Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule.

The therapeutic potential of carbon monoxide.

Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies

Critical illness polyneuropathy (CIP) and myopathy (CIM) are complications of critical illness that present with muscle weakness and failure to wean from the ventilator. In addition to prolonging mechanical ventilation and hospitalisation, CIP and CIM increase hospital mortality in patients who are critically ill and cause chronic disability in survivors of critical illness. Structural changes associated with CIP and CIM include axonal nerve degeneration, muscle myosin loss, and muscle necrosis. Functional changes can cause electrical inexcitability of nerves and muscles with reversible muscle weakness. Microvascular changes and cytopathic hypoxia might disrupt energy supply and use. An acquired sodium channelopathy causing reduced muscle membrane and nerve excitability is a possible unifying mechanism underlying CIP and CIM. The diagnosis of CIP, CIM, or combined CIP and CIM relies on clinical, electrophysiological, and muscle biopsy investigations. Control of hyperglycaemia might reduce the severity of these complications of critical illness, and early rehabilitation in the intensive care unit might improve the functional recovery and independence of patients.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(11)70178-8.pdf

Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis

Sepsis: Current Dogma and New Perspectives

Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 pr...

Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1

The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

/pdf/the-co-ho-system-reverses-inhibition-of-mitochondrial-1bbh173pyi.pdf

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Rationale: The extent, timing, and significance of mitochondrial injury and recovery in bacterial sepsis are poorly characterized, although oxidative and nitrosative mitochondrial damage have been implicated in the development of organ failure.Objectives: To define the relationships between mitochondrial biogenesis, oxidative metabolism, and recovery from Staphylococcus aureus sepsis.Methods: We developed a murine model of fibrin clot peritonitis, using S. aureus. The model yielded dose-dependent decreases in survival and resting energy expenditure, allowing us to study recovery from sublethal sepsis.Measurements and Main Results: Peritonitis caused by 106 colony-forming units of S. aureus induced a low tumor necrosis factor-α state and minimal hepatic cell death, but activated prosurvival protein kinase A, B, and C sequentially over 3 days. Basal metabolism by indirect calorimetry was depressed because of selective mitochondrial oxidative stress and subsequent loss of mitochondrial DNA copy number. Durin...

/pdf/mitochondrial-biogenesis-restores-oxidative-metabolism-10ovwsl53t.pdf

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

http://www.ijidonline.com/article/S1201971222004830/pdf

Acute encephalopathy in a 6-year-old child with concurrent COVID-19 infection: a case report from Saudi Arabia

Meningitis is an inflammation of the brain and spinal cord meninges caused by infectious and non-infectious agents. Infectious agents causing meningitis include viruses, bacteria, and fungi. Viral meningitis (VM), also termed aseptic meningitis, is caused by some viruses, such as enteroviruses (EVs), herpesviruses, influenza viruses, and arboviruses. However, EVs represent the primary cause of VM. The clinical symptoms of this neurological disorder may rapidly be observed after the onset of the disease, or take prolonged time to develop. The primary clinical manifestations of VM include common flu-like symptoms of headache, photophobia, fever, nuchal rigidity, myalgia, and fatigue. The severity of these symptoms depends on the patient's age; they are more severe among infants and children. The course of infection of VM varies between asymptomatic, mild, critically ill, and fatal disease. Morbidities and mortalities of VM are dependent on the early recognition and treatment of the disease. There were no significant distinctions in the clinical phenotypes and symptoms between VM and meningitis due to other causative agents. To date, the pathophysiological mechanisms of VM are unclear. In this scientific communication, a descriptive review was performed to give an overview of pediatric viral meningitis (PVM). PVM may occasionally result in severe neurological consequences such as mental retardation and death. Clinical examinations, including Kernig's, Brudzinski's, and nuchal rigidity signs, were attempted to determine the clinical course of PVM with various success rates revealed. Some epidemiological correlates of PVM were adequately reviewed and presented in this report. They were seen depending mainly on the causative virus. The abnormal cytological and biochemical features of PVM were also discussed and showed potentials to distinguish PVM from pediatric bacterial meningitis (PBM). The pathological, developmental, behavioral, and neuropsychological complications of PVM were also presented. All the previously utilized techniques for the etiological diagnosis of PVM which include virology, serology, biochemistry, and radiology, were presented and discussed to determine their efficiencies and limitations. Finally, molecular testing, mainly PCR, was introduced and showed 100% sensitivity rates.

/pdf/etiology-clinical-phenotypes-epidemiological-correlates-2jj75pcl.pdf

Etiology, Clinical Phenotypes, Epidemiological Correlates, Laboratory Biomarkers and Diagnostic Challenges of Pediatric Viral Meningitis: Descriptive Review

OBJECTIVES
To evaluate the demographics, clinical presentation, laboratory data, chest radiographs, and outcomes of pediatric patients with critical coronavirus disease 2019 (COVID-19).


METHODS
This retrospective study included 34 children who were diagnosed with severe COVID-19 pneumonia between August 2020 and July 2021. Severe pneumonia was defined as fever, respiratory distress (tachypnea, chest retractions, and hypoxia [oxygen saturation <90% in room air]), and obvious infiltrations on chest radiography.


RESULTS
Ages of the patients ranged from newborns to 12 years old, with a median of 24 months (interquartile range: 12-72 months). Preschool-aged children were the most common age group (44%). Levels of inflammatory markers (C-reactive protein, ferritin, and procalcitonin) were elevated in most patients. A total of 13 patients developed severe acute respiratory distress syndrome (ARDS), while 4 developed multiorgan failure. Despite receiving supportive therapy, 2 (5.9%) patients died due to severe septic shock and multiorgan failure. One deceased patient was born prematurely at 30 weeks, while the other had chronic granulomatous disease.


CONCLUSION
This study described a single-center cohort of pediatric patients with severe COVID-19 pneumonia. In this cohort, children with cardiopulmonary comorbidities and ARDS had a high mortality and long-term morbidity, as observed in other pediatric studies.

/pdf/clinical-laboratory-and-chest-radiographic-characteristics-3as228li.pdf

Abdelwahid S. Ali

Papers

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Mitochondrial Biogenesis Restores Oxidative Metabolism during Staphylococcus aureus Sepsis

Acute encephalopathy in a 6-year-old child with concurrent COVID-19 infection: a case report from Saudi Arabia

Etiology, Clinical Phenotypes, Epidemiological Correlates, Laboratory Biomarkers and Diagnostic Challenges of Pediatric Viral Meningitis: Descriptive Review

Clinical, laboratory, and chest radiographic characteristics of COVID-19 associated severe pediatric pneumonia. A retrospective study.