The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.

BACKGROUND: Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. OBJECTIVE: We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations. METHODS: Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. RESULTS: We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. CONCLUSION: These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis.

Multiple Sclerosis (MS) is a neurological condition driven in part by immune cells from the peripheral circulation, the targets for current successful therapies. The autoimmune and MS risk gene ZMIZ1 is underexpressed in blood in people with MS. We show that, from three independent sets of transcriptomic data, expression of ZMIZ1 is tightly correlated with that of hundreds of other genes. Further we show expression is partially heritable (heritability 0.26), relatively stable over time, predominantly in plasmacytoid dendritic cells and non-classical monocytes, and that levels of ZMIZ1 protein expression are reduced in MS. ZMIZ1 gene expression is increased in response to calcipotriol (1,25 Vitamin D3) (p < 0.0003) and associated with Epstein Barr Virus (EBV) EBNA-1 antibody titre (p < 0.004). MS therapies fingolimod and dimethyl fumarate altered blood ZMIZ1 gene expression compared to untreated MS. The phenotype indicates susceptibility to MS, and may correspond with clinical response and represent a novel clinical target.

Expression of polysialyltransferases (STX and PST) in adult rat olfactory bulb after an olfactory associative discrimination task.

Neuronal plasticity and neurogenesis occur in the adult hippocampus and in other brain structures such as the olfactory bulb and often involve the neural cell adhesion molecule NCAM. During an olfactory associative discrimination learning task, NCAM polysialylation triggers neuronal plasticity in the adult hippocampus. The PST enzyme likely modulates this polysialylation, but not STX, a second sialyltransferase. How the two polysialyltransferases are involved in the adult olfactory bulb remains unknown. We addressed this question by investigating the effect of olfactory associative learning on plasticity and neurogenesis. After a hippocampo-dependent olfactory associative task learning, we measured the expression of both PST and STX polysialyltransferases in the olfactory bulbs of adult rats using quantitative PCR. In parallel, immunohistochemistry was used to evaluate both NCAM polysialylation level and newly-born cells, with or without learning. After learning, no changes were observed neither in the expression level of PST and NCAM polysialylation, nor in STX gene expression level and newly-born cells number in the olfactory bulb.

Quality of life, needs, and interest among cocaine users: differences by cocaine use intensity and lifetime severity of addiction to cocaine.

We examined the quality of life (QoL) of 149 patients who were recruited in 2005 at outpatient treatment centers for cocaine dependence in Spain. Important life areas and life areas with potential need and interest to change in order to improve the QoL were analyzed in terms of patients? cocaine use intensity within the previous six months and lifetime severity addiction to cocaine. The Spanish versions of the Drug User Quality of Life Scale and the Lifetime Severity Index for Cocaine were used to measure QoL, needs and interest, and severity addiction to cocaine. The data analysis employed t-tests, linear regression, Mann?Whitney U tests, multivariate regression, and chi-square tests. Tailoring treatment programs to address the life areas that are considered relevant to cocaine users considering their intensity of consumption and lifetime severity addiction to cocaine may improve retention and treatment outcomes. Further research needs to consider patients of different ethnic backgrounds and cultural contexts. The study's limitations are noted.

Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: alteration of c-Fos and polysialylated neural cell adhesion molecule expression.

The aim of this study was to determine the brain structures as well as the plasticity events associated with the behavioral effects of cholinergic damage. Rats were submitted to injection of 192 IgG-saporin in the medial septum/diagonal band of Broca complex and the nucleus basalis magnocellularis. The immunohistochemical expression of c-Fos protein and PSA-NCAM (polysialylated neural cell adhesion molecule) and the behavioral performances in the nonmatching-to-position task were assessed at various post-lesion times. Thus, 3 days after injection of the immunotoxin, increased c-Fos labeling was observed in the areas of infusion, indicating these cells were undergoing some plastic changes and/or apoptotic processes. A drastic increase was observed in the number of PSA-NCAM positive cells and in their dendritic arborization in the dentate gyrus. At 7 days post-lesion, no behavioral deficit was observed in immunolesioned rats despite the drastic loss of cholinergic neurons. These neurons showed decreased c-Fos protein expression in the piriform and entorhinal cortex and in the dentate gyrus. In the latter, PSA-NCAM induction was high, suggesting that remodeling occurred, which in turn might contribute to sustaining some mnemonic function in immunolesioned rats. At 1 month, cholinergic neurons totally disappeared and behavioral deficits were drastic. c-Fos expression showed no change. In contrast, the increased PSA-NCAM-labeling observed at short post-lesion times was maintained but the plastic changes due to this molecule could not compensate the behavioral deficit caused by the immunotoxin. Thus, as the post-lesion time increases, a gradual degeneration process should occur that may contribute to mnemonic impairments. This neuronal loss leads to molecular and cellular alterations, which in turn may aggravate cognitive deficits.

Cross cultural adaptation of the Injection Drug User Quality Of Life Scale (IDUQOL) in Spanish drug dependent population, with or without injectable consumption: Drug User Quality of Life Scale-Spanish (DUQOL-Spanish).

The Injection Drug User Quality of life Scale (IDUQOL) measures the unique and individual circumstances that determine the quality of life of injection drug users. This paper reports the psychometric properties of the Spanish version, for drug dependent persons with or without injectable consumption using a revised instrument: Drug user Quality of Life Scale-Spanish (DUQOL-Spanish). We studied 169 outpatients in 9 Spanish drug treatment centers. Factor analysis, internal consistency, test-retest reliability and criterion-related validity were assessed. The results show the essential unidimensionality of the scale, which supports the use of a total score. Both internal consistency (Cronbach's alpha: 0.86), and test-retest reliability (r=0.79) of the total score were high. Criterion-related validity supports the interpretation of the DUQOL-Spanish total score as measuring a construct consistent with quality of life. This study suggests that the DUQOL-Spanish is a valid instrument to measure subjective quality of life in Spanish drug users, and allows the identification of life areas that are considered by the patient important to change in order to improve their quality of life.

[Utility of FDG-PET for early evaluation of efficiency of imatinib mesylate (Glivec) in the treatment of gastrointestinal stromal tumors]. / Utilidad de la FDG-PET en la evaluación precoz de la eficacia de imatinib (Glivec) en el tratamiento de tumores del estroma gastrointestinal.

The management of gastrointestinal stromal tumors, usually defined as c-KIT-positive mesenchymal neoplasias, has evolved very rapidly in the last five years. Imatinib mesylate (Glivec(R)) is the standard treatment in unresectable or metastatic gastrointestinal stromal tumors. Imatinib should be given until development of intolerance or progressive disease. It is not uncommon for gastrointestinal stromal tumors to become larger during the early post-treatment phase and conventional response to treatment criteria in solid tumors have a limited value for evaluation the efficiency of imatinib in this period. FDG-PET has proven to be highly sensitive in detecting early response tumor. A 53-year old woman was diagnosed of relapsed gastrointestinal stromal tumor 18 months after adyuvant imatinib mesylate finished. Imatinib was started and 72 hours later the tumor showed a decrease of fluorodeoxyglucose F18 uptake on positron emission tomography scan.

Data characterizing the ZMIZ1 molecular phenotype of multiple sclerosis.

The data presented in this article are related to the research article entitled "The autoimmune risk gene ZMIZ1 is a vitamin D responsived marker of a molecular phenotype of multiple sclerosis" Fewings et al. (2017) [1]. Here we identify the set of genes correlated with ZMIZ1 in multiple cohorts, provide phenotypic details on those cohorts, and identify the genes negatively correlated with ZMIZ1 and the cells predominantly expressing those genes. We identify the metabolic pathways in which the molecular phenotype genes are over-represented. Finally, we present the flow cytometry gating strategy we have used to identify the immune cells from blood which are producing ZMIZ1 and RPS6.

Preconditioning tDCS facilitates subsequent tDCS effect on skill acquisition in older adults.

Functional motor declines that often occur with advancing age-including reduced efficacy to learn new skills-can have a substantial impact on the quality of life. Recent studies using noninvasive brain stimulation indicate that priming the corticospinal system by lowering the threshold for the induction of long-term potentiation-like plasticity before skill training may facilitate subsequent skill learning. Here, we used "priming" protocol, in which we used transcranial direct current stimulation (tDCS) applying the cathode over the primary motor cortex (M1) before the anode placed over M1 during unimanual isometric force control training (FORCEtraining). Older individuals who received tDCS with the cathode placed over M1 before tDCS with the anode placed over M1 concurrent with FORCEtraining showed greater skill improvement and corticospinal excitability increases following the tDCS/FORCEtraining protocol compared with both young and older individuals who did not receive the preceding tDCS with the cathode placed over M1. The results suggested that priming tDCS protocols may be used in clinical settings to improve motor function and thus maintain the functional independence of older adults.

Expression of the members of the Ptx family of transcription factors in human pituitary adenomas.

A number of putative transcription factors described in the pituitary have been implicated as key elements in the processes that direct pituitary development. Three recently described proteins, Ptx1, Ptx2, and Ptx3, define a new family of transcription factors, the Ptx subfamily, within the paired-like class of homeodomain factors. In mice, Ptx1 and Ptx2 gene expression has been detected in the area of the pituitary primordium and is maintained throughout development in Rathke pouch and adult pituitary. In the present study, the expression of the Ptx1, Ptx2, and Ptx3 genes was characterized in the normal human pituitary and in the different types of human pituitary adenomas. Although no Ptx3 gene expression could be detected in these tissues, Ptx1 presented with a quite ubiquitous pattern of distribution, being expressed at quite constant levels in normal tissues and in all 60 pituitary tumors analyzed. The pattern of expression of the Ptx2 gene among the different subsets of pituitary adenomas was even more varied. No Ptx2 expression could be detected in corticotroph tumors. In contrast, high levels of Ptx2 messenger ribonucleic acid were measured in the gonadotroph tumors, although no specific correlation to other markers of the gonadotroph lineage differentiation, such as alphaGsu, LHbeta, or FSHbeta, could be evidenced. Finally, Ptx2 was also expressed in pure lactotroph adenomas and not in somatotroph adenomas. Ptx2 is, therefore, the first paired homeodomain pituitary transcription factor differentially expressed in these two lineages, which derive from a common precursor. These results support a role for Ptx2 in the terminal differentiation of somatotroph and lactotroph cell phenotypes.

Expression of E-cadherin in squamous cell carcinomas of the supraglottic larynx with correlations to clinicopathological features.

The aim of this study was to investigate the prognostic significance of E-cadherin expression in squamous cell carcinomas of the supraglottic larynx. 101 primary carcinomas were retrospectively studied. The level of E-cadherin expression was determined by immunohistochemistry. There was a significant correlation between decreased E-cadherin expression and the presence of nodal metastases (P=0.007). T-stage (P=0.025) and histological grade (P=0.043) were also associated with nodal metastases. Multivariate analysis confirmed that these three parameters were independent predictors of nodal metastases. Decreased E-cadherin expression also correlated with an increase in recurrence rates (P=0.019). However, in multivariate analysis only pathological N-stage was significantly associated with disease-specific survival. We conclude that E-cadherin is an independent predictor of nodal metastases in supraglottic squamous cell carcinomas. Determination of E-cadherin expression levels might be useful in identifying patients with clinically negative lymph nodes who are at risk of occult metastases, allowing more effective treatment strategies to be implemented.

Increase of central 5-HT1B binding sites following 5,7-dihydroxytryptamine axotomy in the adult rat.

The effects of selective axotomy of serotoninergic neurons produced by an intracerebroventricular injection of 5,7-dihydroxytryptamine (200 micrograms free base) on 5-HT1B binding sites labeled with S-CM-G-[125I]TNH2 were investigated by quantitative autoradiography in the rat brain. Results show, 21 days after surgery, an upregulation of 5-HT1B receptors in the entorhinal cortex and the dorsomedial and suprachiasmatic nuclei of the hypothalamus. The cellular localization of those 5-HT1B receptors exhibiting post-lesion plastic properties is discussed.

Impairment of serotoninergic transmission is followed by adaptive changes in 5HT1B binding sites in the rat suprachiasmatic nucleus.

Serotonin1B (5-HT1B) receptor binding in the suprachiasmatic nucleus (SCN) following impairment of serotoninergic transmission was studied by quantitative autoradiography. Serotonin (5-HT) denervation with 5,7-dihydroxytryptamine (5,7-DHT) caused a significant increase in the density of 5-HT1B receptors in both the ventral (62%) and dorsal (53%) parts of the SCN as early as 3 days after axotomy. The magnitude of this increase did not differ 3, 15 or 21 days post-lesion. An up-regulation of 5-HT1B receptors with similar magnitude was obtained in the two parts of the SCN after inhibition of 5-HT synthesis by chronic parachlorophenylalanine treatment. In this case, up-regulation was shown to be reversible after restoration of 5-HT synthesis with L-5-hydroxytryptophan. These results indicate that 5-HT1B receptor density in the SCN was inversely correlated with 5-HT levels. These plastic properties exhibited by 5-HT1B receptors in the SCN are discussed in relation to the mode of 5-HT transmission and possible localization of the receptors onto the main chemically defined cell populations of the nucleus.

Post-lesion up-regulation of 5-HT1B binding sites in the suprachiasmatic nucleus may be reversed after spontaneous or graft-induced serotonin reinnervation.

We have previously reported that selective axotomy of serotoninergic neurons produced by an intraventricular injection of 5, 7-dihydroxytryptamine is followed by an increase in 5-HT1B binding sites in the suprachiasmatic nucleus of the hypothalamus. This post-lesion up-regulation is shown here to be spontaneously reversed after long-term survival in spite of an incomplete reinnervation of the nucleus. Recovery may be accelerated by fetal raphe transplants that produce more rapid reinnervation.

Additive and nonadditive genetic variability for growth traits in the Turipaná Romosinuano-Zebu multibreed herd.

Intrabreed additive genetic, environmental, and phenotypic variances and covariances for Romosinuano (R) and Zebu (Z), as well as interbreed nonadditive genetic variances and covariances (sire x breed-group-of-dam interactions), for birth weight (BWT), weaning weight (WW), and postweaning gain (GW) were computed using a Romosinuano-Zebu multibreed data set from the Turipaná Experiment Station in Colombia. Covariances were estimated with a sire-maternal grandsire model, using a multibreed REML procedure. The computing algorithm was a generalized expectation-maximization (GEM) algorithm. This algorithm yields no asymptotic standard errors as part of its computations. Because of the small size of the data set (2,546 calves), these REML covariance estimates should be viewed with caution. Estimates of intrabreed heritabilities were similar to the ratios of interbreed nonadditive to phenotypic variances (interactibilities) for direct and maternal effects of the growth traits evaluated in this study. Intrabreed heritability estimates for BWT, WW, and GW direct genetic effects were .16, .09, and .14, for R and .24, .10, and .14 for Z. Corresponding heritability values for maternal effects were .18, .09, and .23 for R and .14, .13, and .07 for Z. Interactibility estimates were .21, .05, and .12, for direct and .26, .04, and .11, for maternal BWT, WW, and GW. Negative correlations between additive maternal weaning weight and direct and maternal postweaning gain, as well as between environmental weaning weight and postweaning gain, suggested that there was compensatory postweaning gain in this herd. Estimates of genetic variation and predictions of expected progeny differences showed that Romosinuano animals competed well against Zebu and RZ crossbred animals under the tropical environmental conditions at Turipaná.

Genetic and environmental factors affecting serum macrominerals and weights in an Angus-Brahman multibreed herd: I. Additive and nonadditive group genetic effects of serum calcium, phosphorus, and magnesium and weight at weaning.

Amounts of serum calcium, phosphorus, and magnesium at weaning (WCa, WP, and WMg, respectively) and weaning weights (WW) were obtained from 380 Angus (A), Brahman (B), and A x B calves of various expected A and B fractions reared at the Pine Acres Research Station of the University of Florida, Citra from 1989 to 1990. Calves were produced by mating A, .75A, .25B, .5A .5B, .25A .75B, B, and Brangus (.625A .375B) sires to dams of the same expected breed fractions, except for .25A .75B dams. Best linear unbiased estimates (BLUE) of genetic effects, expressed as regression coefficients, were 1) -15.07 +/- 13.65 mg of WCa, -11.21 +/- 12.07 mg of WP, -1.23 +/- 2.99 mg of WMg, and .66 +/- 1.18 kg of WW for the difference between A and B additive direct; 2) 9.79 +/- 6.94 mg of WCa, -5.72 +/- 6.14 mg of WP, 1.64 +/- 1.52 mg of WMg, and .52 +/- .60 kg of WW for the difference between A and B additive maternal; 3) 242.21 +/- 51.56 mg of WCa, 66.67 +/- 45.62 mg of WP, 52.16 +/- 11.27 mg of WMg, and 22.61 +/- 4.44 kg of WW for A x B nonadditive direct; and 4) 373.63 +/- 38.44 mg of WCa, 93.96 +/- 34.02 mg of WP, 69.90 +/- 8.41 mg of WMg, and 36.83 +/- 3.31 kg of WW for A x B nonadditive maternal. Nonadditive (A x B) effects were the main factors affecting total (sum of additive plus nonadditive) genetic effects in this multibreed population. Total genetic effects were used to rank breed group of sire x breed group of dam combinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic and environmental factors affecting serum macrominerals and weights in an Angus-Brahman multibreed herd: II. Heritabilities of and genetic, environmental, and phenotypic correlations among serum calcium, phosphorus, and magnesium and weight at weaning.

Heritabilities of and genetic, environmental, and phenotypic correlations among serum amounts of calcium, phosphorus, and magnesium and weight at weaning (WCa, WP, WMg, and WW, respectively) were estimated for an Angus (A)-Brahman(B) multibreed herd located at the Pine Acres Research Station of the University of Florida, Citra. Records were obtained from 380 calves produced by mating A, .75A .25B, .5A .5B, .25A .75B, B, and Brangus sires across dams of the same breed groups, except for .25A .75B, during 1989 and 1990. Restricted maximum likelihood procedures were used to compute variance and covariance components. Estimates of heritability were .39 (WCa), .40 (WP), .36 (WMg), and .35 (WW). Estimates of genetic, environmental, and phenotypic correlations were .66, .55, .57 (WCa, WP), .70, .71, .70 (WCa, WMg), 1.00, .86, .88 (WCa, WW), .50, .51, .51 (WP, WMg), .78, .60, .63 (WP, WW), and .86, .73, .75 (WMg, WW). These correlations indicate that serum Ca, P, and Mg could be used in multiple-trait genetic evaluation procedures to help identify animals that require low amounts of these macrominerals for preweaning growth. This may prove advantageous in mineral-deficient regions.

[Identification of respiratory syncytial virus and adenovirus in children with chronic serous otitis]. / Identificación del virus respiratorio sincitial y adenovirus en niños con otitis serosa crónica.

OBJECTIVE: To study the presence of respiratory syncytial virus (RSV) and adenovirus in the effusions of the middle ear and adenoid tissue from patients with chronic otitis media with effusion by use of the polymerase chain reaction. METHOD: The effusions and adenoid samples were collected from 32 children undergoing myringotomy and ventilation tube placement for chronic otitis media with effusion. The samples were separated for viral culture, immunofluorescence and PCR analysis. RESULTS: One (3%) effusion sample was positive for adenovirus by the PCR. None of samples (effusion and adenoid) were positives for RSV. The results of viral culture and immunofluorescence were all negative. CONCLUSIONS: Our results can not support that respiratory viruses play a role in the pathogenesis of chronic otitis media with effusion.

Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model.

Methylene blue (MB) belongs to the phenothiazinium family. It has been used to treat a variety of human conditions and has beneficial effects on the central nervous system in rodents with and without brain alteration. The present study was designed to test whether chronic MB treatment taken after (therapeutic effect) or before (preventive effect) the onset of beta-amyloid pathology influences cognition in a transgenic mouse model (APP/PS1). In addition, the present study aims at revealing whether these behavioral effects might be related to brain alteration in beta-amyloid deposition. To this end, we conducted an in vivo study and compared two routes of drug administration, drinking water versus intraperitoneal injection. Results showed that transgenic mice treated with MB orally or following intraperitoneal injection were protected from cognitive impairments in a variety of social, learning, and exploratory tasks. Immunoreactive beta-amyloid deposition was significantly reduced in the hippocampus and adjacent cortex in MB-treated transgenic mice. Interestingly, these beneficial effects were observed independently of beta-amyloid load at the time of MB treatment. This suggests that MB treatment is beneficial at both therapeutic and preventive levels. Using solid-state High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate. We conclude that MB might be useful for the therapy and prevention of Alzheimer's disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

[Positional cranial deformations: a clinical-epidemiological study]. / Deformaciones craneales posicionales: estudio clínico-epidemiológico.

INTRODUCTION: Cranial deformities have always existed, but it is only until recently that they provoked a greater interest. Several reports have demonstrated an increasing tendency for occipital plagiocephaly. This work presents an analysis of the clinical-epidemiological features of these deformities in our area. PATIENTS AND METHODS: The medical records and neuroimaging studies of 158 children seen at our hospital due to a skull deformation were analyzed, paying special attention to risk factors. RESULTS: During the study period, an increase in the number of consultations for skull deformation of children was noted. The mean age for the patients at consultation was 9 months. There was a predominance of boys (68%) over girls. The deformities were: unilateral- (89.2%) or bilateral-posterior plagiocephaly (7.6%), and dolicochephaly (3.2%). In addition to the supine position for sleeping, there were several risk factors, among them pericerebral collections of cerebrospinal fluid found in 50% of children subjected to neuroimaging studies. Most children were managed conservatively, while 12 patients were given helmets, which led to an improvement in 136 cases. DISCUSSION AND CONCLUSIONS: The present findings agree with those in the current literature. A unique result of this study was the high rate of pericerebral fluid collections found in children assessed with neuroimaging methods. The increase in positional plagiocephaly seems to parallel the application of the recommendations for supine sleeping position established by the American Academy of Pediatrics for preventing the sudden infant death syndrome. The role played by Pediatricians in the detection, initial management and referral of these children is highlighted. Prevention measures seem to be more important than those regarding treatment.