Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Acupuncture for sequelae of Bell's palsy: a randomized controlled trial protocol

<p>Abstract</p> <p>Objective</p> <p>Incomplete recovery from facial palsy has a long-term impact on the quality of life, and medical options for the sequelae of Bell's palsy are limited. Invasive treatments and physiotherapy have been employed to relieve symptoms, but there is limited clinical evidence for their effectiveness. Acupuncture is widely used on Bell's palsy patients in East Asia, but there is insufficient evidence for its effectiveness on Bell's palsy sequelae. The objective is to evaluate the efficacy and safety of acupuncture in patients with sequelae of Bell's palsy.</p> <p>Method/Design</p> <p>This study consists of a randomized controlled trial with two parallel arms: an acupuncture group and a waitlist group. The acupuncture group will receive acupuncture treatment three times per week for a total of 24 sessions over 8 weeks. Participants in the waitlist group will not receive any acupuncture treatments during this 8 week period, but they will participate in the evaluations of symptoms at the start of the study, at 5 weeks and at 8 weeks after randomization, at which point the same treatment as the acupuncture group will be provided. The primary outcome will be analyzed by the change in the Facial Disability Index (FDI) from baseline to week eight. The secondary outcome measures will include FDI from baseline to week five, House-Brackmann Grade, lip mobility, and stiffness scales.</p> <p>Trial registration</p> <p>Current Controlled-Trials <a href="http://www.controlled-trials.com/ISRCTN43104115">ISRCTN43104115</a>; registration date: 06 July 2010; the date of the first patient's randomization: 04 August 2010</p

The feasibility of collecting information from people with Multiple Sclerosis for the UK MS Register via a web portal: characterising a cohort of people with MS.

BACKGROUND: A UK Register of people with Multiple Sclerosis has been developed to address the need for an increased knowledge-base about MS. The Register is being populated via: a web-based portal; NHS neurology clinical systems; and administrative data sources. The data are de-identified and linked at the individual level. At the outset, it was not known whether people with MS would wish to participate in the UK MS Register by personally contributing their data to the Register via a web-based system. Therefore, the research aim of this work was to build an internet-mounted recruitment and consenting technology for people with Multiple Sclerosis, and to assess its feasibility as a questionnaire delivery platform to contribute data to the UK MS Register, by determining whether the information provided could be used to describe a cohort of people with MS. METHODS: The web portal was developed using VB.net and JQuery with a Microsoft SQL 2008 database. UK adults with MS can self-register and enter data about themselves by completing validated questionnaires. Descriptive statistics were used to characterise the respondents. RESULTS: The web portal was launched in May 2011, and in first three months 7,279 individuals registered on the portal. The ratio of men to women was 1:2.4 (n = 5,899), the mean self-reported age at first symptoms was 33.8 (SD 10.5) years, and at diagnosis 39.6 (SD 10.3) years (n = 4,401). The reported types of MS were: 15% primary progressive, 63% relapsing-remitting, 8% secondary progressive, and 14% unknown (n = 5,400). These characteristics are similar to those of the prevalent MS population. Employment rates, sickness/disability rates, ethnicity and educational qualifications were compared with the general UK population. Information about the respondents' experience of early symptoms and the process of diagnosis, plus living arrangements are also reported. CONCLUSIONS: These initial findings from the MS Register portal demonstrate the feasibility of collecting data about people with MS via a web platform, and show that sufficient information can be gathered to characterise a cohort of people with MS. The innovative design of the UK MS register, bringing together three disparate sources of data, is creating a rich resource for research into this condition

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a

Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge

Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3

Genome wide association studies (GWAS) for Parkinson's disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD

Murine and Bovine γδ T Cells Enhance Innate Immunity against Brucella abortus Infections

γδ T cells have been postulated to act as a first line of defense against infectious agents, particularly intracellular pathogens, representing an important link between the innate and adaptive immune responses. Human γδ T cells expand in the blood of brucellosis patients and are active against Brucella in vitro. However, the role of γδ T cells in vivo during experimental brucellosis has not been studied. Here we report TCRδ−/− mice are more susceptible to B. abortus infection than C57BL/6 mice at one week post-infection as measured by splenic colonization and splenomegaly. An increase in TCRγδ cells was observed in the spleens of B. abortus-infected C57BL/6 mice, which peaked at two weeks post-infection and occurred concomitantly with diminished brucellae. γδ T cells were the major source of IL-17 following infection and also produced IFN-γ. Depletion of γδ T cells from C57BL/6, IL-17Rα−/−, and GMCSF−/− mice enhanced susceptibility to B. abortus infection although this susceptibility was unaltered in the mutant mice; however, when γδ T cells were depleted from IFN-γ−/− mice, enhanced susceptibility was observed. Neutralization of γδ T cells in the absence of TNF-α did not further impair immunity. In the absence of TNF-α or γδ T cells, B. abortus-infected mice showed enhanced IFN-γ, suggesting that they augmented production to compensate for the loss of γδ T cells and/or TNF-α. While the protective role of γδ T cells was TNF-α-dependent, γδ T cells were not the major source of TNF-α and activation of γδ T cells following B. abortus infection was TNF-α-independent. Additionally, bovine TCRγδ cells were found to respond rapidly to B. abortus infection upon co-culture with autologous macrophages and could impair the intramacrophage replication of B. abortus via IFN-γ. Collectively, these results demonstrate γδ T cells are important for early protection to B. abortus infections

Using Non-Homogeneous Models of Nucleotide Substitution to Identify Host Shift Events: Application to the Origin of the 1918 ‘Spanish’ Influenza Pandemic Virus

Nonhomogeneous Markov models of nucleotide substitution have received scant attention. Here we explore the possibility of using nonhomogeneous models to identify host shift nodes along phylogenetic trees of pathogens evolving in different hosts. It has been noticed that influenza viruses show marked differences in nucleotide composition in human and avian hosts. We take advantage of this fact to identify the host shift event that led to the 1918 ‘Spanish’ influenza. This disease killed over 50 million people worldwide, ranking it as the deadliest pandemic in recorded history. Our model suggests that the eight RNA segments which eventually became the 1918 viral genome were introduced into a mammalian host around 1882–1913. The viruses later diverged into the classical swine and human H1N1 influenza lineages around 1913–1915. The last common ancestor of human strains dates from February 1917 to April 1918. Because pigs are more readily infected with avian influenza viruses than humans, it would seem that they were the original recipient of the virus. This would suggest that the virus was introduced into humans sometime between 1913 and 1918

Reduced Selective Constraint in Endosymbionts: Elevation in Radical Amino Acid Replacements Occurs Genome-Wide

As predicted by the nearly neutral model of evolution, numerous studies have shown that reduced Ne accelerates the accumulation of slightly deleterious changes under genetic drift. While such studies have mostly focused on eukaryotes, bacteria also offer excellent models to explore the effects of Ne. Most notably, the genomes of host-dependent bacteria with small Ne show signatures of genetic drift, including elevated Ka/Ks. Here, I explore the utility of an alternative measure of selective constraint: the per-site rate of radical and conservative amino acid substitutions (Dr/Dc). I test the hypothesis that purifying selection against radical amino acid changes is less effective in two insect endosymbiont groups (Blochmannia of ants and Buchnera of aphids), compared to related gamma-Proteobacteria. Genome comparisons demonstrate a significant elevation in Dr/Dc in endosymbionts that affects the majority (66–79%) of shared orthologs examined. The elevation of Dr/Dc in endosymbionts affects all functional categories examined. Simulations indicate that Dr/Dc estimates are sensitive to codon frequencies and mutational parameters; however, estimation biases occur in the opposite direction as the patterns observed in genome comparisons, thereby making the inference of elevated Dr/Dc more conservative. Increased Dr/Dc and other signatures of genome degradation in endosymbionts are consistent with strong effects of genetic drift in their small populations, as well as linkage to selected sites in these asexual bacteria. While relaxed selection against radical substitutions may contribute, genome-wide processes such as genetic drift and linkage best explain the pervasive elevation in Dr/Dc across diverse functional categories that include basic cellular processes. Although the current study focuses on a few bacterial lineages, it suggests Dr/Dc is a useful gauge of selective constraint and may provide a valuable alternative to Ka/Ks when high sequence divergences preclude estimates of Ks. Broader application of Dr/Dc will benefit from approaches less prone to estimation biases