In vivo testing of novel vaccine prototypes against Actinobacillus pleuropneumoniae

Actinobacillus pleuropneumoniae (A. pleuropneumoniae) is a Gram-negative bacterium that represents the main cause of porcine pleuropneumonia in pigs, causing significant economic losses to the livestock industry worldwide. A. pleuropneumoniae, as the majority of Gram-negative bacteria, excrete vesicles from its outer membrane (OM), accordingly defined as outer membrane vesicles (OMVs). Thanks to their antigenic similarity to the OM, OMVs have emerged as a promising tool in vaccinology. In this study we describe the in vivo testing of several vaccine prototypes for the prevention of infection by all known A. pleuropneumoniae serotypes. Previously identified vaccine candidates, the recombinant proteins ApfA and VacJ, administered individually or in various combinations with the OMVs, were employed as vaccination strategies. Our data show that the addition of the OMVs in the vaccine formulations significantly increased the specific IgG titer against both ApfA and VacJ in the immunized animals, confirming the previously postulated potential of the OMVs as adjuvant. Unfortunately, the antibody response raised did not translate into an effective protection against A. pleuropneumoniae infection, as none of the immunized groups following challenge showed a significantly lower degree of lesions than the controls. Interestingly, quite the opposite was true, as the animals with the highest IgG titers were also the ones bearing the most extensive lesions in their lungs. These results shed new light on A. pleuropneumoniae pathogenicity, suggesting that antibody-mediated cytotoxicity from the host immune response may play a central role in the development of the lesions typically associated with A. pleuropneumoniae infections

Root Fracture in Immature Tooth: Report of a Case

Root fracture injuries affect 0.5–7% of permanent teeth. Although this type of injury is rarely seen in teeth with immature root formation, the prognosis is generally good depending on the site of the fracture. A case report of horizontal root fracture in maxillary central incisor of an 8-year and 3-month-old girl and its treatment was presented

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease

The accumulation of misfolded proteins in neurons, leading to the formation of cytoplasmic and nuclear aggregates, is a common theme in age-related neurodegenerative diseases, possibly due to disturbances of the proteostasis and insufficient activity of cellular protein clearance pathways. Lithium is a well-known autophagy inducer that exerts neuroprotective effects in different conditions and has been proposed as a promising therapeutic agent for several neurodegenerative diseases. We tested the efficacy of chronic lithium 10.4 mg/kg) treatment in a transgenic mouse model of Machado-Joseph disease, an inherited neurodegenerative disease, caused by an expansion of a polyglutamine tract within the protein ataxin-3. A battery of behavioral tests was used to assess disease progression. In spite of activating autophagy, as suggested by the increased levels of Beclin-1, Atg7, and LC3II, and a reduction in the p62 protein levels, lithium administration showed no overall beneficial effects in this model concerning motor performance, showing a positive impact only in the reduction of tremors at 24 weeks of age. Our results do not support lithiumchronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).FCT -Fundação para a Ciência e a Tecnologia(SFRH/BD/51059/2010

Early influences on cardiovascular and renal development

The hypothesis that a developmental component plays a role in subsequent disease initially arose from epidemiological studies relating birth size to both risk factors for cardiovascular disease and actual cardiovascular disease prevalence in later life. The findings that small size at birth is associated with an increased risk of cardiovascular disease have led to concerns about the effect size and the causality of the associations. However, recent studies have overcome most methodological flaws and suggested small effect sizes for these associations for the individual, but an potential important effect size on a population level. Various mechanisms underlying these associations have been hypothesized, including fetal undernutrition, genetic susceptibility and postnatal accelerated growth. The specific adverse exposures in fetal and early postnatal life leading to cardiovascular disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life may underlie the complex associations of fetal growth retardation and low birth weight with cardiovascular disease in later life. To estimate the population effect size and to identify the underlying mechanisms, well-designed epidemiological studies are needed. This review is focused on specific adverse fetal exposures, cardiovascular adaptations and perspectives for new studies. Copyrigh

Global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017

Background Understanding the patterns of HIV/AIDS epidemics is crucial to tracking and monitoring the progress of prevention and control efforts in countries. We provide a comprehensive assessment of the levels and trends of HIV/AIDS incidence, prevalence, mortality, and coverage of antiretroviral therapy (ART) for 1980–2017 and forecast these estimates to 2030 for 195 countries and territories. Methods We determined a modelling strategy for each country on the basis of the availability and quality of data. For countries and territories with data from population-based seroprevalence surveys or antenatal care clinics, we estimated prevalence and incidence using an open-source version of the Estimation and Projection Package—a natural history model originally developed by the UNAIDS Reference Group on Estimates, Modelling, and Projections. For countries with cause-specific vital registration data, we corrected data for garbage coding (ie, deaths coded to an intermediate, immediate, or poorly defined cause) and HIV misclassification. We developed a process of cohort incidence bias adjustment to use information on survival and deaths recorded in vital registration to back-calculate HIV incidence. For countries without any representative data on HIV, we produced incidence estimates by pulling information from observed bias in the geographical region. We used a re-coded version of the Spectrum model (a cohort component model that uses rates of disease progression and HIV mortality on and off ART) to produce age-sex-specific incidence, prevalence, and mortality, and treatment coverage results for all countries, and forecast these measures to 2030 using Spectrum with inputs that were extended on the basis of past trends in treatment scale-up and new infections. Findings Global HIV mortality peaked in 2006 with 1·95 million deaths (95% uncertainty interval 1·87–2·04) and has since decreased to 0·95 million deaths (0·91–1·01) in 2017. New cases of HIV globally peaked in 1999 (3·16 million, 2·79–3·67) and since then have gradually decreased to 1·94 million (1·63–2·29) in 2017. These trends, along with ART scale-up, have globally resulted in increased prevalence, with 36·8 million (34·8–39·2) people living with HIV in 2017. Prevalence of HIV was highest in southern sub-Saharan Africa in 2017, and countries in the region had ART coverage ranging from 65·7% in Lesotho to 85·7% in eSwatini. Our forecasts showed that 54 countries will meet the UNAIDS target of 81% ART coverage by 2020 and 12 countries are on track to meet 90% ART coverage by 2030. Forecasted results estimate that few countries will meet the UNAIDS 2020 and 2030 mortality and incidence targets. Interpretation Despite progress in reducing HIV-related mortality over the past decade, slow decreases in incidence, combined with the current context of stagnated funding for related interventions, mean that many countries are not on track to reach the 2020 and 2030 global targets for reduction in incidence and mortality. With a growing population of people living with HIV, it will continue to be a major threat to public health for years to come. The pace of progress needs to be hastened by continuing to expand access to ART and increasing investments in proven HIV prevention initiatives that can be scaled up to have population-level impact

Pulpal sequelae after trauma to anterior teeth among adult Nigerian dental patients

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies show that about 11.6% to 33.0% of all boys and about 3.6% to 19.3% of all girls suffer dental trauma of varying severity before the age of 12 years. Moderate injuries to the periodontium such as concussion and subluxation are usually associated with relatively minor symptoms and hence may go unnoticed by the patient or the dentist, if consulted. Patients with these kinds of injuries present years after a traumatic accident most of the time with a single discoloured tooth. This study sets out to document the incidence of various posttraumatic sequelae of discoloured anterior teeth among adult Nigerian dental patients.</p> <p>Methods</p> <p>One hundred and sixty eight (168) traumatized discoloured anterior teeth in 165 patients were studied. Teeth with root canal treatment were excluded from the study. Partial obliteration was recorded when the pulp chamber or root canal was not discernible or reduced in size on radiographs, total obliteration was recorded when pulp chamber and root canal were not discernible. A retrospective diagnosis of concussion was made from patient's history of trauma to the tooth without abnormal loosening, while subluxation was made from patient's history of trauma to the tooth with abnormal loosening.</p> <p>Results</p> <p>Of the 168 traumatized discoloured anterior teeth, 47.6% and 31.6% had partial and total obliteration of the pulp canal spaces respectively, 20.8% had pulpal necrosis. Concussion and subluxation injuries resulted more in obliteration of the pulp canal space, while fracture of the teeth resulted in more pulpal necrosis (p < 0.001). Injuries sustained during the 1^stand 2^nddecade of life resulted more in obliteration of the pulp canal space, while injuries sustained in the 3^rddecade resulted in more pulpal necrosis.</p> <p>Conclusion</p> <p>Calcific metamorphosis developed more in teeth with concussion and subluxation injuries. Pulpal necrosis occurred more often in traumatized teeth including fractures.</p