Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to autism spectrum disorders.

Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade. During postnatal days 1-10, male Wistar rat pups (n=5-10/litter) were injected (subcutaneously) with the GRPr antagonist, RC-3095 (1 mg/kg), or a vehicle (control), twice daily. Following the drug treatment regimen, several behaviors were assessed (starting on postnatal day 14) including specific social behaviors (namely, group huddling characteristics, social interaction, and social approach), restrictive/repetitive and stereotyped behaviors (y-maze, repetitive novel object contact task, observation for stereotypies) and anxiety/fear-related responses (open field, elevated plus maze and contextual fear conditioning). Rats treated neonatally with RC-3095 showed reduced sociability, restrictive interests, motor stereotypies and enhanced learned fear response compared to the controls (vehicle-treated rats). These behavioral abnormalities are consistent with those observed in autism spectrum disorders and provide further evidence that neonatal blockade of GRPr could potentially serve as a useful model to gain a better understanding of the underlying neurodevelopmental disruptions contributing to the expression of autism-relevant phenotypes.

DEFB1 gene 5' untranslated region (UTR) polymorphisms are marginally involved in inflammatory bowel disease in south Brazilians.

The possible association of three DEFB1 gene polymorphisms with susceptibility to develop ulcerative colitis (UC) and Crohn's disease (CD) was investigated in Brazilian patients and controls. Although a clear and strong association between functional 5'-UTR DEFB1 SNPs and susceptibility/protection to IBDs cannot be drawn, our results suggest a possible involvement of DEFB1 gene in inflammatory bowel diseases, especially with the colonic localization of Crohn's disease.

ECG-gated imaging of the left atrium and pulmonary veins: Intra-individual comparison of CTA and MRA.

AIM: To compare electrocardiography (ECG)-gated computed tomography angiography (CTA) with ECG-gated magnetic resonance angiography (MRA) for assessment of the left atrium (LA) and pulmonary veins (PVs). MATERIAL AND METHODS: Twenty-nine consecutive patients who underwent both cardiac CTA and MRA were evaluated. Contrast-enhanced CTA was performed with prospective ECG-gating using a 320 detector row CT system. Contrast-enhanced MRA was performed with prospective ECG-gating using a 1.5 T MRI system equipped with a 32 channel cardiac coil. MRA was acquired during free-breathing with a navigator-gated inversion-recovery prepared steady-state free precession sequence. Two readers independently assessed the CTA and MRA images for vascular definition of the PVs (from 0, not visualized, to 4, excellent definition) and ostial PV diameters. Variants of LA anatomy were assessed in consensus. RESULTS: CTA was successfully performed in all patients with a mean radiation exposure of 5.1 ± 2.2 mSv. MRA was successfully performed in 27 of 29 patients (93 %). Visual definition of PVs was rated significantly higher on CTA compared to MRA (p < 0.0001; reader 1: excellent/good ratings of CTA versus MRA: 100% versus 86%; reader 2: excellent/good ratings of CTA versus MRA: 99% versus 89%). Assessment of ostial PV diameters showed good correlation between CTA and MRA (reader 1: Pearson r = 0.91; reader 2: Pearson r = 0.82). Moreover, agreement between both imaging methods for evaluation of variants of LA anatomy was high (agreement rate of 95% (95% CI: 92-99%). CONCLUSION: ECG-gated CTA provides higher image quality compared to ECG-gated MRA. Nevertheless, both CTA and MRA provided similar information of LA anatomy and ostial PV diameters.

Competition of silene/silylene chemistry with free radical chain reactions using 1-methylsilacyclobutane in the hot-wire chemical vapor deposition process.

The gas-phase reaction chemistry of using 1-methylsilacyclobutane (MSCB) in the hot-wire chemical vapor deposition (CVD) process has been investigated by studying the decomposition of MSCB on a heated tungsten filament and subsequent gas-phase reactions in a reactor. Three pathways exist to decompose MSCB on the filament to form ethene/methylsilene, propene/methylsilylene, and methyl radicals. The activation energies for forming propene and methyl radical, respectively, are determined to be 68.7 ± 1.3 and 46.7 ± 2.5 kJ·mol(-1), which demonstrates the catalytic nature of the decomposition. The secondary gas-phase reactions in the hot-wire CVD reactor are characterized by the competition between a free radical chain reaction and the cycloaddition of silene reactive species produced either from the primary decomposition of MSCB on the filament or the isomerization of silylene species. At lower filament temperatures of 1000-1100 °C and short reaction time (t ≤ 15 min), the free radical chain reaction is equally important as the silene chemistry. With increasing filament temperature and reaction time, silene chemistry predominates.

Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group.

Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer.

Memory impairment induced by brain iron overload is accompanied by reduced H3K9 acetylation and ameliorated by sodium butyrate.

Iron accumulation in the brain has been associated to the pathogenesis of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in adult rats. Alterations in histone acetylation have been associated with memory deficits in models of neurological disorders. Here we examine histone acetylation in the brain and the effects of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) on memory in the neonatal iron overload model in rats. Rats received vehicle or 30.0-mg/kg Fe⁺² orally at postnatal days 12-14. When animals reached adulthood, they were given training in either novel object recognition or inhibitory avoidance. Histone acetylation in the dorsal hippocampus and the effects of NaB were examined in separate sets of rats. Iron overload led to a reduction in H3 lysine 9 acetylation in the hippocampus, without affecting the acetylation of other H3 and H4 lysine residues. A single systemic injection of NaB (1.2 g/kg) immediately after training ameliorated iron-induced memory impairments. The results suggest that a reduction in H3K9 acetylation might play a role in iron-induced memory impairment and support the view that HDACis can rescue memory dysfunction in models of brain disorders.

Protective effect of RC-3095, an antagonist of the gastrin-releasing peptide receptor, in experimental arthritis.

OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.

Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets.

Medulloblastoma is the most common malignant brain tumor in children. This malignant tumor of the cerebellum commonly affects children and is believed to arise from the precursor cells of the external granule layer or neuroepithelial cells from the cerebellar ventricular zone of the developing cerebellum. The standard treatment, consisting of surgery, craniospinal radiotherapy and chemotherapy, still provides a poor overall survival for infants and young children. Furthermore, the dose of radiation that can be safely given without causing extensive neurocognitive and endocrinologic sequelae is limited. Therefore, understanding the oncogenic pathways that lead to medulloblastoma, as well as the identification of specific molecular targets with significant therapeutic implications in order to develop new strategies for therapy, is crucial to improve patient survival without substantially increasing toxicity. In this review, we discuss recent therapeutics for treating medulloblastoma, focusing on new molecular targets, as well as advances in translational studies for the treatment of this malignancy.

Ketamine impairs recognition memory consolidation and prevents learning-induced increase in hippocampal brain-derived neurotrophic factor levels.

The non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has been shown to produce cognitive deficits. However, the effects of ketamine on the consolidation phase of memory remain poorly characterized. Here we show that systemic administration of ketamine immediately after training dose-dependently impairs long-term retention of memory for a novel object recognition (NOR) task in rats. Control experiments showed that the impairing effects of ketamine could not be attributed to an influence on memory retrieval or sensorimotor effects. In addition, ketamine prevented the increase in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by NOR learning. Our results show for the first time that ketamine disrupts the consolidation phase of long-term recognition memory. In addition, the findings suggest that the amnestic effects of ketamine might be at least partially mediated by an influence on BDNF signaling in the hippocampus.

Killer cell immunoglobulin-like receptor gene diversity in a Caucasian population of southern Brazil.

Killer immunoglobulin-like receptors (KIR) regulate the activity of natural killer and T cells through an interaction with specific human leucocyte antigen (HLA) class I molecules on target cells. Diversity in KIR gene content, KIR allelic and haplotype polymorphism has been observed between different ethnic groups. However, most population studies on KIR variability have focused on Europe and Asia, while Americas, Oceania and Africa remain poorly studied. The aim of this study was to analyse the variability of KIR genes in 200 healthy nonrelated individuals from the Southern Brazilian population. KIR genes and HLA-A, -B and -Cw were genotyped using polymerase chain reaction-sequence-specific primers. Southern Brazilian population demonstrated several similarities to states that are closer geographically and distinct differences with Northern Brazil in the frequency of genes KIR2DS1, 2DS2, 2DS3, 2DS5, 3DL1, 3DS1, 2DL1 and 2DL2. The activating gene KIR2DS5 was the least frequent locus found in our group. Interaction of KIR/HLA was more common in the 2DS1-/2DL1+/C2+ association. This study demonstrated the diversity of KIR genes and of KIR/HLA association in a Caucasian group of Southern Brazil, establishing differences and similarities to other different populations.

Retrieval mediated by hippocampal extracellular signal-regulated kinase/mitogen-activated protein kinase is required for memory strengthening.

Established memories can be strengthened by additional learning and rehearsal. However, the brain processes enabling memories to be updated by further information is unclear. We found that blockade of retrieval of a stabilized memory by inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway in the hippocampus prevented memory enhancement induced by an additional learning trial in rats. The findings indicate that retrieval is critical for memory strengthening.

Sodium butyrate enhances the cytotoxic effect of antineoplastic drugs in human lymphoblastic T-cells.

Sodium butyrate (NaB), a potent histone deacetylase inhibitor, induces cell cycle arrest and apoptosis in malignant cells. We investigated the effects on cellular proliferation in vitro when combining NaB with antineoplastic drugs commonly used to treat leukemias. Our results demonstrate that NaB increases the cytotoxic effects of cytarabine and etoposide, but not of bleomycin, doxorubicin, vincristine or methotrexate. These data suggest that NaB is a promising adjuvant therapeutic agent for the treatment of lymphoblastic leukemias, and provides a basis for further studies in this field.

Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats.

Increasing evidence indicates that iron deposition in the brain might play a role in cognitive dysfunction associated with neurodegenerative disorders and aging. Previous studies have not examined whether iron-induced memory deficits can be attenuated by acute treatments with memory-enhancing agents. Phosphodiesterase type 4 (PDE4) inhibitors such as rolipram (ROL) ameliorate memory impairments in several rodent models of amnesia and have been proposed as candidate cognitive-enhancing drugs. Here we show that a single posttraining systemic injection of ROL dose-dependently attenuates the impairment of memory for novel object recognition (NOR) in rats given neonatal iron loading, a model of iron-induced cognitive impairment. Posttraining administration of ROL also recovered NOR deficits associated with aging in rats. These findings provide the first evidence that stimulation of an intracellular second messenger signaling pathway can attenuate iron-induced memory impairment, and support the view that PDE4 inhibitors might ameliorate cognitive dysfunction associated with aging and neurodegenerative disorders.

Effects of an antagonist of the bombesin/gastrin-releasing peptide receptor on complete Freund's adjuvant-induced arthritis in rats.

OBJECTIVE: To determine the effects of RC-3095 in clinical and histopathologic parameters and inflammatory mediators on complete Freund's adjuvant-induced arthritis (CFA). METHODS: The arthritis was induced by injection of CFA into the left hind footpad. The animals were divided into control, vehicle injected control, placebo group (saline subcutaneously 50ml/kg, once daily for 8 days after modeling), treatment group (0.3mg/kg of RC-3095 subcutaneously, once daily for 8 days after induction). Clinical evaluation was accomplished daily, through scoring of the paw edema. The animals were sacrificed 15 days after induction for collection of hind foot joints for histology. We used a histological scoring system which was previously described, and interferon (INF)-gamma, interleukin (IL)-1beta, tumor necrosis factor (TNF), interleukin (IL)-6 and interleukin (IL)-10 were measured by ELISA. RESULTS: There was a significant inhibition of joint histological findings in the RC-3095 treated group, including synovial inflammatory infiltration and hyperplasia, cartilage and bone erosion. IFN-gamma, IL-1beta, TNF, IL-6 and IL-10 serum levels were significantly lower in the treated group. Paw swelling and subcutaneous inflammation, evaluated clinically, were not different between CFA-induced groups. CONCLUSIONS: RC-3095 was able to improve experimental arthritis, attenuate joint damage and decrease serum levels of IFN-gamma, IL-1beta, TNF, IL-6 and IL-10. These data indicate that interference with GRP pathway is a potential new strategy for the treatment of RA that needs further investigational studies.

Pharmacology and toxicology of diphenyl diselenide in several biological models

The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS) in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of d-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy.

Over the last two decades, several lines of experimental evidence have suggested that the gastrin-releasing peptide (GRP) may act as a growth factor in many types of cancer. For that reason, gastrin-releasing peptide receptor (GRPR) antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumoral activity both in vitro and in vivo in various murine and human tumors. In this article, the GRPR cell surface expression profile in human malignancies is reviewed aiming at the identification of potential tumor types for future clinical trials with GRP analogues and antagonists. In this review, we summarize the current literature regarding the GRPR status in human malignancies. Source data were obtained by searching all published material available through Medline, PubMed and relevant articles from 1971 to 2006. The data available demonstrated a high expression of GRPRs in a large spectrum of human cancers, demonstrating the potential relevance of this intracellular signaling pathway in various human tumor models. The GRPR may be an interesting target for therapeutic intervention in human malignancies, as carriers for cytotoxins, immunotoxins or radioactive compounds, being also a potential tool for tumor detection.

Pharmacology and toxicology of diphenyl diselenide in several biological models.

The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS) in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of delta-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus.

Although the gastrin-releasing peptide-preferring bombesin receptor (GRPR) has been implicated in memory formation, the underlying molecular events are poorly understood. In the present study, we examined interactions between the GRPR and cellular signaling pathways in influencing memory consolidation in the hippocampus. Male Wistar rats received bilateral infusions of bombesin (BB) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intermediate doses of BB enhanced, whereas a higher dose impaired, 24-h IA memory retention. The BB-induced memory enhancement was prevented by pretraining infusions of a GRPR antagonist or inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) kinase and protein kinase A (PKA), but not by a neuromedin B receptor (NMBR) antagonist. We next further investigated the interactions between the GRPR and the PKA pathway. BB-induced enhancement of consolidation was potentiated by coinfusion of activators of the dopamine D1/D5 receptor (D1R)/cAMP/PKA pathway and prevented by a PKA inhibitor. We conclude that memory modulation by hippocampal GRPRs is mediated by the PKC, MAPK, and PKA pathways. Furthermore, pretraining infusion of BB prevented beta-amyloid peptide (25-35)-induced memory impairment, supporting the view that the GRPR is a target for the development of cognitive enhancers for dementia.