Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis.

Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe-/-) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe-/- mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm-/-) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.

A Case of Severe COVID-19 Pneumonia Diagnosed in Bronchoscopy With Negative Repeated Nasopharyngeal Swabs.

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic that had emerged in China since December 2019. The disease affects all age groups, with clinical manifestations in the spectrum from asymptomatic to rapidly lethal multi-organ failure, mainly involving the respiratory system. Diagnosis is confirmed mainly by a positive real-time polymerase chain reaction (PCR) nasopharyngeal swab. It is highly recommended to avoid performing invasive procedures in COVID-19 subjects to prevent the potential for dissemination of the pathogen. Treatment consists in particular of respiratory support and symptom relief. Dexamethasone is widely used with encouraging response. There were no cases in the literature that were diagnosed with positive reverse transcription-polymerase chain reaction (RT-PCR) testing only from fluid of involved organs, while repeated nasopharyngeal swabs returned negative for COVID-19. We here describe a case of COVID-19 that presented with moderate-severe pulmonary involvement, diagnosed by RT-PCR testing from broncho-alveolar lavage, while several nasopharyngeal swabs were consistently negative. The patient experienced no improvement under wide-spectrum antibiotics administered initially, and greatly improved after receiving systemic corticosteroids. One can realize from our case that COVID-19 could not be ruled out upon repeated negative RT-PCR nasopharyngeal swabs, and in subjects with highly suspected COVID-19, it is justified to perform invasive procedures, but still using maximal protective measures.

Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis.

Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient (Apoe-/-) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe-/- mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe-/- mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.

A case of rapidly progressive upper limb ischemic necrosis in a patient with COVID-19.

BACKGROUND: For more than a year, health systems all over the world have been combating the global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first described in the city of Wuhan in China, presenting as an atypical infection of the lower respiratory tract. METHODS: COVID-19 is characterized by multisystemic involvement, and mortality is attributed mainly to the respiratory system involvement, which may lead to severe acute respiratory distress syndrome and respiratory failure. Several COVID-19-associated complications are being increasingly reported, including arterial and venous thromboembolic events that may lead to amputation of the affected limbs. So far, a large number of reports have described hypercoagulability crises leading to amputation of the lower limbs. However, a search of the National Library of Medicine (MEDLINE) revealed no cases of urgent upper limb amputation in COVID-19 patients. RESULTS: This article describes a novel case of upper limb ischemia in a COVID-19 patient, with rapid progression to hand necrosis, requiring urgent through-arm amputation of the upper limb. CONCLUSIONS: This case emphasizes the need for anticoagulant therapy in COVID-19 patients and to maintain a constant awareness of the possible thromboembolic COVID-19-related sequelae.

Sodium-glucose cotransporter-2-induced euglycemic diabetic ketoacidosis unmasks latent autoimmune diabetes in a patient misdiagnosed with type 2 diabetes mellitus: a case report.

BACKGROUND: Euglycemic diabetic ketoacidosis is an uncommon but life-threatening complication associated with the use of sodium-glucose cotransporter 2 inhibitors that causes lower than expected blood glucose levels typically seen in diabetic ketoacidosis. CASE PRESENTATION: We present a case of 64-year-old Caucasian male patient previously diagnosed with type 2 diabetes treated with a sodium-glucose cotransporter 2 inhibitor who developed severe ketoacidosis. Serum glucose levels on initial presentation were slightly above normal baseline level. The patient was revealed to have latent autoimmune diabetes in adults. CONCLUSION: This case highlights the importance of prescribing sodium-glucose cotransporter 2 inhibitors to the correct patient population and the significance of accurately differentiating between various types of diabetes.

Screening of Abdominal Aortic Aneurysm Using Portable Transthoracic Echocardiography among Patients with Acute Coronary Syndrome.

BACKGROUND: Abdominal aortic aneurysm (AAA) and acute coronary syndrome (ACS) share common risk factors. OBJECTIVES: To assess the abdominal aortic diameter (AAD) among patients with ACS using transthoracic echocardiography (TTE). METHODS: Patients with ACS admitted to our intensive cardiac care unit from December 2013 to June 2014 were screened prospectively for AAA via AAD measurement in the subcostal TTE view. AAA was defined as an aneurysm with a transverse diameter of ≥30 mm. RESULTS: Sixty seven patients were included. The male-to-female sex ratio was 7 : 1. The vast majority of patients were admitted due to STEMI (73%), and the rest were equally divided as NSTEMI and unstable angina. The mean patient age was 58.4 ± 10.4 years. AAD measurements were feasible in 57 patients (85%); among them, AAA was diagnosed in six patients (10.5%). The average additional time required to measure the abdominal aorta was 4 ± 1 min. All patients with AAA were men and had a higher prevalence of smoking (83.3% vs. 60.6%, p < 0.003) and a lower incidence of diabetes mellitus than those without aneurysm. The prevalence of AAA tended to be related to age (12.5% in those older than 60 years and 18.7% in those older than 65 years). CONCLUSIONS: The overall prevalence of AAA is significantly high among patients with ACS and increases with age. AAA screening as a part of routine cardiac TTE can be easily, rapidly, and feasibly performed and yield accurate findings. AAD measurement in the subcostal view should be implemented as a part of routine TTE in patients with ACS.