Quantification of lower leg arterial calcifications by high-resolution peripheral quantitative computed tomography

Vascular calcifications and bone health seem to be etiologically linked via common risk factors such as aging and subclinical chronic inflammation. Epidemiologic studies have shown significant associations between low bone mineral density (BMD), fragility fractures and calcifications of the coronary arteries and the abdominal aorta. In the last decade, high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as in-vivo research tool for the assessment of peripheral bone geometry, density, and microarchitecture. Although vascular calcifications are frequently observed as incidental findings in HR-pQCT scans, they have not yet been incorporated into quantitative HR-pQCT analyses. We developed a semi-automated algorithm to quantify lower leg arterial calcifications (LLACs), captured by HR-pQCT. The objective of our study was to determine validity and reliability of the LLAC measure. HR-pQCT scans were downscaled to a voxel size of 250μm. After subtraction of bone volumes from the scans, LLACs were detected and contoured by a semi-automated, dual-threshold seed-point segmentation. LLAC mass (in mg hydroxyapatite; HA) was calculated as the product of voxel-based calcification volume (mm(3)) and mean calcification density (mgHA/cm(3))/1000. To determine validity, we compared LLACs to coronary artery calcifications (CACs), as quantified by multi-detector computed tomography (MDCT) and Agatston scoring in forty-six patients on chronic hemodialysis. Moreover, we investigated associations of LLACs with age, time on dialysis, type-2 diabetes mellitus, history of stroke, and myocardial infarction. In a second step, we determined intra- and inter-reader reliability of the LLAC measure. In the validity study, LLACs were present (>0mgHA) in 76% of patients, 78% of patients had CACs (>0mgHA). Median LLAC was 6.65 (0.08-24.40)mgHA and median CAC as expressed by Agatston score was 266.3 (15.88-1877.28). We found a significant positive correlation between LLAC and CAC (rho=0.6; p<0.01). Dialysis patients with type-2 diabetes mellitus (DM; 35%) and history of stroke (13%) had higher median LLAC than patients without those conditions (DM 20.0 fold greater, p=0.006; Stroke 5.1 fold greater, p=0.047). LLAC was positively correlated with time on dialysis (rho=0.337, p=0.029), there was a trend towards a positive association of LLAC and age (rho=0.289, p=0.053). The reliability study yielded excellent intra- and inter-reader agreement of the LLAC measure (intra-reader ICC=0.999, 95% CI=0.998-1.000; inter-reader ICC=0.998, 95% CI=0.994-0.999). Our study indicates that the LLAC measure has good validity and excellent reliability. The use of HR-pQCT for the simultaneous evaluation of arterial calcifications, peripheral bone geometry, bone density, and bone microarchitecture should facilitate future research on osteo-vascular interactions and potential associations with cardiovascular events

Dickkopf-1 is a master regulator of joint remodeling

Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-alpha (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodelin

Bringing fear into focus: The intersections of HIV and masculine gender norms in Côte d'Ivoire.

This qualitative research study explored the role of masculinity in men's engagement in the HIV care continuum in Côte d'Ivoire. The researchers conducted 73 in-depth interviews and 28 focus group discussions with 227 Ivoirian men between November and December 2016 across three urban sites. Participants in the study expressed that fear was the primary barrier to HIV testing and treatment. These men described five value domains-health, sexuality, work and financial success, family, and social status. Men saw HIV as a direct threat to their agency and strength with respect to each of these value domains, thus shedding light on their reluctance to discover their HIV status through HIV testing. With this data, the researchers created the Masculine Values Framework, a descriptive framework of masculine values that can be applied to better understand the behavior men exhibit in Côte d'Ivoire in the face of HIV. The Masculine Values Framework offers practical guidance for developing gender-sensitive HIV-focused social and behavior change programming in Côte d'Ivoire and similar contexts to reach the UNAIDS 90-90-90 targets

Men's perceptions of HIV care engagement at the facility- and provider-levels: Experiences in Cote d'Ivoire.

Men in sub-Saharan Africa have lower rates of HIV testing and are less likely to initiate treatment compared to women. Service delivery dimensions are a key factor in facilitating engagement along the HIV treatment continuum for men and women, yet male specific overall perceptions of the service delivery environment have received little attention in West Africa. This study draws on qualitative data collected in Côte d'Ivoire to explore provider-level and structural factors affecting men's engagement in HIV testing and treatment through interviews and focus group discussions conducted with health workers and men living with HIV (some on ART) or whose HIV status was unknown. Factors influencing decisions to test or initiate treatment were considered in terms of perceived benefits and costs. Men described costs at the interpersonal (client-provider) level, such as unwanted disclosure or stigma, which were weighed against the potential for social support and clinical guidance. Likewise, fear of unwanted disclosure operated at the facility level, as the layout of facilities sometimes grouped clients living with HIV together. Notably, the benefits men described from engaging in HIV testing and care all operated at the interpersonal level and none at the facility level. In light of the fact that provider- and facility-level factors influenced the perceptions and experiences of men along the treatment continuum, we offer recommendations to reduce barriers to testing and engagement in care related to service delivery

A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression

Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages