Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer

BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Adaptation of canine distemper virus to canine footpad keratinocytes modifies polymerase activity and fusogenicity through amino acid substitutions in the P/V/C and H proteins

The wild-type canine distemper virus (CDV) strain A75/17 induces a non-cytocidal infection in cultures of canine footpad keratinocytes (CFKs) but produces very little progeny virus. After only three passages in CFKs, the virus produced 100-fold more progeny and induced a limited cytopathic effect. Sequence analysis of the CFK-adapted virus revealed only three amino acid differences, of which one was located in each the P/V/C, M and H proteins. In order to assess which amino acid changes were responsible for the increase of infectious virus production and altered phenotype of infection, we generated a series of recombinant viruses. Their analysis showed that the altered P/V/C proteins were responsible for the higher levels of virus progeny formation and that the amino acid change in the cytoplasmic tail of the H protein was the major determinant of cytopathogenicity.

Methodology and models in erosion research: discussion and conclusions

This paper summarises the discussions which took place at the Workshop on Methodology in Erosion Research in Zürich, 2010, and aims, where possible, to offer guidance for the development and application of both in vitro and in situ models for erosion research. The prospects for clinical trials are also discussed. All models in erosion research require a number of choices regarding experimental conditions, study design and measurement techniques, and these general aspects are discussed first. Among in vitro models, simple (single- or multiple-exposure) models can be used for screening products regarding their erosive potential, while more elaborate pH cycling models can be used to simulate erosion in vivo. However, in vitro models provide limited information on intra-oral erosion. In situ models allow the effect of an erosive challenge to be evaluated under intra-oral conditions and are currently the method of choice for short-term testing of low-erosive products or preventive therapeutic products. In the future, clinical trials will allow longer-term testing. Possible methodologies for such trials are discussed.

Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: an illustration of the 4P's modeling approach

The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

Swiss recommendations for the management of varicella zoster virus infections

Infections with varicella zoster virus (VZV) are common viral infections associated with significant morbidity. Diagnosis and management are complex, particularly in immunocompromised patients and during pregnancy. The present recommendations have been established by a multidisciplinary panel of specialists and endorsed by numerous Swiss medical societies involved in the medical care of such patients (Appendix). The aim was to improve the care of affected patients and to reduce complications.

Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

BACKGROUND Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost fatal. Due to its rarity, only few prospective controlled therapeutic trials are available. OBJECTIVES For this reason, a group of European dermatologists with a long-standing interest and expertise in basic and clinical pemphigus research has sought to define diagnostic and therapeutic guidelines for the management of patients with pemphigus. RESULTS This group identified the statements of major agreement or disagreement regarding the diagnostic and therapeutic management of pemphigus. The revised final version of the pemphigus guideline was finally passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV) and the European Union of Medical Specialists (UEMS).

Human TOP1 residues implicated in species specificity of HIV-1 infection are required for interaction with BTBD2, and RNAi of BTBD2 in old world monkey and human cells increases permissiveness to HIV-1 infection

Host determinants of HIV-1 viral tropism include factors from producer cells that affect the efficiency of productive infection and factors in target cells that block infection after viral entry. TRIM5 restricts HIV-1 infection at an early post-entry step through a mechanism associated with rapid disassembly of the retroviral capsid. Topoisomerase I (TOP1) appears to play a role in HIV-1 viral tropism by incorporating into or otherwise modulating virions affecting the efficiency of a post-entry step, as the expression of human TOP1 in African Green Monkey (AGM) virion-producing cells increased the infectivity of progeny virions by five-fold. This infectivity enhancement required human TOP1 residues 236 and 237 as their replacement with the AGM counterpart residues abolished the infectivity enhancement. Our previous studies showed that TOP1 interacts with BTBD1 and BTBD2, two proteins which co-localize with the TRIM5 splice variant TRIM5 in cytoplasmic bodies. Because BTBD1 and BTBD2 interact with one HIV-1 viral tropism factor, TOP1, and co-localize with a splice variant of another, we investigated the potential involvement of BTBD1 and BTBD2 in HIV-1 restriction.

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study

The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS).

Developing European conservation and mitigation tools for pollination services: approaches of the STEP (Status and Trends of European Pollinators) project

Pollinating insects form a key component of European biodiversity, and provide a vital ecosystem service to crops and wild plants. There is growing evidence of declines in both wild and domesticated pollinators, and parallel declines in plants relying upon them. The STEP project (Status and Trends of European Pollinators, 2010-2015, www.step-project.net) is documenting critical elements in the nature and extent of these declines, examining key functional traits associated with pollination deficits, and developing a Red List for some European pollinator groups. Together these activities are laying the groundwork for future pollinator monitoring programmes. STEP is also assessing the relative importance of potential drivers of pollinator declines, including climate change, habitat loss and fragmentation, agrochemicals, pathogens, alien species, light pollution, and their interactions. We are measuring the ecological and economic impacts of declining pollinator services and floral resources, including effects on wild plant populations, crop production and human nutrition. STEP is reviewing existing and potential mitigation options, and providing novel tests of their effectiveness across Europe. Our work is building upon existing and newly developed datasets and models, complemented by spatially-replicated campaigns of field research to fill gaps in current knowledge. Findings are being integrated into a policy-relevant framework to create evidence-based decision support tools. STEP is establishing communication links to a wide range of stakeholders across Europe and beyond, including policy makers, beekeepers, farmers, academics and the general public. Taken together, the STEP research programme aims to improve our understanding of the nature, causes, consequences and potential mitigation of declines in pollination services at local, national, continental and global scales.