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Background and Purpose: Statins are competitive inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen‐induced Hmgcr‐knockout (KO) mouse model, a multi‐omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. Experimental Approach: We established a new mouse strain using the Cre/loxP system, which enabled whole‐body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time‐dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr‐KO mice. Key Results: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β‐oxidation and very high accumulation of long‐chain (LC) acylcarnitines in both male and female mice. Gene expression and KO‐related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole‐body hypoglycaemia. Conclusion and Implications: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β‐oxidation. Moreover, statin‐induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation. [ABSTRACT FROM AUTHOR]

Background. The endocardium and cardiac valves undergo severe impact during infective endocarditis (IE), and the formation of vegetation places IE patients at a heightened risk of embolic complications and mortality. The relevant literature indicates that 50% of IE cases exhibit structurally normal cardiac valves, with no preceding history of heart valve disease. Gram-positive cocci emerge as the predominant causative microorganisms in IE, while Gram-negative Bartonella spp., persisting in the endothelium, follow pathogenic pathways distinct from those of typical IE-causing agents. Employing clinical as well as advanced microbiological and molecular assays facilitated the identification of causative pathogens, and various morphological methods were applied to evaluate heart valve damage, shedding light on the role of neutrophilic leukocytes in host defense. In this research, the immunohistochemical analysis of neutrophilic leukocyte activation markers such as myeloperoxidase, neutrophil elastase, calprotectin, and histone H3, was performed. A distinct difference in the expression patterns of these markers was observed when comparing Bartonella spp.-caused and non-Bartonella spp.-caused IE. The markers exhibited significantly higher expression in non-Bartonella spp.-caused IE compared to Bartonella spp.-caused IE, and they were more prevalent in vegetation than in the valvular leaflets. Notably, the expression of these markers in all IE cases significantly differed from that in control samples. Furthermore, we advocated the use of 16S rRNA Next-Generation Sequencing on excised heart valves as an effective diagnostic tool for IE, particularly in cases where blood cultures yielded negative results. The compelling results achieved in this study regarding the enigmatic nature of Bartonella spp. IE's pathophysiology contribute significantly to our understanding of the peculiarities of inflammation and immune responses. [ABSTRACT FROM AUTHOR]

Secondary systemic (AA) amyloidosis is reported as a serious complication that occurs in long-standing Crohn's disease (CD), with an incidence of 0.3-10.9%. Various therapeutic approaches using medicines and elemental diet have been recomended, but still there are no established standards of treatment for secondary systemic amyloidosis in CD. Only a few studies have shown the role of TNFα ihibitors in the treatment of AA amyloidosis over a long term period. We report the case of a 24-year-old male with CD complicated by AA amyloidosis with renal and gastrointestinal tract involvement treated with infliximab as induction therapy. Intestinal AA amyloidosis progression occurred at the same time with the development of CD as an early complication, whereas duration of CD prior to the diagnosis of renal AA amyloidosis was 6 years. Infliximab therapy (3 infusions) caused a significant decrease of serum amyloid A protein (by 97.9%), C-reactive protein (by 70%), improvement of disease activity index, and CD caused clinical symptoms. At the same time gradual progression of the renal damage (reduction of renal function) was not affected by the treatment. Direct efficacy of infliximab infusions on serum amyloid protein level may support the hypothesis of TNFα induced reduction on the progression of AA amyloidosis described in previous study reports. Targeted histological analysis of tissue biopsy is crucial to clarify the presence of AA amyloidosis in CD induced multiorgan damage cases. [ABSTRACT FROM AUTHOR]

Background: The implications of inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) in solid organ transplantation remain uncertain. Although this trait has been linked to unfavorable clinical outcomes, an association between viral reactivation and complications has only been conclusively established in a few cases. In contrast to these studies, which followed donor-derived transmission, our investigation is the first to examine the pathogenicity of a recipient´s iciHHV-6B and its impact on the graft., Methods: We used hybrid capture sequencing for in-depth analysis of the viral sequences reconstructed from sequential liver biopsies. Moreover, we investigated viral replication through in situ hybridization (U38-U94 genes), real-time PCR (U89/U90 genes), immunohistochemistry, and immunofluorescence (against viral lysate). We also performed whole transcriptome sequencing of the liver biopsies to profile the host immune response., Results: We report a case of reactivation of a recipient´s iciHHV-6B and subsequent infection of the graft. Using a novel approach integrating the analysis of viral and mitochondrial DNAs, we located the iciHHV-6B intra-graft. We demonstrated active replication via the emergence of viral minor variants across time points, in addition to positive viral mRNAs and antigen stainings in tissue sections. Furthermore, we detected significant upregulation of cell surface molecules, transcription factors, and cytokines associated with antiviral immune responses, arguing against immunotolerance., Conclusions: Our analysis underscores the potential pathological impact of iciHHV-6B, emphasizing the need for close monitoring of reactivation in transplant recipients. Most crucially, it highlights the critical role that the host's virome can play in shaping the outcome of transplantation, urging further investigations., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)