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Objective: The BRAIN Study was established to assess the associations between self‐reported concussions and cognitive function among retired rugby players. Methods: Former elite‐level male rugby union players (50+ years) in England were recruited. Exposure to rugby‐related concussion was collected using the BRAIN‐Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. Results: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby‐related concussion(s). No association was found between concussion and PACC (β –0.03 [95% confidence interval (CI): –1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (β –1.04 [95% CI: –1.62, –0.47]). Conclusions: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants. [ABSTRACT FROM AUTHOR]

Background: Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) is a Gram-negative bacterium present in the oral cavity and is usually associated with localized aggressive periodontitis. Isolated antigens from A. actinomycetemcomitans can activate innate immune cells through Toll-like receptors (TLRs), which are molecules that recognize structural components conserved among microorganisms. In this study, we evaluate the role of TLR2 in the recognition of A. actinomycetemcomitans. Methods: Macrophages and neutrophils from knockout mice with targeted disruption of TLR2 (TLR2-/- mice) and wild-type mice were collected and used for the subsequent assays. The production of cytokines and chemokines was evaluated by enzyme-linked immunosorbent assay (ELISA), and the presence of apoptotic cells was determined by flow cytometry. In addition, the mechanisms that modulate the outcome of A. actinomycetemcomitans-induced periodontal disease in TLR2-/- mice were examined. Results: The results show that TLR2-deficient mice developed more severe periodontitis after A. actinomycetemcomitans infection, characterized by significantly higher bone loss and inflammatory cell migration to periodontal tissues. The inflammatory cell influx into the peritoneal cavities of TLR2-/- mice was three-fold lower than that observed for the littermate controls. A significantly diminished production of the cytokines tumor necrosis factor-alpha and interleukin-1β as well as the chemokine CC-ligand-5 in the peritoneal cavities of TLR2-/--mice was observed. In addition, a high frequency of apoptotic cells in the inflammatory exudates from TLR2-/- mice was observed. Phagocytosis and nitric oxide production was diminished in cells from TLR2-/--mice, facilitating the dissemination of the pathogen to the spleen. Conclusion: The results of this study highlight the involvement of TLR2 in recognizing A. actinomycetemcomitans and its essential role in controlling A. actinomycetemcomitans infection. [ABSTRACT FROM AUTHOR]

In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, succinate semialdehyde dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134-147 ms; normal <118 ms. We hypothesize that elevated GABA in ocular tissue of SSADH patients leads to a use-dependent downregulation of the major GABAergic receptor in eye, GABA, and that the VEP recordings' abnormalities, as evidenced by P100 latency and/or amplitude measurements, may be reflective of abnormalities within visual systems. This is a preliminary finding that may suggest the utility of performing VEP analysis in a larger sample of SSADH-deficient patients, and encourage a neurophysiological assessment of GABA receptor function in Aldh5a1 mice to reveal new pathophysiological mechanisms of this rare disorder of GABA degradation. [ABSTRACT FROM AUTHOR]

To analyze the contribution of the Czech population to the Y-chromosome diversity landscape of Europe and to reconstruct past demographic events, we typed 257 males from five locations for 21 UEPs. Moreover, 141 carriers of the three most common haplogroups were typed for 10 microsatellites and coalescent analyses applied. Sixteen Hg's characterized by derived alleles were identified, the most common being R1a-SRY10831 and P-DYS257*(xR1a). The pool of haplogroups within I-M170 represented the third most common clade. Over-all, the degree of population structure was low. The ages for Hg I-M170, P-DYS257*(xR1a), and R1a-SRY10831 appeared to be comparable and compatible with their presence during or soon after the LGM. A signal of population growth beginning in the first millennium B.C. was detected. Its similarity among the three most common Hg's indicated that growth was characteristic for a gene pool that already contained all of them. The Czech population appears to be influenced, to a very moderate extent, by genetic inputs from outside Europe in the post-Neolithic and historical times. Population growth post-dated the archaeologically documented introduction of Neolithic technology and the estimated central value coincides with a period of repeated changes driven by the development of metal technologies and the associated social and trade organization. [ABSTRACT FROM AUTHOR]

The Mediterranean region has been characterised by a number of pre-historical and historical demographic events whose legacy on the current genetic landscape is still a matter of debate. In order to investigate the degree of population structure across the Mediterranean, we have investigated Y chromosome variation in a large dataset of Mediterranean populations, 11 of which are first described here. Our analyses identify four main clusters in the Mediterranean that can be labelled as North Africa, Arab, Central-East and West Mediterranean. In particular, Near Eastern samples tend to separate according to the presence of Arab Y chromosome lineages, suggesting that the Arab expansion played a major role in shaping the current genetic structuring within the Fertile Crescent. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Linkage exclusion in Italian families with hereditary essential tremor," by A. Novelletto, R. Gulli, P. Ciotti, and colleagues that was published in the 2011 issue.

In this work we focus on a microsatellite-defined Y-chromosomal lineage (network 1.2) identified by us and reported in previous studies, whose geographic distribution and antiquity appear to be compatible with the Neolithic spread of farmers. Here, we set network 1.2 in the Y-chromosomal phylogenetic tree, date it with respect to other lineages associated with the same movements by other authors, examine its diversity by means of tri- and tetranucleotide loci and discuss the implications in reconstructing the spread of this group of chromosomes in the Mediterranean area. Our results define a tripartite phylogeny within HG 9 (Rosser et al. 2000), with the deepest branching defined by alleles T (Haplogroup Eu10) or G (Haplogroup Eu9) at M172 (Semino et al. 2000), and a subsequent branching within Eu9 defined by network 1.2. Population distributions of HG 9 and network 1.2 show that their occurrence in the surveyed area is not due to the spread of people from a single parental population but, rather, to a process punctuated by at least two phases. Our data identify the wide area of the Balkans, Aegean and Anatolia as the possible homeland harbouring the largest variation within network 1.2. The use of recently proposed tests based on the stepwise mutation model suggests that its spread was associated to a population expansion, with a high rate of male gene flow in the Turkish-Greek area.

We typed 1801 males from 55 locations for the Y-specific binary markers YAP, DYZ3, SRY10831 and the (CA)n microsatellites YCAII and DYS413. Phylogenetic relationships of chromosomes with the same binary haplotype were condensed in seven large one-step networks, which accounted for 95% of all chromosomes. Their coalescence ages were estimated based on microsatellite diversity. The three largest and oldest networks undergo sharp frequency changes in three areas. The more recent network 3.1A clearly discriminates between Western and Eastern European populations. Pairwise Fst showed an overall increment with increasing geographic distance but with a slope greatly reduced when compared to previous reports. By sectioning the entire data set according to geographic and linguistic criteria, we found higher Fst-on-distance slopes within Europe than in West Asia or across the two continents.

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.

We characterized four DNA polymorphisms on the Y chromosomes of 123 males from five Caucasian populations. Three markers on the male specific portion of the chromosome varied appreciably in frequency among the populations. When combined, these markers define a limited number of haplotypes compared with the maximum expected on the basis of random association. The associations found in the five groups are qualitatively similar and are thus considered to be relatively stable on an evolutionary time-scale and possibly to predate the divergence of Caucasian populations. However, the haplotype frequencies varied markedly among populations, even between weakly isolated areas such as northern vs. southern Sardinia. This may indicate rapid progression towards fixation of alternative types of Y chromosomes. We also report data suggesting that the same associations no longer hold when examining a marker as close as 275 bp from the boundary of the pseudoautosomal region on the Y chromosome.

Two large Italian pedigrees with HLA-linked spinocerebellar ataxia (SCA1) were typed for HLA-A, -B and -DR as well as for markers either distal (F13A, D6S8) or proximal (D6S29, GLO1) to HLA. Pairwise linkage analyses of SCA1 vs. HLA-A, -B, and -DR showed peak lodscores of 5.3, 5.6 and 3.3 respectively at 7% recombination. Negative lodscores significantly excluded linkage with F13A at less than 5% and with GLO1 at less than 10%. The lodscores with D6S8 and D6S29 had only low peaks. Recombination events in the two pedigrees and the estimated genetic distances of SCA1 from GLO1 and HLA favour the hypothesis of a SCA1 location distal to both of them. An order cen-GLO1-HLA-SCA1-tel appears therefore most likely with present data. These results are discussed in relation to previous reports placing SCA1 distal to HLA in two families and

Six new Y-specific probes have been isolated and are reported. Along with another six already described they have been used in a systemic search for male specific RFLPs. An overall number of 46515 nucleotides have been screened with 12 enzymes and no polymorphic pattern observed. Our data reveal a greatly reduced level of polymorphism compared with other chromosomes.

Huntington's chorea is a late onset disease of the nervous system whose mode of inheritance conforms to the autosomal dominant model. The present paper shows how the problem of estimating the distribution of age at onset of the disease can be dealt with as an incomplete data problem via the EM algorithm, both in the parametric and non-parametric setting. In this way it is possible to take into account not only the heterozygotes in the population under study who are manifestly affected, but also those who are apparently unaffected. The estimation of the distribution of age at onset of the disease is required for estimating the posterior probability of heterozygosity of the individual at risk using Bayes' theorem. The proposed approach was applied to data derived from a survey carried out on the population of Latium, Italy.