Gut-oriented interventions in patients with multiple sclerosis: fact or fiction?

OBJECTIVE: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, disimmune disease of the central nervous system whose etiology and pathogenesis remain poorly understood, due to its complex and multifactorial nature. Evidence of a bidirectional connection linking the gut microbiome with the intestinal barrier and the immune system (the gut-brain axis) may have implications for the pathogenesis of inflammatory demyelinating diseases such as MS. This narrative review summarizes the evidence for the gut-brain axis involvement in the pathogenesis of MS and examines the role of gut-oriented interventions in MS. PATIENTS AND METHODS: We reviewed all available studies in PubMed concerning gut-directed interventions and MS. This research was conducted using different combinations of pertinent keywords (multiple sclerosis, immune-mediated inflammatory diseases, autoimmune diseases, first demyelinating event, neurocognition, neurological disorders, neurology practice, risk factors, taxonomic biomarkers, nutrition, diet, dietary additives, complementary treatment, gut bacteria, gut microbiome, microbiome, gut-brain axis, epidemiology, alpha-linolenic acid, fermentative metabolites, fat, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 fatty acids, calorie restricted diet, fasting, fecal microbiome, fecal microbiota transplantation, animal testing). RESULTS: There is an emerging evidence that alterations in the gut microbiome and increased intestinal permeability may be causative factors in the complex interplay between nutrition, metabolic status and the immune-inflammatory response in patients with MS. This suggests the possibility that modification of lifestyle and the microbiome, for example by specific diets or fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers, may positively influence the pathogenesis of MS. CONCLUSIONS: Although the role of nutritional factors in the pathogenesis of MS remains to be established, there is evidence that appropriate gut-directed interventions such as diet, nutritional supplementation or fecal transplantation may modulate the inflammatory response and improve the course of MS as a complementary treatment in the disease.

Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica.

OBJECTIVE: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). METHODS: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994-2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO-immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. RESULTS: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1-27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received ≥2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12-151). Mean corpuscular volume increase influenced ARR change (p = 0.049). CONCLUSIONS: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders.

Impact of emergency oral rabies vaccination of foxes in northeastern Italy, 28 December 2009-20 January 2010: preliminary evaluation.

Fox rabies re-emerged in northeastern Italy in 2008, in an area bordering Slovenia. In 2009, the infection spread westward to Veneto region and in 2010 to the provinces of Trento and Bolzano. Aerial emergency oral fox vaccination was implemented in the winter 2009-10. Since this vaccination was performed at altitudes below the freezing level, a statistical analysis was conducted to evaluate its impact. Of the foxes sampled following the vaccination campaign, 77% showed a rabies antibody titre of >or=0.5 IU/ml.

Role of BDNF Val66Met functional polymorphism in Alzheimer's disease-related depression.

BACKGROUND: The gene encoding brain-derived neurotrophic factor (BDNF) has been suggested as a candidate for major depression, and for depression susceptibility in different neurological and psychiatric diseases. No study has investigated the role of BDNF genetic variation and depressive symptoms in Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to assess the genetic contribution of BDNF Val66Met functional polymorphism to AD-related depression. METHODS: Two-hundred and sixty-four AD patients underwent clinical and neuropsychological examination as well as an evaluation of behavioral and psychiatric disturbances. They were subsequently divided into two subgroups according to the presence (AD-D) or the absence (AD-nD), based on DSM-IV criteria for depression in AD. In each subject, BDNF Val66Met functional polymorphism and apolipoprotein E (APOE) genotype were evaluated. RESULTS: In our sample, 35.2% of patients (n=93) reported AD-related depressive symptoms. Compared to patients bearing no polymorphisms (BDNF G/G), BDNF G/A carriers showed more than twofold-time risk (OR=2.38; 95%CI=1.38-4.13), and BDNF A/A carriers had a threefold-time risk (OR=3.04; 95%CI=1.15-8.00) for depression in AD. Accordingly, considering the allele frequencies, BDNF A allele was significantly over-represented in AD-D (32.8%) compared to AD-nD (19.0%) (OR=2.08; 95%CI=1.38-3.13). An association between the number of carried A allele and the severity of depressive symptoms was observed (P<0.002). No effect of APOE genotype on risk for depression was found. CONCLUSIONS: The present findings provide evidence of BDNF genetic variation role in the susceptibility to AD-related depression. This study puts emphasis on the usefulness of considering genetic background for better defining individualized risk profiles in AD.

Haplotypes in cathechol-O-methyltransferase gene confer increased risk for psychosis in Alzheimer disease.

BACKGROUND: The gene encoding catechol-O-methyltransferase (COMT) has been suggested as a candidate for Alzheimer-related psychosis (AD-P) susceptibility, and an association between AD-P and a functional valine to methionine polymorphism has been reported. OBJECTIVE: The aim of this study was to assess the genetic contribution of other COMT variants to the risk of AD-P. METHODS: Two hundred and forty-six AD patients underwent clinical and neuropsychological examination as well as an evaluation of behavioural and psychiatric disturbances. They were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Four single-nucleotide polymorphisms (SNPs) within COMT gene were evaluated, i.e. rs737865, rs737864, intron 1 C2754delC, and the well-known valine/methionine variant (rs4680). Analyses were performed on the single locus and pairwise disequilibrium of loci, and multi-locus haplotype. RESULTS: The individual SNP analysis confirmed an association for the valine/methionine variant with AD-P. Haplotype analyses revealed that the alleles at four loci (rs737865, rs737864, intron 1 C2754delC, rs4680) interacted to create the risk of psychosis in AD, as A-C-C-G haplotype (OR=2.08, 95% CI=1.02-4.27, P=0.044) and G-C-delC-G haplotype (OR=2.54, 95% CI=1.32-4.90, P=0.006) in respect to the most common and not-at-risk A-C-C-A haplotype which was significantly overrepresented in AD-P. CONCLUSIONS: The present findings provide evidence of COMT genetic variations' role in the susceptibility to AD-related psychosis. The observation of a haplotype effect of different polymorphisms within the COMT gene puts emphasis on the usefulness of haplotype analysis in better defining individualized genetic risk profiles in AD.

The Italian version of the pain assessment in advanced dementia (PAINAD) scale.

Pain is an unpleasant sensory and emotional experience. It's recognized to be modified by individual memory, expectation, and emotion. The most accurate evidence of pain and its intensity is based on patient's description and self-report. One of the main problems in assessing pain in dementia concerns with the impairment of communication and memory. Unfortunately, the most used tools to evaluate pain have been developed for normal aging people, requiring verbal and cognitive skills. Therefore, proper instruments are urged to be developed, tested, and validated to assess pain in a cognitively impaired population. The purpose of this study was to assess the validity of the PAINAD in the Italian version as a reliable tool for measuring pain in demented people.

Primitive reflex evaluation in the clinical assessment of extrapyramidal syndromes.

The aim of the present study was to evaluate the role of primitive reflexes (PRs) as additional alert sign in routine clinical practice in patients with extrapyramidal syndrome. We considered glabellar, snout, palmomental and grasp reflexes in patients with mild stage of Lewy body dementia (LBD), corticobasal degeneration, progressive supranuclear palsy or Parkinson disease (PD). We also enrolled mild Alzheimer disease (AD) patients, and healthy subjects, as controls. LBD patients showed the highest prevalence of PRs compared with the other groups. The odds ratio of the risk of LBD in PRs > or = 2 was 27.9 (95% CI 2.9-269.0) compared with control group, 14.6 (95% CI 2.7-79.6) compared with mild AD, and 19.7 (95% CI 3.7-104.3) compared with PD. These data suggest that the occurrence of combination of PRs might be an useful additional warning sign of possible diffuse Lewy body pathology more than other causes of extrapyramidal syndrome.

Parkinson's disease and dementia.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting about 1% of the population over the age of 60. In addition to motor abnormalities, there are several non-motor signs and symptoms that may create a considerable burden for patients and care-givers. Dementia is common and affects approximately 40% of PD patients during the course of the disease, the risk for the development of dementia being 6 times higher than in non-PD age-matched controls. In most cases, PD patients with dementia (PDD) display a dysexecutive syndrome and visuospatial deficits, while memory is relatively unaffected. The overlap between PDD and dementia with Lewy bodies suggests that they likely share similar underlying neuropathological processes.

Genetic correlates of behavioral endophenotypes in Alzheimer disease: role of COMT, 5-HTTLPR and APOE polymorphisms.

Several studies have been conducted to understand the genetic correlates of Alzheimer disease (AD)-related behavioral and psychological symptoms in dementia (BPSD). However, given that BPSD rarely occur in isolation, it has been suggested that targeting BPSD individually is too narrow of an approach if one wants to accurately define all the associated risk factors. To date, we know of no work on genetic polymorphisms related to behavioral endophenotypes in AD. The present study sought to evaluate the relationship between such behavioral endophenotypes in AD and genetic variations in dopamine- or serotonin-related genes, such as catechol-O-methyltransferase (COMT) or 5-HTT gene-linked promoter region (5-HTTLPR), and apolipoprotein E (APOE). Among 232 AD patients who underwent clinical and neuropsychological examination, a behavioral and psychiatric evaluation, and genotyping at COMT, 5-HTTPLR, and APOE; 66.4% showed more than one behavioral symptom. By Principal Component Analysis of Neuropsychiatric Inventory (NPI) symptoms four endophenotypes were identified, these were termed "psychosis", "moods", "apathy", and "frontal". Modeling NPI symptom-endophenotype-genotype relationships, and taking into account possible confounds (i.e. demographic characteristics, comorbidities, concomitant pharmacological treatments, and disease severity) by latent variable models, COMT and 5-HTTLPR genetic variations correlated with "frontal" and "psychosis" endophenotypes. APOE genotype did not correlate with any endophenotype. These findings suggest that the possibility of identifying distinct phenotypes on a genetic basis among AD patients exists, and suggest that clustering of BPSD into endophenotypes might provide a new strategy for guiding future research on this issue.

MACROH2A2, a new member of the MARCOH2A core histone family.

MACROH2As are core histones that have a unique hybrid structure consisting of an amino-terminal domain that closely resembles a full-length histone H2A followed by a large nonhistone region. The human MACROH2A1 gene, on chromosome 5, encodes two MACROH2A subtypes, MACROH2A1.1 and MACROH2A1.2, produced by alternate splicing. Here we report the identification of MACROH2A2, a new MACROH2A subtype encoded by a separate gene on human chromosome 10, MACROH2A2. The amino acid sequence of human MACROH2A2 is 68% identical to human MACROH2A1.2. We show by immunofluorescence on mouse tissue sections that MACROH2A2, like MACROH2A1.2, is concentrated in the inactive X chromosome. However, MACROH2A2 has a very different pattern of expression in the cell types present in the liver and kidney. When MACROH2A2 and MACROH2A1.2 are present in the same nucleus, they have a similar, though nonidentical, pattern of localization, with both subtypes present in the inactive X chromosome. Our results suggest a developmental role for MACROH2A subtypes.

Histone macroH2A1.2 is concentrated in the XY-body by the early pachytene stage of spermatogenesis.

The pairing of sex chromosomes during meiosis in male mammals is associated with ongoing heterochromatinization and X inactivation. This process occurs in a specific area of the nucleus that can be discerned morphologically: the sex vesicle or XY-body. In contrast to X inactivation in the somatic cells of female mammals the reasons for X inactivation in the male germline remain obscure. We have recently demonstrated that the inactive X chromosome in somatic cells of female mammals is marked by a high concentration of histone macroH2A. Here we investigate X inactivation in the meiotic cells of the male germline. We demonstrate here that macroH2A1.2 is present in the nuclei of germ cells starting first with localization that is largely, if not exclusively, to the developing XY-body in early pachytene spermatocytes. Our results suggest that inactivation of sex chromosomes in the male germ cell includes a major alteration of the nucleosomal structure.

Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos.

MacroH2As are core histone proteins with a hybrid structure consisting of a domain that closely resembles a full-length histone H2A followed by a large nonhistone domain. We recently showed that one of the macroH2A subtypes, macroH2A1.2, is concentrated in the inactive X chromosome in adult female mammals. Here we examine the timing of the association of macroH2A1.2 with the inactive X chromosome during preimplantation mouse development in order to assess the possibility that macroH2A1 participates in the initiation of X inactivation. The association of macroH2A1.2 with one of the X chromosomes was observed in 50% of blastocysts, occurring mostly, if not exclusively, in extraembryonic cells as was expected from previous studies, which indicated that X inactivation in embryonic lineages happens after implantation. Examination of earlier embryonic stages indicates that the association of macroH2A1 with the inactive X chromosome begins between the 8- and 16-cell stages. Of the changes that are known to happen during X inactivation in preimplantation embryos, the accumulation of macroH2A1 appears to be the earliest marker of the inactive X chromosome and is the only change that has been shown to occur during the period when transcriptional silencing is initiated.

Histone macroH2A1.2 relocates to the inactive X chromosome after initiation and propagation of X-inactivation.

The histone macroH2A1.2 has been implicated in X chromosome inactivation on the basis of its accumulation on the inactive X chromosome (Xi) of adult female mammals. We have established the timing of macroH2A1.2 association with the Xi relative to the onset of X-inactivation in differentiating murine embryonic stem (ES) cells using immuno-RNA fluorescence in situ hybridization (FISH). Before X-inactivation we observe a single macroH2A1.2-dense region in both undifferentiated XX and XY ES cells that does not colocalize with X inactive specific transcript (Xist) RNA, and thus appears not to associate with the X chromosome(s). This pattern persists through early stages of differentiation, up to day 7. Then the frequency of XY cells containing a macroH2A1.2-rich domain declines. In contrast, in XX cells there is a striking relocalization of macroH2A1.2 to the Xi. Relocalization occurs in a highly synchronized wave over a 2-d period, indicating a precisely regulated association. The timing of macroH2A1.2 accumulation on the Xi suggests it is not necessary for the initiation or propagation of random X-inactivation.

Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals.

In female mammals one of the X chromosomes is rendered almost completely transcriptionally inactive to equalize expression of X-linked genes in males and females. The inactive X chromosome is distinguished from its active counterpart by its condensed appearance in interphase nuclei, late replication, altered DNA methylation, hypoacetylation of histone H4, and by transcription of a large cis-acting nuclear RNA called Xist. Although it is believed that the inactivation process involves the association of specific protein(s) with the chromatin of the inactive X, no such proteins have been identified. We discovered a new gene family encoding a core histone which we called macroH2A (mH2A). The amino-terminal third of mH2A proteins is similar to a full-length histone H2A, but the remaining two-thirds is unrelated to any known histones. Here we show that an mH2A1 subtype is preferentially concentrated in the inactive X chromosome of female mammals. Our results link X inactivation with a major alteration of the nucleosome, the primary structural unit of chromatin.

Developmental and tissue expression patterns of histone macroH2A1 subtypes.

MacroH2A is a novel nucleosomal core histone that contains a large nonhistone region and a region that closely resembles a full length histone H2A. We have cloned a cDNA that contains the entire coding region of macroH2A1.2, one of the two identified subtypes of macroH2A1. MacroH2A1.2 was found to differ from the other known subtype, macroH2A1.1, in a single segment of the nonhistone region. MacroH2A1 specific antibodies revealed relatively high levels of both subtypes in adult liver and kidney. MacroH2A1.1 was much lower in fetal liver and kidney in comparison to their adult counterparts, and was not detected in adult thymus and testis, tissues with active cell division and differentiation. Both subtypes were present at very low levels or absent from mouse embryonic stem cells maintained in an undifferentiated state by growth in the presence of leukemia inhibitory factor. MacroH2A1.2 increased when the embryonic stem cells were induced to differentiate in vitro, while macroH2A1.1 remained undetectable. These results support the idea that macroH2A1.1 and macroH2A1.2 are functionally distinct, and suggest that changes in their expression may play a role in developmentally regulated changes in chromatin structure and function.

Definition of a second dimeric subfamily of human alpha satellite DNA.

We describe a new human subfamily of alpha satellite DNA. The restriction endonuclease XbaI cleaves this subfamily into a collection of fragments which are heterogeneous with respect to size. We compared the sequences of 6 clones from four different XbaI size classes. Clones from a single size class were not necessarily more related than clones from different classes. Clones from different size classes were found to produce almost identical hybridization patterns with XbaI-digested human genomic DNA. All clones were found to share a common dimeric repeat organization, with dimers exhibiting about 84% sequence identities, indicating that the clones evolved from a common progenitor alphoid dimer. We show that this subfamily, and the EcoRI dimer subfamily originally described by Wu and Manuelidis, evolved from different progenitor alphoid dimers, and therefore represent distinct human alphoid subfamilies.

[The Italian experience in the control of rabies. I. Procedural methods]. / L'esperienza italiana nel controllo della rabbia. I. Lavoro operativo.

Oral vaccination of foxes associated with their control has been shown to be a rapid and safe method to extinguish enzootic foci of sylvatic rabies and to prevent the entry and spreading of this zoonosis in free zones of Italy. Domestic animals vaccination with live modified vaccines in zones with sylvatic rabies has proved to be highly effective in limiting the cases, recorded only in non-vaccinated animals.