High frequency of BCP, but less CPP crystal-mediated calcification in cartilage and synovial membrane of osteoarthritis patients.

OBJECTIVE: Ectopic articular calcification is a common phenomenon of osteoarthritic joints, and closely related to disease progression. Identification of the involved calcium crystal types represents an important topic in research and clinical practice. Difficulties in accurate detection and crystal type identification have led to inconsistent data on the prevalence and spatial distribution of Basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) deposition. METHOD: Combining multiple imaging methods including conventional radiography, histology and Raman spectroscopy, this study provides a comprehensive analysis of BCP and CPP-based calcification, its frequency and distribution in cartilage and synovial membrane samples of 92 osteoarthritis patients undergoing knee replacement surgery. RESULTS: Conventional radiography showed calcifications in 35% of patients. Von Kossa staining detected calcified deposits in 88% and 57% of cartilage and synovial samples, respectively. BCP crystals presented as brittle deposits on top of the cartilage surface or embedded in synovial tissue. CPP deposits appeared as larger granular needle-shaped clusters or dense circular pockets below the cartilage surface or within synovial tissue. Spectroscopic analysis detected BCP crystals in 75% of cartilage and 43% of synovial samples. CPP deposition was only detected in 18% of cartilage and 15% of synovial samples, often coinciding with BCP deposits. CONCLUSION: BCP is the predominant crystal type in calcified cartilage and synovium while CPP deposition is rare, often coinciding with BCP. Distinct and qualitative information on BCP and CPP deposits in joint tissues gives rise to the speculation that different disease entities are involved that might need different treatment strategies.

Acetylcholine and metacognition during sleep.

Acetylcholine is a neurotransmitter and neuromodulator involved in a variety of cognitive functions. Additionally, acetylcholine is involved in the regulation of REM sleep: cholinergic neurons in the brainstem and basal forebrain project to and innervate wide areas of the cerebral cortex, and reciprocally interact with other neuromodulatory systems, to produce the sleep-wake cycle and different sleep stages. Consciousness and cognition vary considerably across and within sleep stages, with metacognitive capacity being strikingly reduced even during aesthetically and emotionally rich dream experiences. A notable exception is the phenomenon of lucid dreaming-a rare state whereby waking levels of metacognitive awareness are restored during sleep-resulting in individuals becoming aware of the fact that they are dreaming. The role of neurotransmitters in these fluctuations of consciousness and cognition during sleep is still poorly understood. While recent studies using acetylcholinesterase inhibitors suggest a potential role of acetylcholine in the occurrence of lucid dreaming, the underlying mechanisms by which this effect is produced remains un-modelled and unknown; with the causal link between cholinergic mechanisms and upstream psychological states being complex and elusive. Several theories and approaches targeting the association between acetylcholine and metacognition during wakefulness and sleep are highlighted in this review, moving through microscopic, mesoscopic and macroscopic levels of analysis to detail this phenomenon at several organisational scales. Several exploratory hypotheses will be developed to guide future research towards fully articulating how metacognition is affected by activity at the acetylcholine receptor.

Improved Reversion of Calcifications in Porcine Aortic Heart Valves Using Elastin-Targeted Nanoparticles.

Calcified aortic valve disease in its final stage leads to aortic valve stenosis, limiting cardiac function. To date, surgical intervention is the only option for treating calcific aortic valve stenosis. This study combined controlled drug delivery by nanoparticles (NPs) and active targeting by antibody conjugation. The chelating agent diethylenetriaminepentaacetic acid (DTPA) was covalently bound to human serum albumin (HSA)-based NP, and the NP surface was modified using conjugating antibodies (anti-elastin or isotype IgG control). Calcification was induced ex vivo in porcine aortic valves by preincubation in an osteogenic medium containing 2.5 mM sodium phosphate for five days. Valve calcifications mainly consisted of basic calcium phosphate crystals. Calcifications were effectively resolved by adding 1-5 mg DTPA/mL medium. Incubation with pure DTPA, however, was associated with a loss of cellular viability. Reversal of calcifications was also achieved with DTPA-coupled anti-elastin-targeted NPs containing 1 mg DTPA equivalent. The addition of these NPs to the conditioned media resulted in significant regression of the valve calcifications compared to that in the IgG-NP control without affecting cellular viability. These results represent a step further toward the development of targeted nanoparticular formulations to dissolve aortic valve calcifications.

Heterogeneity and Dynamics of Vasculature in the Endocrine System During Aging and Disease.

The endocrine system consists of several highly vascularized glands that produce and secrete hormones to maintain body homeostasis and regulate a range of bodily functions and processes, including growth, metabolism and development. The dense and highly vascularized capillary network functions as the main transport system for hormones and regulatory factors to enable efficient endocrine function. The specialized capillary types provide the microenvironments to support stem and progenitor cells, by regulating their survival, maintenance and differentiation. Moreover, the vasculature interacts with endocrine cells supporting their endocrine function. However, the structure and niche function of vasculature in endocrine tissues remain poorly understood. Aging and endocrine disorders are associated with vascular perturbations. Understanding the cellular and molecular cues driving the disease, and age-related vascular perturbations hold potential to manage or even treat endocrine disorders and comorbidities associated with aging. This review aims to describe the structure and niche functions of the vasculature in various endocrine glands and define the vascular changes in aging and endocrine disorders.

The role of calcium crystals and their effect on osteoarthritis pathogenesis.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degeneration of articular cartilage. Due to its high prevalence and limited treatment options, OA has become one of the most disabling diseases in developed countries. In recent years, OA has been recognized as a heterogenic disease with various phenotypes. Calcium crystal-related endotypes, which are defined by either a distinct functional or pathobiological mechanism, are present in approximately 60% of all OA patients. Two different calcium crystals can accumulate in the joint and thereby calcify the cartilage matrix, which are basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystals. The formation of these crystals depends mainly on the balance of phosphate and pyrophosphate, which is regulated by specific proteins controlling the pyrophosphate metabolism. Dysregulation of these molecules subsequently leads to preferential formation of either BCP or CPP crystals. BCP crystals, on the one hand, are directly associated with OA severity and cartilage degradation. They are mostly located in the deeper cartilage layers and are associated with chondrocyte hypertrophy. CPP crystal deposition, on the other hand, is a hallmark of chondrocalcinosis and is associated with aging and chondrocyte senescence. Therefore, BCP and CPP crystals are associated with different chondrocyte phenotypes. However, BCP and CPP crystals are not mutually exclusive and can coexist in OA, creating a mixed endotype of OA. Both crystals clearly play a role in the pathogenesis of OA. However, the exact impact of each crystal type on either driving the disease progression or being a result of chondrocyte differentiation is still to be elucidated.

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases.

The bone marrow (BM) vascular niche microenvironments harbor stem and progenitor cells of various lineages. Bone angiogenesis is distinct and involves tissue-specific signals. The nurturing vascular niches in the BM are complex and heterogenous consisting of distinct vascular and perivascular cell types that provide crucial signals for the maintenance of stem and progenitor cells. Growing evidence suggests that the BM niche is highly sensitive to stress. Aging, inflammation and other stress factors induce changes in BM niche cells and their crosstalk with tissue cells leading to perturbed hematopoiesis, bone angiogenesis and bone formation. Defining vascular niche remodeling under stress conditions will improve our understanding of the BM vascular niche and its role in homeostasis and disease. Therefore, this review provides an overview of the current understanding of the BM vascular niches for hematopoietic stem cells and their malfunction during aging, bone loss diseases, arthritis and metastasis.