Human oral lectin ZG16B acts as a cell wall polysaccharide probe to decode host-microbe interactions with oral commensals.

The oral microbiome is critical to human health and disease, yet the role that host salivary proteins play in maintaining oral health is unclear. A highly expressed gene in human salivary glands encodes the lectin zymogen granule protein 16 homolog B (ZG16B). Despite the abundance of this protein, its interaction partners in the oral microbiome are unknown. ZG16B possesses a lectin fold, but whether it binds carbohydrates is unclear. We postulated that ZG16B would bind microbial glycans to mediate recognition of oral microbes. To this end, we developed a microbial glycan analysis probe (mGAP) strategy based on conjugating the recombinant protein to fluorescent or biotin reporter functionality. Applying the ZG16B-mGAP to dental plaque isolates revealed that ZG16B predominantly binds to a limited set of oral microbes, including Streptococcus mitis, Gemella haemolysans, and, most prominently, Streptococcus vestibularis. S. vestibularis is a commensal bacterium widely distributed in healthy individuals. ZG16B binds to S. vestibularis through the cell wall polysaccharides attached to the peptidoglycan, indicating that the protein is a lectin. ZG16B slows the growth of S. vestibularis with no cytotoxicity, suggesting that it regulates S. vestibularis abundance. The mGAP probes also revealed that ZG16B interacts with the salivary mucin MUC7. Analysis of S. vestibularis and MUC7 with ZG16B using super-resolution microscopy supports ternary complex formation that can promote microbe clustering. Together, our data suggest that ZG16B influences the compositional balance of the oral microbiome by capturing commensal microbes and regulating their growth using a mucin-assisted clearance mechanism.

Radiation-Associated Primary Osteosarcoma of the Breast.

INTRODUCTION: Non-epithelial primary mammary osteosarcomas are extremely rare. The differentials include metaplastic carcinoma and malignant phyllodes tumour. This is the first published case of primary breast osteosarcoma arising after local radiotherapy. CASE PRESENTATION: A 73-year-old female presented with a right-sided breast lump. The same breast had been irradiated 11 years previously for invasive ductal carcinoma. Diagnostic excision revealed a highly cellular, malignant spindle-cell lesion merged with an osteoid matrix and foci of calcification and bone formation. Immunohistochemistry and molecular studies showed no lines of differentiation. Due to the lack of epithelial/glandular differentiation, in situ carcinoma or leaf-like pattern, the diagnosis of post-irradiation osteosarcoma was made. She underwent mastectomy and is disease-free at 8 months of follow-up. CONCLUSION: Post-irradiation osteosarcoma should be considered in the differential diagnosis of breast lesions showing malignant osteoid. Extensive sampling and careful search for epithelial differentiation is required to guide management. Complete surgical excision is recommended.

Targeting intracellular nontuberculous mycobacteria and M. tuberculosis with a bactericidal enzymatic cocktail.

To address intracellular mycobacterial infections, we developed a cocktail of four enzymes that catalytically attack three layers of the mycobacterial envelope. This cocktail is delivered to macrophages, through a targeted liposome presented here as ENTX_001. Endolytix Cocktail 1 (EC1) leverages mycobacteriophage lysin enzymes LysA and LysB, while also including α-amylase and isoamylase for degradation of the mycobacterial envelope from outside of the cell. The LysA family of proteins from mycobacteriophages has been shown to cleave the peptidoglycan layer, whereas LysB is an esterase that hydrolyzes the linkage between arabinogalactan and mycolic acids of the mycomembrane. The challenge of gaining access to the substrates of LysA and LysB provided exogenously was addressed by adding amylase enzymes that degrade the extracellular capsule shown to be present in Mycobacterium tuberculosis. This enzybiotic approach avoids antimicrobial resistance, specific receptor-mediated binding, and intracellular DNA surveillance pathways that limit many bacteriophage applications. We show this cocktail of enzymes is bactericidal in vitro against both rapid- and slow-growing nontuberculous mycobacteria (NTM) as well as M. tuberculosis strains. The EC1 cocktail shows superior killing activity when compared to previously characterized LysB alone. EC1 is also powerfully synergistic with standard-of-care antibiotics. In addition to in vitro killing of NTM, ENTX_001 demonstrates the rescue of infected macrophages from necrotic death by Mycobacteroides abscessus and Mycobacterium avium. Here, we demonstrate shredding of mycobacterial cells by EC1 into cellular debris as a mechanism of bactericide.IMPORTANCEThe world needs entirely new forms of antibiotics as resistance to chemical antibiotics is a critical problem facing society. We addressed this need by developing a targeted enzyme therapy for a broad range of species and strains within mycobacteria and highly related genera including nontuberculous mycobacteria such as Mycobacteroides abscessus, Mycobacterium avium, Mycobacterium intracellulare, as well as Mycobacterium tuberculosis. One advantage of this approach is the ability to drive our lytic enzymes through encapsulation into macrophage-targeted liposomes resulting in attack of mycobacteria in the cells that harbor them where they hide from the adaptive immune system and grow. Furthermore, this approach shreds mycobacteria independent of cell physiology as the drug targets the mycobacterial envelope while sidestepping the host range limitations observed with phage therapy and resistance to chemical antibiotics.

Time use, role participation and life satisfaction of older people: impact of driving status.

BACKGROUND/AIM: Driving cessation has been recognised as affecting the health and wellbeing of older people. Further exploration of the impact of driving status on time use, role participation and life satisfaction was required. METHODS: A cross-sectional survey of 234 older people (current drivers, retired drivers and people who have never driven) was employed. Time use in the previous week, role participation and life satisfaction were measured and compared between the groups, while controlling for sociodemographic variables (health status, activities of daily living and instrumental activities of daily living status, gender, age and living situation). RESULTS: When compared to current drivers, retired drivers had significantly lower life satisfaction (P = 0.01), fewer present roles (P < 0.0001) and were less likely to participate in volunteer (P = 0.005) and family member roles (P = 0.009). Retired drivers spent less time on social leisure (P = 0.002) and away from home (P = 0.0001), and more time in solitary leisure (P= 0.0001). Comparing the participation of retired drivers with those who had never driven indicated that retired drivers spent significantly less time in volunteer work (P = 0.009). CONCLUSIONS: The findings indicate that older non-drivers may require support for participation and wellbeing.

Silver Memories: implementation and evaluation of a unique radio program for older people.

OBJECTIVES: A unique radio program, Silver Memories, specifically designed to address social isolation and loneliness in older people by broadcasting music (primarily), serials and other programs relevant to the period when older people grew up--the 1920-1950s--first aired in Brisbane, Australia, in April 2008. The impact of the program upon older listeners' mood, quality of life (QOL) and self-reported loneliness was independently evaluated. METHOD: One hundred and thirteen community-dwelling persons and residents of residential care facilities, aged 60 years and older participated in a three month evaluation of Silver Memories. They were asked to listen to the program daily and baseline and follow-up measures of depression, QOL and loneliness were obtained. Participants were also asked for their opinions regarding the program's quality and appeal. RESULTS: The results showed a statistically significant improvement in measures of depression and QOL from baseline to follow-up but there was no change on the measure of loneliness. The results did not vary by living situation (community vs. residential care), whether the participant was lonely or not lonely, socially isolated or not isolated, or whether there had been any important changes in the participant's health or social circumstances throughout the evaluation. CONCLUSION: It was concluded that listening to Silver Memories appears to improve the QOL and mood of older people and is an inexpensive intervention that is flexible and readily implemented.

Reflexivity and minimization of the impact of age-cohort differences between researcher and research participants.

Reflexivity in research can be defined as (a) the acknowledgment and identification of one's place and presence in the research, and (b) the process of using these insights to critically examine the entire research process. Many authors implore qualitative researchers to be reflexive. Very few, however, specify how to do this in practice. Furthermore, in discussions of the presence and place of the researcher, the tendency has been to focus on such factors as gender and race or ethnicity with very little attention being given to age or cohort. In this article we seek to redress this deficiency by examining how reflexivity was practiced in a context in which there was a marked difference in age and cohort membership between researcher and research participants. Specifically, we describe the methodological challenges faced by a younger researcher conducting research with older study participants on the lived experience of the body, and how reflexivity was used to adapt the methodology employed so it became more appropriate and productive within this context.

Rhetoric to action: a study of stakeholder perceptions of aging well in two local communities.

This qualitative study of local perceptions of policy goals and action in relation to aging reports 31 stakeholder interviews within 2 Australian communities exploring (a) the meaning of aging well; and (b) preferred policy actions to achieve positive aging outcomes. Findings suggest that community perceptions of aging well are broadly consistent with the goals of national and international policy frameworks in focusing on 3 dimensions--health, social engagement, and security. Further, participants believe that achievement of positive aging outcomes requires a mix of self-help, community action, and government intervention--particularly government support and encouragement for aging well initiatives.

Professional and personal attitudes of researchers in ageing towards life extension.

It is often assumed that there is broad public support for strong life extension research (i.e. research aimed at the dramatic extension of human life beyond the current maximum), and that there would be a near universal interest in using any life extending technologies that this research may produce. In this paper we report the opinions of researchers in ageing on the controversial promise of life extension, and compare these views. This paper describes the professional attitudes, personal interest and concerns expressed by Australian and international researchers in ageing (n = 14) as expressed during semi-structured, in-depth interviews. Researchers held varying opinions about the possibility of significantly extending human life. Some saw a limit to the extension of human life, while others did not. Some felt that research into the fundamental ageing process was a priority; others did not. Researchers tended to weigh up the potential risks and benefits of life extension with most expressing a personal interest in life extension that was contingent on the technology providing a good quality of life. Some participants were not interested in the prospect of life extension for personal reasons, because they felt the potential risks outweighed the potential benefits, or because life extension raised issues of justice and equity.

Community perceptions on the significant extension of life: an exploratory study among urban adults in Brisbane, Australia.

Some researchers in the field of ageing claim that significant extension of the human lifespan will be possible in the near future. While many of these researchers have assumed that the community will welcome this technology, there has been very little research on community attitudes to life extension. This paper presents the results of an in-depth qualitative study of community attitudes to life extension across age groups and religious boundaries. There were 57 individual interviews, and 8 focus groups (totalling 72 focus group participants) conducted with community members in Brisbane, Australia. Community attitudes to life extension were more varied and complex than have been assumed by some biogerontologists and bioethicists. While some participants would welcome the opportunity to extend their lives others would not even entertain the possibility. This paper details these differences of opinion and reveals contrasting positions that reflect individualism or social concern among community members. The findings also highlight the relationship between Christianity, in particular belief in an afterlife, and attitudes to life extension technology. Overall, the study raises questions about the relationship between interest in life extension, the medicalisation of ageing and the increasing acceptability of enhancement technologies that need to be addressed in more representative samples of the community.

Ethical concerns in the community about technologies to extend human life span.

Debates about the ethical and social implications of research that aims to extend human longevity by intervening in the ageing process have paid little attention to the attitudes of members of the general public. In the absence of empirical evidence, conflicting assumptions have been made about likely public attitudes towards life-extension. In light of recent calls for greater public involvement in such discussions, this target article presents findings from focus groups and individual interviews which investigated whether members of the general public identify ethical issues surrounding life-extension, and if so, what these ethical issues are? In this study, while some participants were concerned primarily with the likely personal consequences of life-extension, for others the question of whether or not to pursue interventions to extend longevity, and how they should be implemented, clearly raised important ethical issues, many of which have been prominent in debates among bioethicists.

Functional Comparison of Blood-Stage Plasmodium falciparum Malaria Vaccine Candidate Antigens.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage Plasmodium falciparum malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC). However, many other antigens could also elicit neutralizing antibodies against the merozoite, and most of these have never been compared directly to RH5. The objective of this study was to compare a range of blood-stage antigens to RH5, to identify any antigens that outperform or synergize with anti-RH5 antibodies. We selected 55 gene products, covering 15 candidate antigens that have been described in the literature and 40 genes selected on the basis of bioinformatics functional prediction. We were able to make 20 protein-in-adjuvant vaccines from the original selection. Of these, S-antigen and CyRPA robustly elicited antibodies with neutralizing properties. Anti-CyRPA IgG generally showed additive GIA with anti-RH5 IgG, although high levels of anti-CyRPA-specific rabbit polyclonal IgG were required to achieve 50% GIA. Our data suggest that further vaccine antigen screening efforts are required to identify a second merozoite target with similar antibody-susceptibility to RH5.

Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an immune-mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom-AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3-positive (FOXP3POS) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C-X-C motif) ligand 10. Chemokine secretion by cultured primary hepatocyte and biliary epithelial cells was measured by enzyme-linked immunosorbent assay. Functional coculture assays with stimulated NK cells and Tregs were performed. CD161 ligand, lectin-like transcript-1 expression by intrahepatic immune cells was demonstrated with flow cytometry. Frequencies of NKbright cells declined with therapy (P < 0.001) and correlated with levels of alanine aminotransferase (P = 0.023). The Treg:NKbright ratio was lower pretreatment, and Tregs had an activated memory phenotype with high levels of CD39, cytotoxic T lymphocyte antigen 4, and FOXP3 but also high programmed death ligand 1, indicating exhaustion. Coculture experiments suggested the Tregs could not efficiently suppress interferon-γ secretion by NK cells. Both Tregs and NK cells had high expression of liver infiltration and T helper 17 plasticity-associated marker CD161 (P = 0.04). Pretreatment and CD161pos NK cells expressed high levels of perforin and granzyme B, consistent with an activated effector phenotype (P < 0.05). Lectin-like transcript 1, a ligand for CD161, is expressed on intrahepatic B cells, monocytes, and neutrophils. Conclusion: Activated effector NK cells, which correlate with biochemical measurements of hepatitis, and exhausted memory Tregs are increased in the blood of patients with treatment-naive AIH and decline with corticosteroid therapy. Inadequate regulation of NK cells by exhausted FOXP3pos Tregs may play a role in AIH pathogenesis and contribute to liver injury. (Hepatology Communications 2018;2:421-436).

Community attitudes to the regulation of life extension.

Technologies purported to extend human life are already being marketed widely, and are being used by community members, despite a lack of evidence on their efficacy or safety: in fact, the use of some putative anti-aging technologies (e.g., human growth hormone) is illegal. Existing regulation is proving to be ineffective, especially in the face of Internet sales. Further advances in the field of life extension are a distinct possibility, exacerbating the need for a policy response. This paper presents the preliminary results of a study of community attitudes to life extension, with a focus on attitudes to the control and availability of strong life-extending technologies.

Healthy aging as an intervention to minimize injury from falls among older people.

With global trends toward population aging, many countries are adopting healthy aging policies to minimize disability and increase quality in the extended years of life. Falls in older people are a major contributor to functional decline generally associated with aging. Based on a study quantifying the relationship between healthy aging factors and risk of fall-related hip fracture in community-dwelling older people, this paper discusses evidence for the promotion of healthy aging as a population-based intervention for prevention of injuries from falls. To examine the protective effect of healthy aging on the risk of fall-related hip fractures, a case-control study was conducted with 387 participants. Persons aged 65 and over hospitalized with a fall-related hip fracture were matched with community-based controls recruited via electoral roll sampling. A questionnaire designed to assess lifestyle risk factors, identified as determinants of healthy aging, was administered during face-to-face interviews. After adjustment for health status and demographic factors, a number of lifestyle factors were seen to have a significant independent protective effect on the risk of hip fracture. These included never smoking, moderate alcohol consumption, being active, maintaining normal weight, and being proactive in preventive health care. Psychosocial factors included having supportive environments and personal resources to cope with stress. This study identified a range of modifiable lifestyle factors associated with fall-related hip fracture, suggesting that the "healthy aging" paradigm offers a comprehensive approach to falls injury prevention, and thus supports the adoption of healthy aging policies to extend years of quality life among older persons.

Should mental health issues be addressed in primary care, and can it be done? Views of rural general practitioners in Queensland.

OBJECTIVE: The aim of this paper was to examine self-efficacy and perceived appropriateness among rural general practitioners (GPs) in regards to screening and intervention for physical, lifestyle and mental health issues. METHOD: Fifty GPs from 25 practices in eight rural Queensland towns completed a written survey designed for the study. RESULTS: General practitioners rated opportunistic screening or assessment for smoking and for detection of relapse of mental disorders as the most appropriate, with even cardiovascular and diabetes risk falling behind these. Self-efficacy was highest for medical disorders for smoking assessment. It was significantly lower for alcohol, mental health issues, and addressing risks of physical disorder in people with mental disorders. CONCLUSIONS: High appropriateness ratings suggest that current strategies to boost self-efficacy of GPs in addressing mental health issues are timely.

Regulatory T Cell Metabolism in the Hepatic Microenvironment.

Thymic-derived naturally occurring regulatory T cells (tTreg) are crucial for maintaining peripheral immune homeostasis. They play a crucial role in preventing autoimmunity and maintaining organ transplant without requiring immunosuppression. Cellular metabolism has recently emerged as an important regulator of adaptive immune cell balance between Treg and effector T cells. While the metabolic requirements of conventional T cells are increasingly understood, the role of Treg cellular metabolism is less clear. The continuous exposure of metabolites and nutrients to the human liver via the portal blood flow influences the lineage fitness, function, proliferation, migration, and survival of Treg cells. As cellular metabolism has an impact on its function, it is crucial to understand the metabolic pathways wiring in regulatory T cells. Currently, there are ongoing early phase clinical trials with polyclonal and antigen-specific good manufacturing practice (GMP) Treg therapy to treat autoimmune diseases and organ transplantation. Thus, enhancing immunometabolic pathways of Treg by translational approach with existing or new drugs would utilize Treg cells to their full potential for effective cellular therapy.

Behavioral determinants of healthy aging.

With global trends in population aging, many nations are developing and implementing healthy aging policies to promote quality as well as years of healthy life. To broaden the evidence base for such policy development, a review of the literature was conducted to summarize the existing evidence regarding the behavioral determinants of healthy aging. Such research is needed so that the efficacy of modes of intervention can be better understood. The outcome of "healthy" or "successful" aging was selected for this review since this nomenclature dominates the literature describing a global measure of multidimensional functioning at the positive end of the health continuum in older age. Studies published between 1985 and 2003 that reported statistical associations between baseline determinants and healthy aging outcome were identified from a systematic search of medical, psychological, sociological, and gerontological databases. Eight studies satisfied the search criteria. Modifiable risk factors among the behavioral determinants included smoking status, physical activity level, body mass index, diet, alcohol use, and health practices. On the basis of these findings, effective healthy aging policies need to enhance opportunities across the life span for modification of lifestyle risk factors. Efforts to standardize concepts and terminology will facilitate further research activity in this important area.

The association between depressive symptoms and social support in Taiwanese women during the month.

The purpose of the study was to explore the association between depressive symptoms and social support in Taiwanese women doing the month. A correlational survey design using the Postpartum Social Support Questionnaire (PSSQ) and the Edinburgh Postnatal Depression Scale (EPDS) to measure social support and postnatal depressive symptomatology was employed. Two hundred and forty postpartum women receiving care in two teaching hospitals in Taipei, Taiwan, aged between 20 and 35, with no peri-natal complications or previous psychiatric history, experiencing a normal spontaneous delivery of one full term healthy baby, were selected. Each was mailed the PSSQ and the EPDS as well as a short, semi-structured self-report questionnaire requesting demographic details and subjective data relating to the experience of doing the month and depressive symptoms during the fourth week following birth. One hundred and eighty six women (78%) returned questionnaires. Taiwanese postpartum women were less depressed when they stayed in their parents' home and had their own mothers take care of them. It was found that the greater the level of postpartum social support received by the women doing the month, the lower the risk of postnatal depressive symptoms experienced. Almost a quarter (24%) of the variance of the symptoms was attributed to dissatisfaction with parents' instrumental support and unwanted emotional support from parents-in-law. It is concluded that the ritual of doing the month provides valuable social support and may help to prevent postnatal depression in Taiwanese women.

The impact of ageing-in-place policies on structural change in residential aged care.

OBJECTIVES: This paper reports findings from a study to investigate the impact of ageing-in-place policies on resident dependency levels and to explore the relationship between structural variables and outcome ratings. METHODS: The study involved a time series data collection of high- and low-care places and accreditation ratings from both the first and the second accreditation cycles in Queensland (N = 482 and 499). Paired-samples t-tests were also conducted on a sample of homes providing both high- and low-level care to assess changing dependency levels over the two time periods. RESULTS: A statistically significant increase (0.005) was found in the proportion of residents classified as high care living in low-care homes between the first and the second accreditation cycles. CONCLUSIONS: The findings suggest that the ageing-in-place regulatory intervention achieved the intended policy goal and homes have effectively implemented staffing and quality control strategies to accommodate the changes.