvirus 6, and 2 (3%) for herpes simplex virus 2. Our results show a varied frequency of viral encephalitis in mestizo patients due to herpesviruses in a tertiary neurological center and point out the importance of modern molecular technology to reach the etiological diagnosis in cases of encephalitis.