Acute-on-chronic inflammation in acute myocardial infarction.

PURPOSE OF REVIEW: Acute myocardial infarction (AMI) is heralded by chronic inflammation and entails an excessive burst of acute-on-chronic inflammation (AoCI). This review describes the evolution from understanding atherosclerosis as a chronic inflammatory disease, to recent efforts in optimizing anti-inflammatory therapy to patients with AMI. It highlights the challenges and opportunities in selecting the optimal patient with AMI to derive maximal benefit from early anti-inflammatory therapy. RECENT FINDINGS: The causal role of inflammation in atherosclerosis has been proven in large outcome trials. Since then, several smaller trials have sought to translate the concept of anti-inflammatory therapy targeting residual inflammatory risk to the dynamic early phase of AoCI after AMI. Current evidence highlights the importance of selecting patients with a high inflammatory burden. Surrogate criteria for large AMI (e.g., angiographic or electrocardiographic), as well as novel point-of-care biomarker testing may aid in selecting patients with particularly elevated AoCI. Additionally, patients presenting with AMI complicated by pro-inflammatory sequelae (e.g., atrial fibrillation, acute heart failure, left ventricular thrombosis) may dually profit from anti-inflammatory therapy. SUMMARY: Improved understanding of the mechanisms and dynamics of acute and chronic inflammatory processes after AMI may aid the strive to optimize early anti-inflammatory therapy to patients with AMI.

Successful bedaquiline-containing antimycobacterial treatment in post-traumatic skin and soft-tissue infection by Mycobacterium fortuitum complex: a case report.

BACKGROUND: Mycobacterium fortuitum complex is a group of rapidly growing nontuberculous mycobacteria (NTM) associated with skin and soft-tissue infections after surgery or trauma. Treatment of NTM is challenging, due to resistance to multiple antimycobacterial agents. Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP-synthase. The drug has recently been approved for the treatment of multidrug-resistant tuberculosis and evidence of its in vitro efficacy against NTM, including Mycobacterium fortuitum complex, has been published. CASE PRESENTATION: A 20-year-old Caucasian woman with chronic skin and soft tissue infection in the lower leg following a traffic accident in Vietnam underwent a tedious journey of healthcare visits, hospital admissions, empiric antimicrobial treatments, surgical debridement and plastic reconstruction before definite diagnosis of Mycobacterium fortuitum complex-infection was established by culture from a tissue biopsy and targeted antimycobacterial therapy was administered. Histopathological examination revealed granulomatous purulent inflammation, which strongly supported the diagnosis. Genotypic identification was performed and broth microdilution for susceptibility testing showed macrolide resistance. Five weeks of induction treatment with intravenous amikacin, imipenem / cilastin, and oral levofloxacin was administered, followed by all-oral treatment with bedaquiline combined with levofloxacin for four months, which was well-tolerated and led to persistent healing with scars but without signs of residual infection. CONCLUSIONS: Bedaquiline is a promising novel agent for NTM treatment, although clinical data are limited and trials evaluating efficacy, safety, and resistance of bedaquiline are required. To our knowledge, this is the first reported case of successful in vivo use of bedaquiline for a skin and soft tissue infection caused by Mycobacterium fortuitum complex.

Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons.

Background: Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. Methods: We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. Results: TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Conclusion: Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.