The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases.

BACKGROUND: During corona virus pandemic, various neurological complications of COVID-19 have been reported. Recent studies demonstrated different pathophysiology for neurological manifestations of COVID-19 such as mitochondrial dysfunction and damage to cerebral vasculature. In addition, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder with a variety of neurological symptoms. In this study, we aim to assess a potential predisposition in mitochondrial dysfunction of COVID-19, leading to MELAS presentation. METHODS: We studied three previously healthy patients with the first presentation of acute stroke-like symptoms, following COVID-19 infection. We analyzed the patients' clinical data and brain magnetic resonance imaging (MRI) lesions that presented to the neurological center of a university-affiliated hospital in Tehran, Iran, from September 2020 to August 2021. RESULTS: All cases are characterized by a temporoparietal abnormality in imaging studies and electroencephalogram (EEG). Based on electrodiagnostic tests, three patients were diagnosed with myopathy. In two brothers with relatively the same symptoms, one performed muscle biopsy finding myopathic process, and genetic testing confirmed a 3243A>G point mutation in a heteroplasmic state in one of our patients. CONCLUSION: Although MELAS is not a prevalent condition, the recent increase in the number of these patients in our center might indicate the potential role of COVID-19 in triggering the silent pre- existing mitochondrial dysfunction in these patients.

Encephalopathy in short bowel syndrome: a diagnostic challenge.

A 15-year-old boy was admitted to the hospital due to ataxia, drowsiness and bradypsychia. He was known to have a short bowel syndrome Initial venous blood gases revealed a metabolic acidosis with a high anion gap of 24 mmol/L and normal L-lactate. He improved with fasting and fluids and was discharged with oral metronidazole. 2 weeks later he was admitted again with similar symptoms. A specific study of D-Lactic acidosis was carried out, confirming the diagnosis. D-lactic acidosis is an uncommon complication of short bowel syndrome. It occurs as a consequence of the metabolism of unabsorbed carbohydrates. The symptoms are mainly neurological. Limiting the dietary carbohydrates is useful to avoid recurrences. Poorly absorbable antibiotics are used but with varying results. Surgery may be an option if medical treatment fails. Probiotics might be useful to avoid symthoms recurrence.

Resistant Lactic Acidemia Due to Accidental Cheese Starter Culture Ingestion.

Lactic acid is the end-product of anaerobic glycolysis. It is generally believed that elevated blood lactate levels are associated with poor patient outcomes. Literature reports that lactic acidosis can be related to supplementary food intake in the pediatric age group however, in adult patients, it is not common to see lactic acidosis due to oral ingestion unless the patient has a history of short bowel syndrome or jejunoileal bypass surgery. With the current case presentation, we report an accidental cheese starter culture intake that resulted in resistant lactic acidosis with no signs of critical illnesses.

Type B lactic acidosis associated with diffuse large B-cell lymphoma and the Warburg effect.

Type B lactic acidosis is a rare complication of non-tissue perfusion abnormalities caused by solid tumors or hematologic malignancies. Herein, we present the case of a 42-year-old man with type B lactic acidosis and hypoglycemia who was found to have a diffuse large B-cell lymphoma. The cause of lactic acidosis and/or hypoglycemia is thought to be the Warburg effect, which is when the metabolic rate of a rapidly growing malignant tumor is very high and dominated by glycolysis. Systemic damage from type B lactic acidosis can occur when the increased rate of glycolysis exceeds the normal muscle and liver lactic acid clearance rate. The Warburg effect is a rare but serious condition that needs to be recognized, not only in diffuse large B-cell lymphoma, but also in other malignancies. The prognosis of lactic acidosis in patients with malignant tumors is very poor. Currently, effective chemotherapy seems to be the only hope for survival.

[Postoperative cognitive dysfunction in elderly patients after aorta-coronary bypass under conditions of artificial blood circulation.]

In patients undergoing open myocardial revascularization under cardiopulmonary bypass (CB), one of the complications is cognitive dysfunction. The aim of the work is to study the effect of intraoperative lactic acidosis, anemia and the duration of myocardial anoxia on the change in cognitive status with the help of FAB after coronary artery bypass grafting (CABG) with CB. The negative impact of lactic acidosis on cognitive status in patients after CABG has been proven. The relationship between the decrease in hemoglobin concentration during surgery and the negative dynamics of cognitive changes in the postoperative period (R=0,41; p=0,021) was determined. A negative effect of prolonged myocardial anoxia during surgery on the dynamics of cognitive functions of patients was revealed. Thus, the above indicators may be markers of the formation of postoperative cognitive dysfunction in patients undergoing CABG with CB.

Leber hereditary optic neuropathy and dystonia overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes due to m.14459G>A mutation.

OBJECTIVE: To report a Chinese family with combined m.14459G>A mutation and m.6064A>T mutation of which the female proband presenting unique Leber hereditary optic neuropathy and dystonia (LDYT) overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. METHODS: Clinical information of the pedigree was collected. We performed muscle biopsy and whole-length mitochondrial DNA (mtDNA) sequencing on the proband. The activity of respiratory chain complexes in immortalized lymphoblasts was determined. RESULTS: The current 23-year-old proband suffered from vision decline at age 15 and developed seizures and dystonia with bilateral lesions in precentral gyri at age 18. When she was 21, the lesions in bilateral putamen were found with elevated cerebrospinal fluid lactate. Her mother had optic atrophy; one of her brother died at age 4 with respiratory distress; and the other 8-year-old brother was asymptomatic. Muscle biopsy of the proband was unremarkable. The mtDNA sequencing revealed a heteroplasmic m.14459G>A mutation and a previously unreported m.6064A>T mutation. The respiratory chain complex I activity in the proband's immortalized lymphoblasts was 50% less than the normal control; while there was no statistical difference between the proband and the normal control in the activity of complex IV. CONCLUSIONS: We presented the first case exhibiting LDYT and MELAS phenotype with m.14459G>A mutation, and the decreased complex I activity contributed to the pathogenicity. Our study expanded the clinical spectrum of m.14459G>A mutation.

Clinicopathological findings of a mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome overlap patient with a novel m.3482A>G mutation in MT-ND1.

We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.

Metformin induced lactic acidosis impaired response of cancer cells towards paclitaxel and doxorubicin: Role of monocarboxylate transporter.

Abnormal glucose metabolism in cancer cells causes generation and secretion of excess lactate, which results in acidification of the extracellular microenvironment. This altered metabolism aids not only in survival and proliferation but also in suppressing immune-mediated destruction of cancer cells. However, how it influences the response of cancer cells to chemotherapeutic drugs is not clearly understood. We employed appropriate in vitro approaches to explore the role of mono-carboxylate transporter 4 (MCT4) mediated altered intra and extracellular pH on the outcome of the therapeutic efficacy of chemotherapeutic drugs in breast and lung cancer models. We demonstrate by in vitro experiments that inhibition of complex I enhances glycolysis and increases expression as well as membrane translocation of MCT4. It causes a decrease in extracellular pH (pHe) and impairs doxorubicin and paclitaxel's therapeutic efficacy. Acidic pHe inhibits doxorubicin's uptake, while acidic intracellular pH (pH i) impairs the efficacy of paclitaxel. Under in vivo experimental settings, the modulation of pHe with phloretin or alkalizer (NaHCO3) enhances cytotoxicity of drugs and inhibits the growth of MCF-7 xenografts in mice. In a nutshell, this study indicates that MCT4 mediated extracellular acidosis is involved in impairing chemotherapeutic drugs' efficacy on cancer cells. Therefore, the use of pH neutralizing agents or MCT inhibitors may be beneficial towards circumventing impairment in the efficacy of certain drugs that are sensitive to pH changes.

Disturbance of consciousness due to hyperammonemia and lactic acidosis during mFOLFOX6 regimen: Case report.

INTRODUCTION: FOLFOX therapy is the main chemotherapy regimen for colorectal cancer. Peripheral neuropathy, hematotoxicity, and digestive symptoms are known to be the most frequent adverse events. Hyperammonemia and lactic acidosis rarely occur simultaneously during treatment with FOLFOX therapy; the number of case reports is limited worldwide. We report a case of disturbance of consciousness, considered to be caused by hyperammonemia and lactic acidosis that occurred during treatment with mFOLFOX6 therapy that was administered as postoperative adjuvant treatment for rectal cancer. PATIENT CONCERNS: This case was of a 71-year-old man who had been receiving oral treatment for chronic kidney disease and diabetes mellitus. Laparoscopic low anterior resection and artificial anal construction surgery were performed for stage III rectal cancer. As adjuvant postoperative therapy, mFOLFOX6 therapy was started but was followed by a disturbance of consciousness. DIAGNOSES: Results of the blood tests revealed notable hyperammonemia (ammonia level, 1,163 µg/dl) and lactic acidosis (pH 7.207; lactate, 17.56 mmol/L); however, imaging diagnosis did not reveal intracranial lesions that could cause disturbance of consciousness. INTERVENTIONS: For hyperammonemia, branched-chain amino acid agents and Ringers solution supplementation were administered. For acidosis, 7% sodium hydrogen carbonate was administered as treatment. OUTCOMES: The disturbance of consciousness improved within 12 hours of initiating the treatment, and the patient was discharged with no sequelae on 7th day after hospitalization. CONCLUSION: In patients with chronic kidney disease, FOLFOX regimen may confer risks of hyperammonemia and lactic acidosis.

[The 475th case: renal tubular acidosis, renal failure, anemia, and lactic acidosis].

A 47-year-old female patient presented nausea and vomiting for half a year and elevated serum creatinine for 3 days. Proximal renal tubular acidosis (RTA) complicated with anemiawas confirmed after admission. Secondary factors, such as autoimmune disease, drugs, poison, monoclonal gammopathy, were excluded. Renal biopsy revealed acute interstitial nephritis. The patient was administrated with daily prednisone 50 mg, sodium bicarbonate 4 g, 3 times per day, erythropoietin 3 000 U, 2 times per week, combined with potassium, calcium, and calcitriol tablets. Serum creatinine reduced to 90 µmol/L. However nausea and vomiting deteriorated with lactic acidosis. Bone marrow biopsy indicated the diagnosis of non-Hodgkin lymphoma, therefore the patient was treated with chemotherapy. Although metabolic acidosis improved gradually after chemotherapy, severe pneumocystis carinii pneumonia developed two weeks later. The patient refused further treatment and was discharged.

A Case of Lung Involvement in Peripheral T Cell Lymphoma.

BACKGROUND: Lung involvement is rare in peripheral T cell lymphoma, and there is a lack of sufficient clinical study. The authors describe a rare case of lung involvement in a 40-year-old male patient with peripheral T cell lymphoma. METHODS: Hematological investigation, bone marrow aspirate, and lung biopsy were performed. RESULTS: The patient received 4 courses of CHOP regimen chemotherapy. He achieved partial response (PR) at the 2nd course, but showed disease progressive (PD) at the 4th course. Then he received 2 courses of GDP regimen chemotherapy. Unfortunately, the patient died of tumor overload with hyper-lactacidemia 6 months after the onset of the disease. CONCLUSIONS: Lung biopsy is important to confirm a diagnosis of primary pulmonary lymphoma. Lung involvement in peripheral T cell lymphoma as a prognostic factor needs further studies.

Pifithrin-µ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial-mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis.

Heat shock protein 70 (HSP70), a chaperone protein associated with tumorigenesis and chemoresistance, has attracted significant attention as a potential therapeutic target for the development of anticancer drugs. Here, the effects of pifithrin-µ, an effective dual inhibitor of HSP70 and p53, on anticancer activities and epithelial-mesenchymal transition (EMT) were investigated in malignant mesothelioma (MM) cells. MSTO-211HAcT cells, pre-incubated in a medium containing lactic acid, showed more potent resistance to cisplatin and gemcitabine, compared with their acid-sensitive parental MSTO-211H cells. Pifithrin-µ treatment induced both apoptosis and necroptosis, which were accompanied by an EMT-like phenomenon, as evidenced by an elongated cell morphology, decreased levels of epithelial cell markers including E-cadherin, claudin-1, and ß-catenin, increased levels of mesenchymal markers including Snail, Slug, and vimentin, and increased cell migratory property. Moreover, pifithrin-µ increased intracellular ROS levels, which is associated with mitochondrial dysfunction and decreased cellular ATP content. A series of changes caused by pifithrin-µ treatment were effectively restored by lowering the ROS level through pretreatment with N-acetylcysteine. Collectively, our results suggest that pifithrin-µ may promote the metastatic behavior of surviving cells by triggering the EMT, despite its effective cell-killing action against MM cells, possibly linked to oxidative mitochondrial dysfunction and ATP depletion.

Liver neoplasms in methylmalonic aciduria: An emerging complication.

Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients.

Severe and persistent hypoglycemia with lactic acidosis in an elderly lady with type 2 diabetes mellitus and lymphoma∖leukemia: A rare case report.

We present here a case of hypoglycemia and lactic acidosis in an elderly diabetic lady with underlying leukemia∖lymphoma. Possible mechanisms responsible for both hypoglycemia as well as lactic acidosis are discussed. The case emphasizes the need for thorough chasing of all clinical leads obtained from history taking, physical examination, as well as laboratory evaluation in order to avoid getting misled by apparently obvious diagnosis. To the best of the author's knowledge, this is the first time such a case is reported in Indian literature.

Metabolic Response to BRAF-MEK Combination Therapy in Cecal Neuroendocrine Carcinoma With BRAFV600E Mutation and Refractory Lactic Acidosis.

We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.

Stercoral colitis complicated with ischemic colitis: a double-edge sword.

BACKGROUND: Stercoral colitis is a rare inflammatory process involving the colonic wall secondary to fecal impaction with high morbidity and mortality; especially if complicated with ischemic colitis, stercoral ulcer formation and subsequent perforation. There are several case reports published on abdominal perforation resulting from stercoral colitis. However, stercoral colitis complicated by ischemic colitis is rare. The purpose of this case report is to describe the potential challenges in the diagnosis and management of stercoral colitis with ischemic colitis. CASE PRESENTATION: An 87 years old male with history of chronic constipation presents with severe abdominal pain to the emergency department. The patient was hemodynamically stable. On physical examination, the abdomen was mildly distended with moderate tenderness. Lab work was significant for leukocytosis and lactic acidosis. Abdominal CT scan revealed large amount of retained stool in the colon, bowel wall thickening and infiltration of peri-colonic fat, which were suggestive for stercoral colitis. Patient was started on IV fluids and antibiotics. He was given an enema, followed by laxative and manual disimpaction of stool. Colonoscopy was performed and biopsies were obtained. Tissue biopsy was significant for focal active colitis with regenerative glandular changes and neural hyperplasia. CONCLUSION: Elevated lactic acid level secondary to ischemia of the bowel wall with CT scan findings aid in establishing the diagnosis of stercoral colitis complicated with ischemic colitis. Urgent treatment with laxatives and fecal disimpaction is indicated to prevent perforation and peritonitis.

Role of cathepsin K in the development of chronic subdural hematoma.

Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PVCSDH) were simultaneously collected. As controls, peripheral venous blood (PVControl) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PVCSDH. Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PVCSDH were significantly higher than in PVControl (P<0.0001). In contrast, CysC levels in PVCSDH were significantly lower than in PVControl (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH.

Postoperative Abdominal NIRS Values Predict Low Cardiac Output Syndrome in Neonates.

BACKGROUND: The development of low cardiac output syndrome (LCOS) after cardiopulmonary bypass (CPB) occurs in up to 25% of neonates and is associated with increased morbidity. Invasive cardiac output monitors such as pulmonary artery catheters have limited availability and are costly. Near-infrared spectroscopy (NIRS) is a noninvasive tool for monitoring regional oxygenation in neonates in the cardiac intensive care unit (CICU). We hypothesize that anterior abdominal NIRS may aid in the early identification of LCOS after cardiac surgery. METHODS: Prospective observational study from October 2013 to October 2014 of all neonates with congenital heart disease admitted to the CICU following CPB. Abdominal NIRS values were continuously recorded upon CICU admission and for the subsequent 24-hour period. The primary outcome was the development of LCOS. Low cardiac output syndrome was defined as the presence of metabolic lactic acidosis (pH < 7.3 and lactate > 4) or addition of a new vasoactive agent or a vasoactive inotropic score > 15. Autoregressive time series models were constructed for each patient based on the continuously recorded NIRS values, and patients were stratified by development of LCOS. RESULTS: Twenty-seven neonates met inclusion criteria, of whom 11 developed LCOS. Neonates who developed LCOS had lower constant NIRS values (49% vs. 66%, P < .001). Constant NIRS values less than 58% best predicted development of LCOS with a sensitivity of 100% and specificity of 69%. CONCLUSION: Lower constant anterior abdominal NIRS values in the early postoperative period may allow early identification of neonates at risk for LCOS.

Sigmoid volvulus in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a rare occurrence.

Mitochondrial diseases are rare and devastating, with a wide spectrum of clinical presentations and systemic symptoms. The majority of the published literature focuses on the neuromuscular manifestations and genetic components of this mitochondrial cytopathy, however, cardiac, renal, endocrine and gastrointestinal manifestations may also be present. The authors report a case detailing a 56-year-old woman's final hospitalisation from the gastrointestinal sequelae of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) (Co Q10 deficiency variant). She presented with abdominal pain and distension associated with lactic acidosis, and was shown on imaging to have a colon perforation. This resulted in emergent surgery at which a necrotic colon secondary to a sigmoid colon was identified. Following four subsequent operations, and the development of multiorgan failure, care was eventually withdrawn. Practitioners of patients with MELAS should be cognisant of the rare but devastating gastrointestinal consequences of mitochondrial diseases.