PATHOPHYSIOLOGY OF LACTIC ACIDOSIS IN PATIENTS WITH ASTHMA

SESSION TITLE: Challenges in Asthma SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Asthma is a chronic illness affecting 334 million people worldwide[1]. Asthma affects the respiratory gas exchange, which plays a significant role in acid-base balance. Acid-base disorders in asthma involve respiratory alkalosis, respiratory acidosis, and AG acidosis[2]. CASE PRESENTATION: A 37 years old Hispanic male with a PMH of intermittent asthma presents with progressive dyspnea for three days, worse with activity and decreases with rest. He reported no [cough, fever, rhinorrhea, chest pain]. No orthopnea. He is vaccinated for COVID ( 2 Pfizer doses), has no sickness exposure, and works as a driver. The patient is not a smoker. Physical Exam: Blood pressure 124/72 mmHg. Heart Rate 100 PPM. Temperature 97.1 F.Respiratory Rate 21BPM.SPO2 90% General appearance: acute distress with nasal flaring. Heart: Normal S1, S2. RRR. Lung: Poor air entry with diffuse wheeze bilaterally. He was placed on a 6 LPM NC. CBC and differential were unremarkable. He was started on methylprednisone, Ceftriaxone, and azithromycin. The patient was started on inhaled Salbutamol and Budesonide. Chest X-ray was unremarkable, Chemistry was unremarkable except for elevated Lactic acid 4.7, There was no concern for reduced tissue perfusion or hypoxia, with no evidence of an infectious process because both viral and bacterial causes for pneumonia were excluded, and antibiotics were stopped. A serial lactic acid level trend was 4.5/4.3/ 4.1/ 4 on the first day, while on the next day, it was 3.1/ 2.9/ 2.7/ 2.5/ 3.5, we stopped trending his lactic acid level. He improved and was discharged on an oral taper steroid and inhaled steroids with a B2 agonist. DISCUSSION: There are two types of Lactic acidosis in patients with asthma: 1- Type-A results from impaired oxygen delivery to tissues and reduced tissue perfusion in severe acute asthma may be accompanied by reduced cardiac output. 2- Type B where oxygen delivery is normal, but the cellular function is impaired due to increased norepinephrine in plasma, increasing metabolic rate and lactate production, drugs like beta-agonists increase glycogenolysis leading to an increased pyruvate concentration;pyruvate is converted to lactic acid. B2 agonist increases lipolysis and increases Acetyl CoA, this increase in Acetyl CoA inhibits the conversion of pyruvate to Acetyl CoA, increasing pyruvate which will be converted to lactic acid[2], Theophylline is a non-selective 5'-phosphodiesterase inhibitor and potentiates the activity of ß-adrenergic agents by increasing the intracellular concentration of cAMP, Glucocorticoids are also known to increase the ß-receptor's sensitivity to ß-adrenergic agonists. CONCLUSIONS: Providers are increasingly challenged by hyperlactatemia,it is not harmful but elevated Lactic acid levels and clearance rate is used for prognostication,hyperlactatemia might be misleading,and all possible causes of elevated lactic acid levels must be explored. Reference #1: 10.5334/aogh.2412 Reference #2: https://doi.org/10.3390/jcm8040563 Reference #3: Edwin B. Liem, Stephen C. Mnookin, Michael E. Mahla;Albuterol-induced Lactic Acidosis. Anesthesiology 2003;99:505–506 doi: https://doi.org/10.1097/00000542-200308000-00036 DISCLOSURES: No relevant relationships by Vasudev Malik Daliparty No relevant relationships by Abdallah Khashan No relevant relationships by Samer Talib No relevant relationships by MATTHEW YOTSUYA

Social isolation promotes mammary cancer recurrence, increases IL6/JAK/STAT3 signaling and causes mitochondrial dysfunction in tamoxifen treated rats, and a traditional herbal mixture reverses all these changes

Social isolation is associated with increased risk and mortality from many diseases, such as breast cancer. Socially isolated breast cancer survivors have a 43% higher risk of recurrence and a 64% higher risk of breast cancer-specific mortality than socially integrated survivors. Since Covid-19 has dramatically increased the incidence of social isolation, it is important to determine if social isolation affects the response to endocrine therapy and/or recurrence after the therapy is completed. Since previous studies indicate that social isolation increases circulating inflammatory cytokines, we investigated if an anti-inflammatory herbal mixture Jaeumkanghwa-tang (JGT) prevents the adverse effects of social isolation on breast cancer mortality. Estrogen receptor positive mammary tumors were initiated with 7,12-dimethylbenz[a]anthracene. When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing it singly or a rat was allowed to remain group-housed (GH). Tamoxifen (340ppm via diet) or tamoxifen + JGT (500ppm via drinking water) started when the first mammary tumor reached a size of 11 mm in diameter. Tamoxifen administration ended when a complete response to this therapy had lasted for 9 weeks (corresponds to 5 years in women). During tamoxifen therapy, social isolation non-significantly reduced the rate of complete responses to 21%, from 31% in GH group (p>0.05). After the therapy was completed, SI significantly increased local mammary tumor recurrence (p<0.001;45% GH vs 75% SI). RNAseq analysis was performed in the mammary glands. Gene set enrichment analysis (GSEA) of transcriptome showed that the increased recurrence risk in socially isolated rats was associated with an enrichment of IL6/JAK/STAT3 signaling: this result was confirmed in the tumors. In addition, oxidative phosphorylation (OXPHOS) pathway was suppressed: the suppressed genes included those involved in mitochondrial pyruvate transport and conversion of pyruvate to acetyl CoA as well as genes in the TCA cycle and mediating electron transport in mitochondrial complexes I-IV. Social isolation also increased the expression of inflammatory receptor for advanced glycation end-products (RAGE) (p≤0.05). Consumption of an anti-inflammatory JGT inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling and prevented the increased risk of mammary cancer recurrence in socially isolated animals. The percentage of recurrences in the SI rats dropped from 75% without JGT to 22% with JGT (p<0.001). Breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and correct disrupted OXPHOS and mitochondrial dysfunction.

Efficient One-Pot Synthesis of Indolhydroxy Derivatives Catalyzed by SnCl2, DFT Calculations and Docking Study

In this work we used an efficient and simple synthesis for the preparation of new indolhydroxy derivatives that has been performed by the reduction reaction of 2-nitrocinnamic acid or 2-nitrophenyl pyruvic acid with anhydrous stannous chloride (SnCl2) as a metal catalyst in different alcoholic solvents. During this transformation there was the involvement of intramolecular elimination cyclization. In the case of the reduction of 2-nitrocinnamic acid we obtained hydroxyindole plus hydroxyquinoline, on the other hand, the reduction of 2-nitrophenyl pyruvic acid gives hydroxyindole only, the products were obtained in suitable yields. The structures of all the synthesized compounds were fully characterized by different spectroscopic techniques such as 1H NMR, 13C NMR. In addition, the obtained products have been tested in silico against anti-human immunodeficiency virus type 1 (HIV-1) and SARS-CoV-2 virus. The outcomes of this work are very promising to develop more efficient antiviral compounds, indicating that these products may be a probable drugs for the SARS-CoV-2. © 2022, The Tunisian Chemical Society and Springer Nature Switzerland AG.

TYPE 2 DIABETES IMPAIRS ANTIVIRAL IMMUNITY BY PREVENTING THE INDUCTION OF FASTING METABOLISM

Background and Aims: Type 2 diabetes (T2D) is a major risk factor for developing severe infectious disease, such as COVID-19. The endocrine and immune system closely interact following viral infection, which is deregulated in T2D. Previously, we showed in humans and mice that viral infection causes transient insulin resistance, which can lead to permanent loss of glycemic control in subjects with pre-diabetes. How changes in systemic glycemia benefit the antiviral response, and how this derails in T2D is mostly unknown. Methods: Mice were infected with virulent strains of cytomegalovirus or lymphocytic choriomeningitis virus. Glucose-, insulin- and pyruvate-tolerance tests and hyperinsulinemic euglycemic clamping were used to determine the metabolic state of animals. Conditional knock-out models were used to measure the impact of cytokines on metabolism of specific organs. Dietinduced obesity models were used to determine the impact of hyperglycemia on the antiviral response. Results: Severe viral infection causes pancreatic β-cell hyperfunctionality following their stimulation with the cytokine IFNγ by local T cells. Virus-induced hyperinsulinemia impaired glucose release by the liver and promoted induction of fasting metabolism, because of reduced hepatic glycogenolysis, causing relative, transient hypoglycemia (RHG). RHG was beneficial to the antiviral response by promoting the release of antiviral cytokines by endothelial cells, which impaired viral replication. Obese mice failed to induce fastng metabolsim, resulting in lower antiviral cytokines, higher viral titers and increased pathology. Conclusions: Metabolic adaptations following infection are of major importance for optimal control of viral replication. In context of T2D, these changes cannot be accomplished, thus leading to more frequent and severe infections.

SARS-2 related HUPRA syndrome presenting with neonatal lactic acidosis

Introduction: Mitochondria are organelles that fulfill the energy requirements for cells, which is essential for their survival and function. Mitochondria function is dependent on both mitochondrial (mtDNA) and nuclear genes (Tucker, 2010). SARS2 is a nuclear gene that encodes the mitochondria seryl-tRNA synthetase precursor. It catalyzes the attachment of serine to tRNA and in the biosynthesis of selenocysteinyl-tRNA in the mitochondria. Pathogenic variation in the gene is associated with HUPRA syndrome, which is characterized by hyperuricemia, pulmonary hypertension, renal failure, and metabolic alkalosis (Rivera, 2013). It is important to recognize this autosomal recessive condition as it presents in infancy, can lead to death, and has recurrence implications for carrier couples. Case Description: We present a term neonate male who experienced tachypnea at birth requiring respiratory support;echocardiogram concerning for pulmonary hypertension and right ventricular hypertrophy requiring ionized nitric oxide. During his hospitalization, he developed lactic acidosis (consistently 10–12 mmol/L, reaching 26 mmol/L), seizures, and his newborn screen results flagged as abnormal for severe combined immunodeficiency (SCID) due to low Tcell count. He was transferred to a tertiary medical center due to continued elevated lactate levels. During admission to the tertiary medical center, he was found to have hyperkalemia, elevated BUN/Cr, and elevated lactate levels. Additionally, pre-prandial and postprandial lactate and pyruvate levels were obtained. It was found that hyperlactatemia was persistent and not related to feedings. The patient developed a presumed pulmonary hypertensive crisis at 8 weeks of age, and in the setting of chronic intrinsic renal dysfunction and chronic lactic acidosis, the family elected to transfer him to the home hospital for compassionate extubation where he died. Notable genetics evaluation findings included urine organic acid results showing markedly and persistently elevated levels of fumaric acid and lactic acid concerning for fumarase deficiency or a mitochondrial oxidative phosphorylation disorder and plasma amino acids showing elevated alanine and proline indicative of lactic acidosis. An array CGH showed 2% areas of homozygosity, consistent with known shared parental ancestry. The results of combined mitochondrial genome and Mitochondrial Nuclear Gene Panel was ordered. The results revealed two SARS2 variants: (c.988C>T,p.R330W and c.173T>A, p.L58Q). Both variants were classified as variants of uncertain significance (VUS) based on ACMG-AMP criteria (Richards, 2015) and parental testing to determine phase is ongoing. Discussion: Pathogenic variants in SARS2 lead to dysfunction of seryltRNA synthetase and is associated with HUPRA syndrome. Our patient harbors two variants in SARS2 classified as VUSes but based on clinical presentation the phenotype is consistent with HUPRA syndrome. The condition was first described in 2011 (Belostotsky, 2011) with 6 reported patients from 3 families (Belostotsky, 2011 and Rivera, 2013). Further study into pathogenic mechanism is important as no treatment exists, and the disease leads to death of the infants affected. Although the disease is very rare, it must be considered in infants with who present with symptoms of failure to thrive, hyperuricemia, pulmonary hypertension, renal failure, and metabolic alkalosis.

Research in brief

SARS-CoV-2 evades antibodies Cell-culture experiments have shown that SARS-CoV-2 can hide from the immune system and spread through cell-to-cell transmission by limiting the release of viral particles that can be inactivated by antibodies. Zika pathogenesis Pyruvic acid, a compound in the glucose metabolism pathway and a readily available supplement, may protect babies from neurological disorders and other birth defects caused by the Zika virus if taken by pregnant women. Scientists have discovered a critical gene change that turns the Zika virus from its weakened form into a mildly pathologenic form called M-F37L.