Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) R47H Variant Causes Distinct Age- and Sex-Dependent Musculoskeletal Alterations in Mice

Previous studies proposed the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed in myeloid cells including microglia in brain and osteoclasts in bone, as a link between brain and bone disease. The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD), the most common form of dementia. To investigate whether altered TREM2 signaling could contribute to bone and skeletal muscle loss, independently of central nervous system defects, we used mice globally hemizygous for the TREM2 R47H variant (TREM2^R47H/+), which do not exhibit AD pathology, and wild-type (WT) littermate control mice. Dxa/Piximus showed bone loss in female TREM2^R47H/+ animals between 4 and 13 months of age and reduced cancellous and cortical bone (measured by micro-computed tomography [μCT]) at 13 months, which stalled out by 20 months of age. In addition, they exhibited decreased femoral biomechanical properties measured by three-point bending at 13 months of age, but not at 4 or 20 months. Male TREM2^R47H/+ animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20 months of age versus WT. Only male TREM2^R47H/+ osteoclasts differentiated more ex vivo after 7 days with receptor activator of nuclear factor κB ligand (RANKL)/macrophage colony-stimulating factor (M-CSF) compared to WT littermates. Yet, estrogen receptor alpha expression was higher in female and male TREM2^R47H/+ osteoclasts compared to WT mice. However, female TREM2^R47H/+ osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2^R47H/+ cells. Despite lower bone volume/strength in TREM2^R47H/+ mice, skeletal muscle function measured by plantar flexion and muscle contractility was increased in 13-month-old female mutant mice. Overall, these data demonstrate that an AD-associated TREM2 variant can alter bone and skeletal muscle strength in a sex-dimorphic manner independent of central neuropathology, potentially mediated through changes in osteoclastic intracellular signaling. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

The health of workers in the global gig economy

Background

The “gig” economy connects consumers with contractors (or workers) through online platform businesses to perform tasks (or “gigs”). This innovation in technology provides businesses and consumers access to low-cost, on-demand labour, but gig workers’ experiences are more complex. They have access to very flexible, potentially autonomous work, but also deal with challenges caused by the nature of the work, its precariousness, and their relationships with the platform businesses. Workers in the Global North and South may also experience these challenges very differently. Based on our report “Towards an Understanding of Canadian Workers in the Global Gig Economy”, we present a commentary on the implications of a globalized online platform labour market on the health of gig workers in Canada and globally.

Main body

Based on our scoping review of peer and grey literature, we categorized gig worker vulnerabilities in three ways: 1) occupational vulnerabilities, 2) precarity, and 3) platform-based vulnerabilities. Occupational vulnerabilities are connected to the work being performed (e.g. driving a car or computer work) and are not specific to platform labour. Precarity refers to the short-term, contingent nature of the work, characteristics that may be shared with other forms of work. Some examples of precariousness are lack of health insurance, collective bargaining, or career training and promotion. Finally, platform-based vulnerabilities are particular to the way platform labour is structured. These vulnerabilities include worker misclassification, information asymmetries, and the culture of surveillance. We suggest that, together, these vulnerabilities challenge gig workers’ right to health.

Conclusions

We propose that the experience of gig workers around the world must be understood in the context of neoliberalism, which has increased both the globalization and precaritization of work. While gig workers share some vulnerabilities, which have important negative consequences on their health, with other workers, the platform-specific vulnerabilities of workers require further inquiry. In particular, the specific health and overall experience of gig workers in different regions of the world – with different labour policies and sociopolitical contexts for work – must be disentangled as workers in the Global North and South experience this work very differently.

     

Different in vitro and in vivo tools for elucidating the human metabolism of alpha‐cathinone‐derived drugs of abuse

In vitro and in vivo experiments are widely used for studying the metabolism of new psychoactive substances (NPS). The availability of such data is required for toxicological risk assessments and development of urine screening approaches. This study investigated the in vitro metabolism of the 5 pyrrolidinophenone‐derived NPS alpha‐pyrrolidinobutyrophenone (alpha‐PBP), alpha‐pyrrolidinopentiothiophenone (alpha‐PVT), alpha‐pyrrolidinohexanophenone (alpha‐PHP), alpha‐pyrrolidinoenanthophenone (alpha‐PEP, PV8), and alpha‐pyrrolidinooctanophenone (alpha‐POP, PV9). First, they were incubated with pooled human liver microsomes (pHLM) or pooled human liver S9 fraction (pS9) for identification of the main phase I and II metabolites. All substances formed hydroxy metabolites and lactams. Longer alkyl chains resulted in keto group and carboxylic acid formation. Comparing these results with published data obtained using pHLM, primary human hepatocytes (PHH), and authentic human urine samples, PHH provided the most extensive metabolism. Second, enzyme kinetic studies showed that the initial metabolic steps were formed by cytochrome P450 isoforms (CYP) CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 resulting in pyrrolidine, thiophene or alkyl hydroxy metabolites depending on the length of the alkyl chain. The kinetic parameters indicated an increasing affinity of the CYP enzymes with increase of the length of the alkyl chain. These parameters were then used to calculate the contribution of a single CYP enzyme to the in vivo hepatic clearance. CYP2C19 and CYP2D6 were mainly involved in the case of alpha‐PBP and CYP1A2, CYP2C9 and CYP2C19 in the case of alpha‐PVT, alpha‐PHP, alpha‐PEP, and alpha‐POP.     

USE OF DIAGNODENT? FOR DIAGNOSIS OF NON-CAVITATED OCCLUSALDENTIN CARIES

The purpose of this study was to evaluate the use of a laser fluorescence device for detection of occlusal caries in permanent teeth. One hundred and ninety-nine non-cavitated teeth from 26 patients aged 10 to 13 years were selected. After dental prophylaxis, two previously calibrated dentists examined the teeth. Visual inspection, radiographic examination and laser measurements were performed under standardized conditions. The validation method was cavity preparation with a small cone-shaped diamond bur, when the two examiners agreed about the presence of dentin caries. It was found that the laser detection method produced high values of sensitivity (0.93) and specificity (0.75) and a moderate positive predictive value (0.63). The laser device showed the lowest value of likelihood ratio (3.68). Kappa coefficient showed good repeatability for all methods. Although the laser device had an acceptable performance, this equipment should be used as an adjunct method to visual inspection to avoid false positive results.     

The significance of alveolar bone in periodontal disease

The present experiment was designed to study if a gingival unit with a long supraalveolar connective tissue attachment provides less resistance against progression of periodontal disease than a unit with a supraalveolar connective tissue attachment of normal length. A long supraalveolar connective tissue attachment was established at the buccal aspect of mandibular premolars and molars in dogs by surgical removal of the marginal portion of the buccal alveolar bone after elevation of a muco-periosteal flap. Attempts were made to minimize mechanical injury to the root cementum and the supraalveolar fibrous attachment during the surgical procedure. Contralateral, non-operated teeth with a supraalveolar connective tissue attachment of normal length were used as controls. Following surgery, plaque control was initiated and maintained for 3 months by topical application of 0.2% chlorhexidine digluconate solution twice daily. During the following 6 months, the oral hygiene measures were abandoned and plaque was allowed to accumulate on both groups of teeth. In order to enhance plaque formation and to promote the development of subgingival plaque, cotton floss ligatures were placed at the entrance of the gingival sulci. The dogs were sacrificed 6 months after the initiation of the plaque accumulation period. The jaws were removed and histological sections prepared of test and control teeth including their surrounding periodontal tissues. The histological analysis revealed that the plaque induced inflammatory lesion in the gingival connective tissue did not extend more apically in sites with a long supraalveolar connective tissue attachment than in sites with a supraalveolar fibrous attachment of normal length. A small but statistically significant loss of connective tissue attachment had occurred in both groups of teeth. This attachment loss, however, was similar in sites with a long supraalveolar connective tissue attachment and in sites with a supraalveolar fibrous attachment of normal length. These findings suggest that the loss of attachment in periodontal disease is unrelated to the presence or absence of the bony component of the periodontium.