New evidence on the management of Lewy body dementia

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordNote that the article title of the accepted author manuscript is different to that of the final published version.Dementia with Lewy bodies and Parkinson’s disease dementia, jointly known as Lewy body dementia (LBD), are common neurodegenerative conditions. Patients with LBD present with a wide range of cognitive, neuropsychiatric, sleep, motor, and autonomic symptoms. The expression of these varies between individual patients, and over time. Treatments may benefit one symptom, but at the expense of worsening another, making management difficult. Often symptoms are managed in isolation and by different specialists, which undermines high quality care. Clinical trials and meta-analyses now provide an improved evidence base for the treatment of cognitive, neuropsychiatric and motor symptoms in LBD, in addition to which expert consensus opinion supports the application of treatments from related conditions such as Parkinson’s disease (PD) for the management of, for example, autonomic symptoms. There remain however clear evidence gaps and there is a high need for future clinical trials focused on specific symptoms in LBD.National Institute for Health Research (NIHR

Clinical diagnosis of Lewy body dementia

This is the final version. Available on open access from Cambridge University Press via the DOI in this recordBackground Lewy body dementia consisting of both dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) dementia (PDD) is considerably under-recognised clinically compared to its frequency in autopsy series. Aims This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis maybe contributing to these differences. Methods We reviewed the medical notes of 74 DLB and 72 non-DLB dementia cases matched for age, gender and cognitive performance, together with 38 PDD cases and 35 PD cases, matched for age and gender, from two geographically distinct UK regions. Results DLB cases took longer to reach a final diagnosis (1.2v0.6 years, p=0.003), underwent more scans (1.7v1.2, p=0.017) and had more alternative prior diagnoses (0.8v0.4, p=0.002), than non-DLB cases. Cases diagnosed in one region had significantly more core features (2.1v1.5, p=0.007) than in the other and were less likely to have dopamine transporter imaging (p<0.001). For PDD cases, more than 1.4 years prior to receiving a dementia diagnosis, 46% had documented impaired activities of daily living due to cognitive impairment, 57% had cognitive impairment in multiple domains, with 38% having both, and 39% already receiving anti-dementia drugs. 3 Conclusions Our results show the pathway to diagnosis of DLB is longer and more complex than nonDLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. Whilst for PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.National Institute for Health Research (NIHR

The impact of childhood vaccines on bacterial carriage in the nasopharynx: a longitudinal study.

BACKGROUND: There is increasing evidence that childhood vaccines have effects that extend beyond their target disease. The objective of this study was to assess the effects of routine childhood vaccines on bacterial carriage in the nasopharynx. METHODS: A cohort of children from rural Gambia was recruited at birth and followed up for one year. Nasopharyngeal swabs were taken immediately after birth, every two weeks for the first six months and then every other month. The presence of bacteria in the nasopharynx (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus) was compared before and after the administration of DTP-Hib-HepB and measles-yellow fever vaccines. RESULTS: A total of 1,779 nasopharyngeal swabs were collected from 136 children for whom vaccination data were available. The prevalence of bacterial carriage was high: 82.2% S. pneumoniae, 30.6%, S.aureus, 27.8% H. influenzae. Carriage of H. influenzae (OR = 0.36; 95% CI: 0.13, 0.99) and S. pneumoniae (OR = 0.25; 95% CI: 0.07, 0.90) were significantly reduced after measles-yellow fever vaccination; while DTP-Hib-HepB had no effect on bacterial carriage. CONCLUSIONS: Nasopharyngeal bacterial carriage is unaffected by DTP-Hib-HepB vaccination and reduced after measles-yellow fever vaccination

Genome-wide evolutionary dynamics of influenza B viruses on a global scale

The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly-sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co-circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally

Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth

To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines

Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies

The aim of this study was to characterize myelin loss as one of the features of white matter abnormalities across three common dementing disorders. We evaluated post-mortem brain tissue from frontal and temporal lobes from 20 vascular dementia (VaD), 19 Alzheimer’s disease (AD) and 31 dementia with Lewy bodies (DLB) cases and 12 comparable age controls. Images of sections stained with conventional luxol fast blue were analysed to estimate myelin attenuation by optical density. Serial adjacent sections were then immunostained for degraded myelin basic protein (dMBP) and the mean percentage area containing dMBP (%dMBP) was determined as an indicator of myelin degeneration. We further assessed the relationship between dMBP and glutathione S-transferase (a marker of mature oligodendrocytes) immunoreactivities. Pathological diagnosis significantly affected the frontal but not temporal lobe myelin attenuation: myelin density was most reduced in VaD compared to AD and DLB, which still significantly exhibited lower myelin density compared to ageing controls. Consistent with this, the degree of myelin loss was correlated with greater %dMBP, with the highest %dMBP in VaD compared to the other groups. The %dMBP was inversely correlated with the mean size of oligodendrocytes in VaD, whereas it was positively correlated with their density in AD. A two-tier regression model analysis confirmed that the type of disorder (VaD or AD) determines the relationship between %dMBP and the size or density of oligodendrocytes across the cases. Our findings, attested by the use of three markers, suggest that myelin loss may evolve in parallel with shrunken oligodendrocytes in VaD but their increased density in AD, highlighting partially different mechanisms are associated with myelin degeneration, which could originate from hypoxic–ischaemic damage to oligodendrocytes in VaD whereas secondary to axonal degeneration in AD

The anti-bacterial iron-restriction defence mechanisms of egg white; the potential role of three lipocalin-like proteins in resistance against Salmonella

Salmonella enterica serovar Enteritidis (SE) is the most frequently-detected Salmonella in foodborne outbreaks in the European Union. Among such outbreaks, egg and egg products were identified as the most common vehicles of infection. Possibly, the major antibacterial property of egg white is iron restriction, which results from the presence of the iron-binding protein, ovotransferrin. To circumvent iron restriction, SE synthesise catecholate siderophores (i.e. enterobactin and salmochelin) that can chelate iron from host iron-binding proteins. Here, we highlight the role of lipocalin-like proteins found in egg white that could enhance egg-white iron restriction through sequestration of certain siderophores, including enterobactin. Indeed, it is now apparent that the egg-white lipocalin, Ex-FABP, can inhibit bacterial growth via its siderophore-binding capacity in vitro. However, it remains unclear whether ex-FABP performs such a function in egg white or during bird infection. Regarding the two other lipocalins of egg white (Cal-γ and α-1-glycoprotein), there is currently no evidence to indicate that they sequester siderophores