An Age-Associated Decline in Thymic Output Differs in Dog Breeds According to Their Longevity

The age associated decline in immune function is preceded in mammals by a reduction in thymic output. Furthermore, there is increasing evidence of a link between immune competence and lifespan. One approach to determining thymic output is to quantify signal joint T cell receptor excision circles (sj-TRECs), a method which has been developed and used in several mammalian species. Life expectancy and the rate of aging vary in dogs depending upon their breed. In this study, we quantified sj-TRECs in blood samples from dogs of selected breeds to determine whether there was a relationship between longevity and thymic output. In Labrador retrievers, a breed with a median expected lifespan of 11 years, there was an age-associated decline in sj-TREC values, with the greatest decline occurring before 5 years of age, but with sj-TREC still detectable in some geriatric animals, over 13 years of age. In large short-lived breeds (Burnese mountain dogs, Great Danes and Dogue de Bordeaux), the decline in sj-TREC values began earlier in life, compared with small long-lived breeds (Jack Russell terriers and Yorkshire terriers), and the presence of animals with undetectable sj-TRECs occurred at a younger age in the short-lived breeds. The study findings suggest that age-associated changes in canine sj-TRECs are related to breed differences in longevity, and this research highlights the use of dogs as a potential model of immunosenescence.     

A Multiple Case Study of Mental Health Interventions in Middle Income Countries: Considering the Science of Delivery

In the debate in global mental health about the most effective models for developing and scaling interventions, there have been calls for the development of a more robust literature regarding the "non-specific", science of delivery aspects of interventions that are locally, contextually, and culturally relevant. This study describes a rigorous, exploratory, qualitative examination of the key, non-specific intervention strategies of a diverse group of five internationally-recognized organizations addressing mental illness in middle income countries (MICs). A triangulated approach to inquiry was used with semi-structured interviews conducted with service recipients, service providers and leaders, and key community partners (N = 159). The interview focus was upon processes of implementation and operation. A grounded theory-informed analysis revealed cross cutting themes of: a holistic conceptualization of mental health problems, an intensive application of principles of leverage and creating the social, cultural, and policy “space” within which interventions could be applied and resourced. These findings aligned with key aspects of systems dynamic theory suggesting that it might be a helpful framework in future studies of mental health service implementation in MICs.     

Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi

Background

Lymphatic filariasis is caused by the parasitic worms Wuchereria bancrofti, Brugia malayi or B. timori, which are transmitted via the bites from infected mosquitoes. Once in the human body, the parasites develop into adult worms in the lymphatic vessels, causing severe damage and swelling of the affected tissues. According to the World Health Organization, over 1.2 billion people in 58 countries are at risk of contracting lymphatic filariasis. Very few drugs are available to treat patients infected with these parasites, and these have low efficacy against the adult stages of the worms, which can live for 7–15 years in the human body. The requirement for annual treatment increases the risk of drug-resistant worms emerging, making it imperative to develop new drugs against these devastating diseases.

Methodology/Principal Findings

We have developed a yeast-based, high-throughput screening system whereby essential yeast genes are replaced with their filarial or human counterparts. These strains are labeled with different fluorescent proteins to allow the simultaneous monitoring of strains with parasite or human genes in competition, and hence the identification of compounds that inhibit the parasite target without affecting its human ortholog. We constructed yeast strains expressing eight different Brugia malayi drug targets (as well as seven of their human counterparts), and performed medium-throughput drug screens for compounds that specifically inhibit the parasite enzymes. Using the Malaria Box collection (400 compounds), we identified nine filarial specific inhibitors and confirmed the antifilarial activity of five of these using in vitro assays against Brugia pahangi.

Conclusions/Significance

We were able to functionally complement yeast deletions with eight different Brugia malayi enzymes that represent potential drug targets. We demonstrated that our yeast-based screening platform is efficient in identifying compounds that can discriminate between human and filarial enzymes. Hence, we are confident that we can extend our efforts to the construction of strains with further filarial targets (in particular for those species that cannot be cultivated in the laboratory), and perform high-throughput drug screens to identify specific inhibitors of the parasite enzymes. By establishing synergistic collaborations with researchers working directly on different parasitic worms, we aim to aid antihelmintic drug development for both human and veterinary infections.     

A simple recipe for setting up the flux equations of cyclic and linear reaction schemes of ion transport with a high number of states: The arrow scheme

The calculation of flux equations or current-voltage relationships in reaction kinetic models with a high number of states can be very cumbersome. Here, a recipe based on an arrow scheme is presented, which yields a straightforward access to the minimum form of the flux equations and the occupation probability of the involved states in cyclic and linear reaction schemes. This is extremely simple for cyclic schemes without branches. If branches are involved, the effort of setting up the equations is a little bit higher. However, also here a straightforward recipe making use of so-called reserve factors is provided for implementing the branches into the cyclic scheme, thus enabling also a simple treatment of such cases.     

The Role of Oxidative Stress in the Longevity and Insecticide Resistance Phenotype of the Major Malaria Vectors Anopheles arabiensis and Anopheles funestus

Oxidative stress plays numerous biological roles, both functional and pathological. The role of oxidative stress in various epidemiologically relevant biological traits in Anopheles mosquitoes is not well established. In this study, the effects of oxidative stress on the longevity and insecticide resistance phenotype in the major malaria vector species An. arabiensis and An. funestus were examined. Responses to dietary copper sulphate and hydrogen peroxide were used as proxies for the oxidative stress phenotype by determining the effect of copper on longevity and hydrogen peroxide lethal dose. Glutathione peroxidase and catalase activities were determined colorimetrically. Oxidative burden was quantified as protein carbonyl content. Changes in insecticide resistance phenotype were monitored by WHO bioassay. Insecticide resistant individuals showed an increased capacity for coping with oxidative stress, mediated by increased glutathione peroxidase and catalase activity. This effect was observed in both species, as well as in laboratory strains and F₁ individuals derived from wild-caught An. funestus mothers. Phenotypic capacity for coping with oxidative stress was greatest in strains with elevated Cytochrome P450 activity. Synergism of oxidative stress defence enzymes by dietary supplementation with haematin, 3-Amino-1, 2, 4-triazole and Sodium diethyldithiocarbamate significantly increased pyrethroid-induced mortality in An. arabiensis and An. funestus. It is therefore concluded that defence against oxidative stress underlies the augmentation of the insecticide resistance phenotype associated with multiple blood-feeding. This is because multiple blood-feeding ultimately leads to a reduction of oxidative stress in insecticide resistant females, and also reduces the oxidative burden induced by DDT and pyrethroids, by inducing increased glutathione peroxidase activity. This study highlights the importance of oxidative stress in the longevity and insecticide resistance phenotype in malaria vectors.     

Self-Reported Empathy in Adult Women with Autism Spectrum Disorders – A Systematic Mini Review

Introduction

There is limited research on Autism Spectrum Disorders (ASD) in females. Although the empathy construct has been examined thoroughly in autism, little attention has been paid to empathy in adult women with this condition or to gender differences within the disorder.

Objective

Self-reported empathy in adult women with ASD was examined and compared to that of typically developed men and women as well as to men with this condition.

Methods

Online databases were searched for articles investigating self-reported empathy among adult women with ASD. Only six studies comparing women to men were identified.

Results

All studies found women with an ASD to report lower levels of empathy than typically developed women, and typically developed men, but similar levels to men with this condition.

Conclusion

The self-reported empathic ability of women diagnosed with ASD resembles that of their male counterparts most closely; they show a hypermasculinisation in empathy. This is particularly surprising considering the large gender difference in empathy in the general population.

Discussion

One of the limitations of this review is that the current diagnostic criteria for ASD are oriented towards male-specific behaviour and fail to integrate gender specific characteristics. Hence, women diagnosed with ASD are likely to be at the male end of the continuum. The suggested hypermasculinisation of women on the spectrum, as evident from this review, may therefore be exaggerated due to a selection bias.     

Renal Transplant Recipients Treated with Calcineurin-Inhibitors Lack Circulating Immature Transitional CD19+CD24hiCD38hi Regulatory B-Lymphocytes

BackgroundCD19⁺CD24^hiCD38^hi transitional immature B-lymphocytes have been demonstrated to play an important role in regulating the alloimmune response in transplant recipients. Here, we analyzed the effect of calcineurin inhibition on these peripherally circulating regulatory B-cells (Breg) in renal transplant recipients receiving cyclosporine A (CsA) or tacrolimus.MethodsPBMCs from healthy subjects (HS) (n = 16) and renal transplant recipients (n = 46) were isolated. Flow cytometry was performed for CD19, CD24, CD38 and IL-10 either after isolation or after 72 hours of co-culture in presence of PMA/Ionomycin and TLR9-ligand in presence or absence of increasing concentrations of tacrolimus or CsA.ResultsThe amount of CD19⁺ B-cells among lymphocytes was ∼9.1% in HS, ∼3.6% in CsA (n = 11, p<0.05) and ∼6.4% in TAC (n = 35, p<0.05) treated patients. Among B-cells, a distinct subset of Breg was found to be 4.7% in HS, 1.4% in tacrolimus treated patients and almost blunted in patients receiving CsA. Similarily, ∼4% of B-cells in HS and even fewer in CsA or tacrolimus treated patients produced IL-10 (0.5% and 1.5%, p<0.05) and this was confirmed both in non-transplanted CsA-treated healthy subjects and in in vitro co-culture experiments. Among 29 patients with <1% of Breg, 9 cases (31%) displayed an allograft rejection in contrast to only one case of rejection (6%) among 17 patients with >1%.ConclusionCalcineurin inhibitors reduce number and IL-10 production of Bregs in the peripheral circulation of both renal transplant recipients and non-transplanted healthy subjects. CNI induced Breg reduction is not restricted to a solid organ transplant setting and is not mediated by co-medication with steroids or MPA. A low proportion of Breg cells is associated with an elevated frequency of allograft rejection events.     

The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region,Russia

BackgroundIn the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy.MethodsA culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm.ResultsAmong smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms.ConclusionThe results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.     

The Distribution and Density of Water Mice (Xeromys myoides) in the Maroochy River of Southeast Queensland,Australia

The water mouse is a small and vulnerable rodent present in coastal areas of south-west Papua New Guinea, and eastern Queensland and the Northern Territory of Australia. Current knowledge regarding the distribution of the water mouse is incomplete and the loss of one local population has been documented in southeast Queensland, a region where pressures from urban and industrial development are increasing. Water mouse populations have not been studied intensively enough to enable the primary factors responsible for the local decline to be identified. We surveyed the distribution and density of the water mouse along the Maroochy River of southeast Queensland, near the southern extent of the species’ range, to gather baseline data that may prove valuable for detecting any future decline in this population’s size or health. All areas of suitable habitat were surveyed on foot or by kayak or boat over a three-year period. We found 180 water mouse nests, of which ~94% were active. Permanent camera monitoring of one nest and limited supplementary live trapping suggested that up to three individual mice occupied active nests. Water mouse density was estimated to be 0.44 per hectare of suitable habitat along the Maroochy River. Should future monitoring reveal an adverse change in the water mouse population on the Maroochy River, a concerted effort should be made to identify contributing factors and address proximate reasons for the decline.