Combination antiretroviral therapy and chronic HIV infection affect serum retinoid concentrations: longitudinal and cross-sectional assessments

Abstract Background Several lines of evidence suggest that retinoids (retinol-ROL or vitamin A, and its active metabolites, retinoic acids-RAs) play important pathogenic roles in HIV infection and combination antiretroviral therapy (cART)-related events. We previously reported that antiretrovirals alter RAs synthesis in vitro. We hypothesised that in vivo serum retinoid concentrations are affected by both cART and HIV infection. This might explain several clinical and laboratory abnormalities reported in HIV-infected patients receiving cART. Methods The effects of optimal cART and chronic HIV on serum retinoids were firstly assessed longitudinally in 10 HIV-infected adults (group1 = G1): twice while on optimal cART (first, during long-term and second, during short term cART) and twice during 2 cART interruptions when HIV viral load (VL) was detectable. Retinoid concentrations during optimal long term cART in G1 were compared with cross-sectional results from 12 patients (G2) with suboptimal cART (detectable VL) and from 28 healthy adults (G3). Serum retinoids were measured by HPLC with ultraviolet detection. Retinoid concentrations were correlated with VL, CD4+ T- cell count and percentages, CD8+38+ fluorescence, triglycerides, cholesterol and C-peptide serum levels. Results During optimal cART, G1 participants had drastically reduced RAs (0.5 ± 0.3 μg/dL; P + T- cell count, CD8+38+ fluorescence, VL. ROL correlated with triglycerides and cholesterol in G1 (rs = 0.8; P = 0.01). Conclusions Serum RAs levels are significantly diminished by cART, whereas ROL concentrations significantly decreased during uncontrolled HIV infection but augmented with optimal cART. These alterations in retinoid concentrations may affect the expression of retinoid-responsive genes involved in metabolic, hormonal and immune processes and be responsible for some adverse events observed in HIV-infected persons treated with antiretrovirals. Further studies should assess concomitant serum and intracellular retinoid levels in different clinical situations in larger, homogenous populations.</p

Continuing professional development (CPD) system development, implementation, evaluation and sustainability for healthcare professionals in low- and lower-middle-income countries: a rapid scoping review

Abstract Background Policymakers and program developers in low-and lower-middle-income countries (LLMICs) are increasingly seeking evidence-based information and guidance on how to successfully develop and implement continuing professional development (CPD) systems. We conducted a rapid scoping review to map and synthesize what is known regarding the development, implementation, evaluation and sustainability of CPD systems for healthcare professionals in LLMICs. Methods We searched MEDLINE, CINAHL and Web of Science. Reference lists were screened and a cited reference search of included articles was conducted. Supplementary information on the CPD systems identified in the articles was also identified via an online targeted grey literature search. English, French and Spanish literature published from 2011 to 2021 were considered. Data were extracted and combined and summarized according to country/region and healthcare profession via tables and narrative text. Results We included 15 articles and 23 grey literature sources. Africa was the region most represented followed by South and Southeast Asia and the Middle East. The literature most often referred to CPD systems for nurses and midwives; CPD systems for physicians were frequently referred to as well. Findings show that leadership and buy-in from key stakeholders, including government bodies and healthcare professional organizations, and a framework are essential for the development, implementation and sustainability of a CPD system in a LLMIC. The guiding framework should incorporate a regulatory perspective, as well as a conceptual lens (that informs CPD objectives and methods), and should consider contextual factors (support for CPD, healthcare context and population health needs). In terms of important steps to undertake, these include: a needs assessment; drafting of a policy, which details the regulations (laws/norms), the CPD requirements and an approach for monitoring, including an accreditation mechanism; a financing plan; identification and production of appropriate CPD materials and activities; a communication strategy; and an evaluation process. Conclusion Leadership, a framework and a clearly delineated plan that is responsive to the needs and context of the setting, are essential for the development, implementation and sustainability of a CPD system for healthcare professionals in a LLMIC

Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

Mitochondrial dysfunction characterizes many rare and common age-associated diseases. The biochemical consequences, underlying clinical manifestations, and potential therapeutic targets, remain to be better understood. We tested the hypothesis that lipid dyshomeostasis in mitochondrial disorders goes beyond mitochondrial fatty acid β-oxidation, particularly in liver. This was achieved using comprehensive untargeted and targeted lipidomics in a case-control cohort of patients with Leigh syndrome French-Canadian variant (LSFC), a mitochondrial disease caused by mutations in LRPPRC, and in mice harboring liver-specific inactivation of Lrpprc (H-Lrpprc–/–). We discovered a plasma lipid signature discriminating LSFC patients from controls encompassing lower levels of plasmalogens and conjugated bile acids, which suggest perturbations in peroxisomal lipid metabolism. This premise was reinforced in H-Lrpprc–/– mice, which compared with littermates recapitulated a similar, albeit stronger peroxisomal metabolic signature in plasma and liver including elevated levels of very-long-chain acylcarnitines. These mice also presented higher transcript levels for hepatic markers of peroxisome proliferation in addition to lipid remodeling reminiscent of nonalcoholic fatty liver diseases. Our study underscores the value of lipidomics to unveil unexpected mechanisms underlying lipid dyshomeostasis ensuing from mitochondrial dysfunction herein implying peroxisomes and liver, which likely contribute to the pathophysiology of LSFC, but also other rare and common mitochondrial diseases

Cyclophilin-D is dispensable for atrophy and mitochondrial apoptotic signalling in denervated muscle

In the present study, we specifically determined whether the regulatory protein cyclophilin-D (CypD), and by extension opening of the permeability transition pore (PTP), is involved in the activation of mitochondria-derived apoptotic signalling previously described in skeletal muscle following loss of innervation. For this purpose, CypD-defficient (CypD-KO) mice and their littermate controls were submitted to unilateral sciatic nerve transection, and mitochondrial resistance to Ca2+-induced opening of the PTP, and muscle apoptotic signalling were investigated 14 days post-surgery. Denervation caused atrophy, facilitated Ca2+-induced opening of the PTP in vitro in permeabilized muscle fibres, and activation of the apoptotic proteolytic cascade in the whole muscle of both mouse strains. In CypD-KO mice, mitochondrial resistance to Ca2+-induced PTP opening was greater than in WT mice, in both the normal and the denervated state, indicating that lack of CypD desensitized to PTP opening. However, denervation in CypD-KO mice still resulted in a facilitation of PTP opening compared to normally innervated contralateral muscle, indicating that in vitro additional factors could poise mitochondria from denervated muscle toward PTP opening. At the whole muscle level, lack of CypD, despite conferring greater resistance to PTP opening, did not protect against atrophy, release of mitochondrial pro-apoptotic factors and activation of caspases following denervation. Altogether, these results provide direct evidence that CypD-dependent PTP opening is dispensable for atrophy and apoptotic signalling in skeletal muscle following denervation

A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome

A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD+ biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases

Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort

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