Big data from small animals: integrating multi-level environmental data into the Dog Aging Project.

Environmental exposures can have large impacts on health outcomes. While many resources have been dedicated to understanding how humans are influenced by the environment, few efforts have been made to study the role of built and natural environmental features on animal health. The Dog Aging Project (DAP) is a longitudinal community science study of aging in companion dogs. Using a combination of owner-reported surveys and secondary sources linked through geocoded coordinates, DAP has captured home, yard and neighbourhood variables for over 40,000 dogs. The DAP environmental data set spans four domains: the physical and built environment; chemical environment and exposures; diet and exercise; and social environment and interactions. By combining biometric data, measures of cognitive function and behaviour, and medical records, DAP is attempting to use a big-data approach to transform the understanding of how the surrounding world affects the health of companion dogs. In this paper, the authors describe the data infrastructure developed to integrate and analyse multi-level environmental data that can be used to improve the understanding of canine co-morbidity and aging.

L'impact des expositions environnementales sur la santé est parfois considérable. Si diverses ressources ont été consacrées à décrire l'influence de l'environnement sur les humains, les efforts visant à étudier l'effet des paramètres environnementaux, tant naturels qu'anthropiques, sur la santé animale sont plus rares. Le Dog Aging Project (DAP) est une étude scientifique longitudinale à base communautaire portant sur le vieillissement du chien de compagnie. À partir d'observations notifiées par les propriétaires de chiens et de sources secondaires reliées par des coordonnées de géocodage, le DAP a réuni des variables sur le foyer d'habitation, l'environnement extérieur immédiat et le voisinage de plus de 40 000 chiens. Les séries de données environnementales du DAP couvrent quatre domaines : l'environnement physique et bâti ; l'environnement chimique et les expositions ; le régime alimentaire et la dépense physique ; et les interactions et l'environnement social. En combinant les données biométriques, les mesures du fonctionnement cognitif et comportemental et les dossiers médicaux, le DAP cherche à utiliser l'approche des mégadonnées pour transformer notre perception de la manière dont le monde qui nous entoure affecte la santé des chiens de compagnie. Les auteurs décrivent l'infrastructure des données mise au point pour intégrer et analyser des données environnementales multi-niveaux, afin de mieux comprendre les phénomènes de comorbidité et de vieillissement chez le chien.

La exposición a factores ambientales puede tener muchas e importantes repercusiones en los resultados sanitarios. Si bien se han dedicado cuantiosos recursos a aprehender la influencia del entorno en las personas, poco se ha hecho para estudiar el modo en que las características del medio, tanto natural como artificial, repercuten en la salud de los animales. El proyecto sobre Envejecimiento canino [Dog Aging Project: DAP] es un estudio longitudinal de ciencia ciudadana centrado en el envejecimiento de los perros de compañía. Combinando la información de encuestas realizadas a propietarios y de fuentes secundarias y vinculando los datos a coordenadas geográficas codificadas, el DAP ha permitido reunir información de variables ligadas al hogar, el jardín y el barrio de más de 40 000 perros. El conjunto de datos ambientales del DAP cubre cuatro grandes ámbitos: medio físico y urbanizado; condiciones químicas del entorno y exposición a sustancias químicas; régimen alimentario y ejercicio; y medio e interacciones sociales. Pasando por el uso combinado de datos biométricos, historias clínicas y mediciones de la función cognitiva y el comportamiento, el DAP apunta ahora a emplear técnicas de trabajo con macrodatos para hacer evolucionar nuestras ideas sobre la influencia del mundo que nos rodea en la salud de los perros de compañía. Los autores describen la infraestructura de datos establecida para integrar y analizar datos ambientales multiestratificados que nos ayuden a conocer mejor los procesos de comorbilidad y envejecimiento en el perro.

Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

How have advances in genetic technology modified movement disorder nosology?

The role of genetics and its technological development have been fundamental in advancing the field of movement disorders, opening the door to precision medicine. Starting from the revolutionary discovery of the locus of the Huntington's disease gene, we review the milestones of genetic discoveries in movement disorders and their impact on clinical practice and research efforts. Before the 1980s, early techniques did not allow the identification of genetic alteration in complex diseases. Further advances increasingly defined a large number of pathogenic genetic alterations. Moreover, these techniques allowed epigenomic, transcriptomic and microbiome analyses. In the 2020s, these new technologies are poised to displace phenotype-based classifications towards a nosology based on genetic/biological data. Advances in genetic technologies are engineering a reversal of the phenotype-to-genotype order of nosology development, replacing convergent clinicopathological disease models with the genotypic divergence required for future precision medicine applications.

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies.

BACKGROUND: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. METHODS: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: 114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. CONCLUSIONS: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.

Antipredator response diminishes during periods of resource deficit for a large herbivore.

The starvation-predation hypothesis predicts that, during resource shortages, prey forego antipredator behavior and forage as much as possible to avoid starvation, even when risk of predation is high. We tested this hypothesis using GPS locations collected simultaneously from moose (Alces alces) and wolves (Canis lupus) in the Greater Yellowstone Ecosystem of North America. We assessed shifts in the speed, displacement, and habitat selection of moose 24 h following encounter with wolves (0-1,500 m distance). We examined whether the strength of antipredator behaviors would weaken as winter progressed and the nutritional condition of moose declined. Moose responded to wolf encounters by increasing their rate of movement in early winter, but only within 500 m distance. Importantly, these responses attenuated as winter progressed. Moose did not avoid their preferred foraging habitat (riparian areas) following encounters with wolves at any distance, and instead they more strongly selected riparian areas, especially in early winter. Our findings support theoretical predictions that resource deficits should dampen prey antipredator behavior, and suggest that nutritional condition of prey may buffer against run-away risk effects in food webs involving large mammalian predators and prey.

KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells.

Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice.

Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

KPT-330 has antitumour activity against non-small cell lung cancer.

BACKGROUND: We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. METHODS: The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed. RESULTS: KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation. CONCLUSIONS: Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276.

RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells (P<0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM (P<0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.

Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells.

Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.

Malformations of cortical development and epilepsy in adult patients.

OBJECTIVE: To describe clinical features of epilepsy secondary to Malformation of Cortical Development (MCD) in a series of adult patients. MATERIALS AND METHODS: We searched our database for all cases with confirmed epilepsy and MCD and included in the study only those with complete data. Mean age, sex, age at seizure onset (ASO), seizure types, abnormal neurological exam (ANE), mental retardation, family history, gestational or perinatal insults (G-PI), interictal EEG and response to treatment were analyzed. Cases were classified into the 3 main groups (G) according to the Barkovich classification (BC) and then compared: (G1) "malformations due to abnormal cell proliferation", (G2) "malformations due to abnormal migration" and (G3) "malformations due to abnormal cortical organization". RESULTS: We identified 152 (5.06%) patients with MCD from a total of 3000 with epilepsy. In total, 138 patients with complete medical data were included in this study. The mean age of patients was 36.2 years, 52.2% were female, the mean ASO was 12.3 years, 5.1% of cases had a positive family history and 21% had G-PI. An ANE was observed in 21% and mental retardation in 31.9%. Most of the patients (84.8%) had refractory epilepsy. The distribution of cases according to the BC was: 51.4% in G1, 28.9% in G2 and 19.6% in G3. Comparing the 3 groups, we found that an ANE was statistically more frequent in G3 and was present in 70.4% of cases. CONCLUSION: Our series of adult patients with epilepsy and MCD suggests that MCD are identified as commonly in a developing country as in previous "first world" series. Neurological deficits were more common in the subgroup of patients with polymicrogyria and schizencephaly (BC Group 3).

[Contribution of diffusion tensor magnetic resonance imaging to the diagnosis of focal cortical dysplasias]. / Contribucion de las imagenes de resonancia magnetica por tensor de difusion al diagnostico de displasias corticales focales.

INTRODUCTION: Focal cortical dysplasias (FCD) are cortical malformations and, although they display typical characteristics in conventional magnetic resonance imaging (MRI), the precise determination of the epileptogenic zone remains a controversial issue. The less favourable progress during the post-operative period with respect to other symptomatic epilepsies could be explained by the existence of epileptogenic areas that do not show up in conventional MRI. Diffusion tensor imaging (DTI) is sensitive to subtle microstructural abnormalities, and fractional anisotropy, which is an indirect indicator, shows areas with reductions in the underlying white matter that go beyond the alterations detected with conventional MRI in isolated cases in previous works. AIM: In this study we analyse the characteristics of fractional anisotropy in a series of patients with FCD in order to evaluate the contribution made to diagnosis by MRI by DTI. SUBJECTS AND METHODS: Twenty-one controls and eleven patients with FCD that was visible in MRI were scanned, and clinical and imaging variables were both recorded. A visual analysis of the fractional anisotropy maps was conducted to search for asymmetries between hemispheres and biases in the clinical or structural MRI data. RESULTS: Two females and nine males, aged 30 ± 9.7 years took part in the study; time to progression of epilepsy: 22 ± 9.3 years; average frequency of the seizures: 3/month (range: 0.16-8/month). All of them showed inter-hemispheric asymmetries, which went beyond the structural limits of FCD in the case of 10 of the patients (90%). None of the controls displayed asymmetries in the fractional anisotropy. No significant relation was found with the variables that were compared. CONCLUSIONS: Further studies need to be conducted with larger numbers of patients in order to evaluate the usefulness of DTI in defining the location and extension of the epileptogenic zone in this population.

European starlings (Sturnus vulgaris) challenged with Escherichia coli O157 can carry and transmit the human pathogen to cattle.

AIMS: European starlings (Sturnus vulgaris) are an invasive species in the United States and are considered a nuisance pest to agriculture. The goal of this study was to determine the potential for these birds to be reservoirs and/or vectors for the human pathogen Escherichia coli O157:H7. MATERIALS AND RESULTS: Under biosecurity confinement, starlings were challenged with various doses of E. coli O157:H7 to determine a minimum infectious dose, the magnitude and duration of pathogen shedding, and the potential of pathogen transmission among starlings and between starlings and cattle. Birds transiently excreted E. coli O157:H7 following low-dose inoculation; however, exposure to greater than 10(5.5) colony-forming units (CFUs) resulted in shedding for more than 3 days in 50% of the birds. Colonized birds typically excreted greater than 10(3) CFU g(-1) of faeces, and the pathogen was detected for as long as 14 days postinoculation. Cohabitating E. coli O157:H7-positive starlings with culture-negative birds or 12-week-old calves resulted in intra- and interspecies pathogen transmission within 24 h. Likewise, E. coli O157:H7 was recovered from previously culture-negative starlings following 24-h cohabitation with calves shedding E. coli O157:H7. CONCLUSIONS: European starlings may be a suitable reservoir and vector of E. coli O157:H7. SIGNIFICANCE AND IMPACT OF THE STUDY: Given the duration and magnitude of E. coli O157:H7 shedding by European starlings, European starlings should be considered a public health hazard. Measures aimed at controlling environmental contamination with starling excrement, on the farm and in public venues, may decrease food-producing animal and human exposure to this pathogen.

Immunogenicity of an interferon-beta1a product.

In order to determine whether Blastoferon®, a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN- beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml. To further assess Blastoferon® immunogenicity, in vivo production of anti-IFN beta antibodies was determined in sera of patients included in the pharmacovigilance plan of Blastoferon® by the level of IFN- beta 1a binding antibodies (by enzyme immunoassay -EIA) and neutralizing antibodies (in the Wish-VSV system). The highly characterized neutralizing monoclonal antibodies A1 and A5 that bind to specific regions of the IFN- beta molecule reacted positively with the three beta 1a IFNs: Blastoferon®, Rebif®, and the IFN- beta WHO Second International Standard 00/572. As expected, the non-neutralizing monoclonal antibodies B4 and B7 did not neutralize any of the IFN- beta preparations. The commercially available monoclonal antibody B-02 reacted essentially equally with Rebif® and Blastoferon®. The WHO Reference Reagent human serum anti-IFN- beta polyclonal antibody neutralized all the IFN- beta products, whereas the WHO Reference Reagent human serum anti-IFN-alpha polyclonal antibody G037-501-572 appropriately failed to react with any of the IFN- beta products. On the basis of in vitro reactivity with known, well-characterized monoclonal and polyclonal antibody preparations, Blastoferon® shares immunological determinants with other human interferon- beta products, especially IFN- beta 1a. In vivo antibodies were detected by EIA in 72.9% of 37 chronically treated multiple sclerosis patients, whereas neutralizing antibodies were found in 8.1% of them. Blastoferon® appears to have immunological characteristics comparable to other IFN- beta 1a products.

Whole genome analysis of the action of interferon-beta.

OBJECTIVES: To characterize the IFNbeta1a-regulated gene expression on leukocytes of Multiple Sclerosis (MS) patients using microarrays with whole human genome representation. METHODS: Genes differentially expressed by interferon-beta were identified by a microarray in vitro study performed in leukocytes obtained from 5 MS relapsing-remitting patients. RESULTS: Following the culture of peripheral blood mononuclear cells from MS relapsing-remitting patients for 24 hs with IFNbeta1a, the expression of 868 genes was modified: 545 increased (including CXCL11, CCL8, INDO, IFI27, CFB, CXCL10 and IFIT1) and 323 diminished (including RBP7, SEPT5, RNF8, ADORA2B and FOS). CONCLUSIONS: Since many of them were previously recognized as involved in MS pathogenesis, the IFNbeta1a mechanism of action could imply a compensatory regulation of systems deregulated in MS.

Clinical spectrum and difficulties in management of hypothalamic hamartoma in a developing country.

AIM: We describe the clinical features, treatment and prognosis in a series of patients with epilepsy secondary to hypothalamic hamarthomas (HH) in a developing country. MATERIALS AND METHODS: Eight patients with epilepsy and HH were included between 1997 and 2006. We analyzed gender, age, age at seizure onset (ASO), seizure types (ST), mental retardation (MR), precocious puberty (PP), electroencephalogram (EEG)-magnetic resonance imaging (MRI) features and response to treatment. RESULTS: Mean age 25.1 years, 2/6 female/male, none had PP, ASO 4.5 years. Complex partial seizure were the most frequent (100%), mean similar to those seen in temporal (62.5%) or frontal lobe epilepsy (37.5%). Exactly 87.5% developed gelastic seizures (GS). Half of the patients showed MR. Mild-to-severe MR was associated with the presence of multiple ST including atonic and complex partial seizures with frontal semiology. Interictal EEG was abnormal in 87.5% patients. Video EEG was performed in three cases with unspecific findings. HH were small and sessile in seven patients whereas large and pedunculated in one. All patients were refractory to medical treatment. In five, an additional procedure was performed without any significant improvement. CONCLUSION: These series show the heterogeneous spectrum of this entity and the difficulties in its treatment in a developing country.