A case of combined oxidative phosphorylation deficiency 32 caused by MRPS34 gene variation and literature review / 中华儿科杂志

Objective: To investigate the clinical features and genetic features of combined oxidative phosphorylation deficiency 32 (COXPD32) caused by MRPS34 gene variation. Methods: The clinical data and genetic test of a child with COXPD32 hospitalized in the Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in March 2021 were extracted and analyzed. A literature search was implemented using Wanfang, China biology medicine disc, China national knowledge infrastructure, ClinVar, human gene mutation database (HGMD) and Pubmed databases with the key words "MRPS34" "MRPS34 gene" and "combined oxidative phosphorylation deficiency 32" (up to February 2023). Clinical and genetic features of COXPD32 were summarized. Results: A boy aged 1 year and 9 months was admitted due to developmental delay. He showed mental and motor retardation, and was below the 3rd percentile for height, weight, and head circumference of children of the same age and gender. He had poor eye contact, esotropia, flat nasal bridge, limbs hypotonia, holding instability and tremors. In addition, Grade Ⅲ/6 systolic murmur were heard at left sternal border. Arterial blood gases suggested that severe metabolic acidosis with lactic acidosis. Brain magnetic resonance imaging (MRI) showed multiple symmetrical abnormal signals in the bilateral thalamus, midbrain, pons and medulla oblongata. Echocardiography showed atrial septal defect. Genetic testing identified the patient as a compound heterozygous variation of MRPS34 gene, c.580C>T (p.Gln194Ter) and c.94C>T (p.Gln32Ter), with c.580C>T being the first report and a diagnosis of COXPD32. His parents carried a heterozygous variant, respectively. The child improved after treatment with energy support, acidosis correction, and "cocktail" therapy (vitaminB1, vitaminB2, vitaminB6, vitaminC and coenzyme Q10). A total of 8 cases with COXPD32 were collected through 2 English literature reviews and this study. Among the 8 patients, 7 cases had onset during infancy and 1 was unknown, all had developmental delay or regression, 7 cases had feeding difficulty or dysphagia, followed by dystonia, lactic acidosis, ocular symptoms, microcephaly, constipation and dysmorphic facies(mild coarsening of facial features, small forehead, anterior hairline extending onto forehead,high and narrow palate, thick gums, short columella, and synophrys), 2 cases died of respiratory and circulatory failure, and 6 were still alive at the time of reporting, with an age range of 2 to 34 years. Blood and (or) cerebrospinal fluid lactate were elevated in all 8 patients. MRI in 7 cases manifested symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia. Urine organic acid test were all normal but 1 patient had alanine elevation. Five patients underwent respiratory chain enzyme activity testing, and all had varying degrees of enzyme activity reduction. Six variants were identified, 6 patients were homozygous variants, with c.322-10G>A was present in 4 patients from 2 families and 2 compound heterozygous variants. Conclusions: The clinical phenotype of COXPD32 is highly heterogenous and the severity of the disease varies from development delay, feeding difficulty, dystonia, high lactic acid, ocular symptoms and reduced mitochondrial respiratory chain enzyme activity in mild cases, which may survive into adulthood, to rapid death due to respiratory and circulatory failure in severe cases. COXPD32 needs to be considered in cases of unexplained acidosis, hyperlactatemia, feeding difficulties, development delay or regression, ocular symptoms, respiratory and circulatory failure, and symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia, and genetic testing can clarify the diagnosis.

BCS1Neonatal growth retardation and lactic acidosis initiated by novel mutation sites in L gene / 中华预防医学杂志

This study aims to analyze the clinical characteristics and genetic variations of two cases with developmental delay and lactic acidosis in a family, and to explore the relationship between genetic variations and clinical features. A retrospective analysis was conducted on the clinical characteristics of two siblings with developmental delay and lactic acidosis who were treated at the Neonatal Department of Children's Hospital of Chongqing Medical University in May 2019 and December 2021, respectively. Whole-exome sequencing was used to detect genetic variations in the affected children. Homology modeling of the BCS1L protein was performed to analyze the structural and functional changes of the protein. The correlation between genetic variations and clinical phenotypes was analyzed. The results showed that the main clinical features of the two affected children in this family were manifestations of mitochondrial respiratory chain complex Ⅲ deficiency, including prematurity, developmental delay, respiratory failure, lactic acidosis, cholestasis, liver dysfunction, renal tubular lesions, coagulation dysfunction, anemia, hypoglycemia, hypotonia, and early death. Whole-exome sequencing revealed a novel deletion mutation c.486_488delGGA (p.E163del) and a novel missense mutation c.992C>T (p.T331I) in the BCS1L gene. Structural analysis of the homology modeling showed that the compound heterozygous mutation had a significant impact on protein function. In conclusion, the novel mutation site c.992C>T (p.T331I) in the BCS1L gene is a "likely pathogenic" mutation, and the compound heterozygous mutation is closely related to the phenotype of mitochondrial respiratory chain complex Ⅲ deficiency.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes / 中南大学学报(医学版)

OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Reacciones adversas por salbutamol en pacientes asmáticos: reflexiones acerca del uso en las exacerbaciones / Adverse reactions from salbutamol in asthmatic patients: reflections on its use and exacerbations / Reações adversas ao salbutamol em pacientes asmáticos: reflexões sobre o seu uso e exacerbações

Las afecciones respiratorias agudas son la primera causa de consulta e ingreso hospitalario en los meses de invierno, y entre ellas el asma ocupa un lugar preponderante. El salbutamol es un broncodilatador con eficacia demostrada en las exacerbaciones y se utiliza de primera línea en el tratamiento. El objetivo de la presente comunicación es analizar dos casos clínicos de niños asmáticos que presentaron efectos adversos al salbutamol y requirieron el ingreso en la Unidad de Terapia Intensiva. Se propone revisar los efectos adversos del salbutamol empleado en crisis asmáticas y analizar las alternativas terapéuticas en esta enfermedad. Los síntomas de los efectos secundarios pueden confundirse con los causados por la propia enfermedad, por lo que puede usarse el fármaco de modo excesivo y es importante conocer el perfil posológico y caracterizar los posibles efectos secundarios en los pacientes para usar de manera racional y segura este medicamento.

Acute respiratory conditions are the first cause of consultation and hospital admission in the Winter months, being asthma the most important. Salbutamol is a bronchodilator with proven efficacy in exacerbations used first-line in treatment. The objective of this paper is to analyze two clinical cases of asthmatic children who presented adverse effects to salbutamol and required admission to the Intensive Care Unit. It is proposed to review the adverse effects of salbutamol used in asthmatic crises and to analyze therapeutic alternatives in this disease. Symptoms of side effects can be confused with those caused by the disease itself, determining the excessive use of this drug, thus, it is important to know the dosage profile and characterize the possible side effects to make rational and safe use of this drug.

As doenças respiratórias agudas são a primeira causa de consultas e internações nos meses de inverno e a asma ocupa é a mais importante. O salbutamol é um broncodilatador com eficácia comprovada nas exacerbações e é usado como tratamento de primeira linha. O objetivo desta comunicação é analisar dois casos clínicos de crianças asmáticas que apresentaram efeitos adversos ao salbutamol e necessitaram de internação em Unidade de Terapia Intensiva. Propõe-se revisar os efeitos adversos do salbutamol utilizado na crise asmática e analisar as alternativas terapêuticas nessa doença. Os sintomas de efeitos colaterais podem ser confundidos com os causados pela própria doença, determinando o uso excessivo desse medicamento, sendo importante conhecer o perfil posológico e caracterizar os possíveis efeitos colaterais nos pacientes para fazer um uso racional e seguro desse medicamento.

Toxicidad por metformina, más allá de la falla renal y la acidosis láctica: reporte de dos casos / Metformin toxicity, beyond renal failure and lactic acidosis: report of 2 cases / Toxicidade da metformina, além de insuficiência renal e acidose láctica: relato de dois casos

El suicidio es un problema de salud pública grave, vincula frecuentemente al consumo de medicamentos. La metformina es un fármaco antihiperglicemiante de fácil acceso y la sobredosis implica riesgos metabólicos, entre ellos, la acidosis láctica es el principal. Teniendo en cuenta la frecuencia de su consumo, es necesario que el personal de salud conozca los riesgos que implica la intoxicación y los signos y síntomas iniciales, pues del manejo adecuado dependerá un pronóstico favorable. El objetivo de este reporte es evidenciar los riesgos metabólicos renales-hemodinámicos, asociados a la toxicidad por metformina, además de resaltar la necesidad de considerar el uso temprano de la terapia de remplazo renal y de concientizar a los clínicos de que exponer a los pacientes a un medicamento, es también exponerlo a efectos adversos o a abuso con fines autolesivos.

Suicide is a serious public health problem that increases worldwide. In Medellín, its incidence is on the rise, and the most frequent mechanism is the ingestion of drugs. Metformin is an antihyperglycemic medication that is easily accessible and frequently used, because it is part of the first line of management of type 2 diabetes mellitus. One of the complications associated with its use is lactic acidosis, which can lead to serious toxicity. Therefore, it is necessary for the health personnel to be aware of the signs and symptoms that can initially appear in the case of intoxication, since a favorable prognosis depends on adequate management. The objective of this report is to present two clinical cases that evidence the wide spectrum of toxicity secondary to the use of metformin and to review the available evidence of the approach to this poisoning, emphasizing the importance of early use of renal replacement therapy.

O suicídio é um grave problema de saúde pública, frequentemente relacionado ao consu-mo de drogas. A metformina é um anti-hiperglicêmico de fácil acesso e a sobredosagem envolve riscos metabólicos, entre eles, a acidose láctica é o principal. Considerando a frequência de seu consumo, é necessário que o pessoal de saúde conheça os riscos das intoxicações e os sinais e sintomas iniciais, pois um prognóstico favorável dependerá de manejo adequado. O objetivo deste relatório é demonstrar os riscos metabólicos renais-hemodinâmicos associados à toxicidade da metformina, além de destacar a necessidade de considerar o uso precoce da terapia de substituição renal e alertar os médicos sobre o que expor os pacientes a um medicamento. a efeitos adversos ou abuso para fins autolesivos.

Intravascular large B-cell lymphoma presenting with fever and refractory acidosis

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma, characterized by malignant B-cells primarily localized to the lumina of small- and medium-sized blood vessels without lymphadenopathy. Two patients initially presented with fever of unknown origin and persistent lactic acidosis without evidence of tissue hypoxia. Neither patient had an identifiable source of infection and both underwent peripheral blood smear demonstrating leukocytosis with a neutrophilic predominance and thrombocytopenia without evidence of hematologic malignancy. One had previously had a bone marrow biopsy which was unremarkable. Both patients' condition deteriorated rapidly, progressing to multiorgan failure requiring pressors and mechanical ventilation, which ultimately resulted in cardiopulmonary arrest. At autopsy, each patient demonstrated malignant lymphocytoid cells, staining positive for CD20, localized to the lumina of small- and medium-sized vessels in multiple organs, including the lungs, liver, spleen, and kidneys, among others, allowing for the diagnosis of IVLBCL. IVLBCL is exceedingly rare, which in combination with significant variability in presentation, can make identification and diagnosis challenging. Diagnosis requires biopsy, therefore a high index of suspicion is needed to obtain an adequate tissue sample, whether pre- or postmortem. In the presented cases, both patients exhibited type B lactic acidosis with an unknown etiology that was ultimately determined at autopsy.

Acidose láctica associada à hipopotassemia grave em paciente sob uso de abacavir, atazanavir, lamivudina, lopinavir/ritonavir e tenofovir: Relato de caso / Lactic acidosis associated with severe hypopotasemia in patients under the use of abacavir, atazanavir, lamivudine, lopinavir / ritonavir and tenofovir: Case report

Os antirretrovirais (ARV) modificaram a evolução natural da síndrome da imunodeficiência adquirida de um quadro inicialmente com perspectiva fatal para doença de convivência crônica, com sobrevida que pode ser próxima daquela esperada para a pessoa hígida. A administração dos ARV, entretanto, requer vigilância médica, não só do especialista, mas de todos os envolvidos na Atenção Básica, na Unidade de Pronto Atendimento e na Terapia Intensiva, para que seus efeitos adversos sejam reconhecidos e abordados convenientemente, o que significará melhores condições de vida para os portadores do vírus da imunodeficiência humana (VIH). Este relato mostra os riscos de associação de ARV, e alerta para situações limites em que alterações metabólicas graves, como acidemia e hipopotassemia, podem colocar em risco a vida do paciente sob terapia ARV

Antirretrovirals (ARV) are medications that have modified the natural evolution of acquired immunodeficiency syndrome from a disease initially with fatal perspective to a chronic coexisting desease, with survival that may be close to that expected for the healthy person. Its administration, however, requires medical supervision, not only of the specialist, but of all those involved in basic care, in the emergency care unit and in the intensive care unit, so that its adverse effects are recognizeed and approached conveniently, which will mean better living conditions for human immunodeficiency vírus (HIV) carriers. This report shows the risk of ARV association, and alerts to limiting situations in whick serious metabolic changes, such as acidemia and hypokalemia, may endanger the lives of patients on ARV therapy.

Renal tubular acidosis associated with trimethoprim-sulfamethoxazole poisoning / Acidosis tubular renal asociada a intoxicación por trimetoprim-sulfametoxazol

Abstract The combination of trimethoprim-sulfamethoxazole (TMP-SMZ or cotrimoxazole) has a bactericidal effect on gram-positive cocci and gram-negative bacilli. It is used clinically for skin and soft tissue, respiratory and urinary tract infections, and is also relevant for prophylaxis and treatment of opportunistic infections in immunosuppressed patients. Its use at established doses in immunocompetent patients is safe, with a low rate of adverse events. However, in immunosuppressed individuals (human immunodeficiency virus [HIV], transplants, or steroid users), the adverse effects (AEs) of this medication reach 83%; and, when administered parenterally at high doses, lactic acidosis has been documented secondary to the polyethylene glycol vehicle. We present two cases of patients who ingested an overdose of TMP-SMZ and developed type 2 renal tubular acidosis (RTA), which has not been described with this medication, and whose hyperlactatemia is not explained by the polyethylene glycol excipient, as it was taken orally.

Resumen La combinación de trimetoprim-sulfametoxazol (TMP-SMZ o cotrimoxazol) tiene efecto bactericida sobre cocos gram positivos y bacilos gram negativos, con uso clínico en infecciones de piel y tejidos blandos, del tracto respiratorio y urinario, además con relevancia en la profilaxis y tratamiento de infecciones oportunistas en pacientes inmunosupresos. Su uso en pacientes inmunocompetentes a dosis establecidas es seguro, con una baja tasa de eventos adversos. Sin embargo, en población con inmunosupresión: virus de inmunodeficiencia humana (VIH), trasplante, o usuarios de esteroides; los efectos adversos (EA) por este medicamento alcanzan 83% y por administración parenteral en dosis elevadas se ha documentado acidosis láctica secundaria al vehículo polietilenglicol. Presentamos dos casos de pacientes que ingirieron TMP-SMZ en sobredosis, desarrollando acidosis tubular renal (ATR) tipo 2, la cual no se ha descrito en este medicamento y cuya hiperlactatemia no es explicable por el excipiente polietilenglicol debido a que el consumo fue oral.

Causes of death in feedlot beef cattle and their control: a brief review / Causas de morte em bovinos de corte confinados e seu controle: uma breve revisão

This review reports the leading causes of death in feedlot beef cattle. It describes economic losses resulting from these deaths and suggests control alternatives. Diseases associated with the respiratory and digestive systems were the most frequently observed. In different geographical areas, the importance of each one might vary. Outbreaks of diseases such as botulism occur occasionally and can cause important economic losses. Cattle tick fever can cause significant losses in zones of enzootic tick instability. Technical assistance and sanitary and food management are critical for the best productivity in feedlot cattle.(AU)

Esta revisão discute as principais causas de morte em bovinos de corte em confinamento. Descreve as perdas econômicas resultantes dessas mortes e sugere alternativas de controle. As doenças associadas aos sistemas respiratório e digestivo foram as mais frequentemente observadas. Em diferentes áreas geográficas, a importância de cada uma pode variar. Surtos de doenças como o botulismo ocorrem ocasionalmente e podem causar importantes perdas econômicas. A tristeza parasitária bovina pode causar perdas significativas em zonas de instabilidade enzoótica do carrapato. A assistência técnica e um bom gerenciamento sanitário e alimentar são essenciais para a melhor produtividade em bovinos de corte confinados.(AU)

Doenças do sistema digestório de pequenos ruminantes no norte do Paraná / Digestive disorders of small ruminants in northern Paraná

As doenças do sistema digestório de ovinos e caprinos no norte do Paraná foram avaliadas por meio de um estudo retrospectivo de 427 pequenos ruminantes atendidos no Ambulatório de Grandes Animais, do Hospital Veterinário da Universidade Estadual de Londrina, no período de janeiro de 2006 a dezembro de 2015. Para isso, foi realizada revisão das fichas clínicas dos pequenos ruminantes com afecções do sistema digestório, determinando a ocorrência, principais características clínicas, tratamentos instituídos e evolução dos casos. Os dados foram tabulados e submetidos a um estudo descritivo das variáveis, observando a distribuição das frequências (%) das condições analisadas. As afecções do sistema digestório foram diagnosticadas em 38,64% (165/427) dos atendimentos realizados. Vinte e seis animais apresentaram duas afecções no momento do atendimento, totalizando 191 enfermidades diagnosticadas. Dentre essas enfermidades, as mais comumente diagnosticadas foram: hemoncose (27,7%; 53/191), acidose láctica ruminal aguda (18,8%; 36/191), eimeriose (13,6%; 26/191) e indigestão simples (6,8%; 13/191). O aumento da criação de ovinos e caprinos no estado do Paraná reitera a importância do desenvolvimento de estudos como o presente trabalho, a fim de identificar as enfermidades mais frequentes e preparar o médico veterinário para o diagnóstico e tratamento correto.

Sheep and Goat's digestive disorders in northern Paraná were evaluated by a retrospective study of 427 small ruminants treated at the State University of Londrina's Veterinary Hospital (HV-UEL), from January 2006 to December 2015. Analysis of medical records of small ruminants with digestive disorder were performed, determining the occurrence, main clinical signs, established treatments and outcome of cases. Data were tabulated and submitted to a descriptive study of variables, observing frequency distribution (%) of analyzed conditions. Digestive disorders occurs in 38,6% (165/427) of cases in small ruminants at the studied period. Among these diseases, the most common were: hemoncose (27.7%; 53/191), acute rumen lactic acidosis (18.8%; 36/191), eimeriosis (13.6%; 26/191) and simple indigestion (6.8%; 13/191). The increase in sheep and goats' flock in the state of Paraná reiterates the importance of developing studies such as the present study, in order to identify the most frequent diseases and prepare the veterinarian for the correct diagnosis and treatment.

Distúrbios ácido-base nas doenças hepáticas / Acid-base disorders in liver diseases

O objetivo deste artigo foi abordar as controvérsias científicas acerca dos distúrbios ácido-base nas doenças hepáticas. Nos estágios avançados da doença hepática, os distúrbios ácido-base atuam de forma complexa, comprometendo a qualidade de vida do paciente e desafiando o manejo clínico. A literatura apresenta a alcalose respiratória como uma das principais alterações, porém há uma longa discussão sobre o mecanismo fisiopatológico; em especial, citam-se a hipóxia, a hipocapnia e o nível de progesterona. Nas desordens metabólicas, com destaque para a acidose, os estudos apontam principalmente o lactato, os unmeasured ions ou íons não medidos e as alterações hidroeletrolíticas, mas cada componente desse sobressai-se dependendo da fase da doença estudada, compensada ou descompensada. As controvérsias dos distúrbios ácido-base nas doenças hepáticas devem-se ora à complexidade da fisiopatologia da própria doença, ora à necessidade de mais estudos esclarecedores.

The aim of this study is to address the scientific controversy about acid-base disorders in liver diseases. In the end stage of liver diseases, the acid-base disorder has a complex performance, impairing the patient's quality of life and challenging the clinic management. Although the literature shows respiratory alkalosis as one of the main alterations, there is a long discussion about the pathophysiological mechanism, specially regarding hypoxia, hypocapnia, and progesterone level. In metabolic disorders, especially acidosis, the studies mainly indicate the lactate, unmeasured ions, and hydroelectrolytic alterations, but, depending on the disease phase, either compensated or decompensated, each element has a particular action. The controversy about acid-base disorders in liver diseases is associated with the complexity of this condition, as well as with the necessity of more specialized research.

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes / myoclonus epilepsy with ragged-red fibers /Leigh overlap syndrome caused by mitochondrial DNA 8344A>G mutation / 北京大学学报(医学版)

OBJECTIVE@#Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. Herein we report a rare case with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes/MERRF/Leigh (MELAS/MERRF/Leigh) overlap syndrome caused by m.8344A>G mutation.@*METHODS@#The clinical and imaging data of the patient were collected and an open muscle biopsy was carried out. We further employed molecular genetic analyses to detect mtDNA mutation in the proband and his mother. And then a clinical and neuroimaging follow-up was performed.@*RESULTS@#This patient was a 25-year-old male, who developed exercise intolerance since the age of 6. At age 10, he suffered from acute episodes of hemianopia, and cranial magnetic resonance imaging (MRI) showed occipital stroke-like lesions and cranial magnetic resonance spectroscopy (MRS) revealed a lactate peak corresponding to the lesion. After that the patient presented slowly progressive psychomotor decline. He had myoclonic seizures and cerebellar ataxia since the age of 12. At age 21, he was admitted to our hospital because of confusion and cranial MRI revealed symmetrical lesions in bilateral posterior putamen, thalami and midbrain. Then repeated MRI showed progression of original lesions and new frontal multiple stroke-like lesions. Symptomatic and rehabilitation treatment relieved his condition. Follow-up cranial MRI at age 24 showed the lesions in basal ganglia and thalami diminished, and the midbrain lesions even completely vanished. Muscle pathology indicated the presence of numerous scattered ragged-red fibers (RRF), suggestive of a mitochondrial disorder. Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) detected the m.8344A>G mutation of the MT-TK gene encoding mitochondrial transfer RNA for lysine in the patient's blood. Next generation sequencing (NGS) of the whole mitochondrial genome identified that the proportion of m.8344A>G was 90%, and no other mtDNA mutation was detected. Sanger sequencing further identified this mutation both in the proband and his mother's blood, although the mutation load was much lower in his mother's blood with approximately 10% heteroplasmy.@*CONCLUSION@#The present study is the first to describe a patient with m.8344A>G mutation in association with the MELAS/MERRF/Leigh overlap syndrome, which expands the phenotypic spectrum of the m.8344A>G mutation.

Acidosis lactica secundaria a intoxicacion por metformina, reporte de caso clinico / Lactic acidosis secondary to metformin poisoning, clinical case report

La metformina es un medicamento ampliamente utilizado como tratamiento de primera línea en diabetes mellitus tipo 2, su mecanismo de acción incluye impedir la elaboración de glucosa hepática, disminuye el transporte de glucosa a nivel intestinal entre otros. Uno de sus efectos adversos es la acidosis láctica, la mortalidad en estos pacientes aún es elevada a pesar de tratamientos modernos con terapia de sustitución renal. Presentación del caso: Presentamos el caso de una paciente femenina de 16 años que ingresó al servicio de emergencia debido a intoxicación con metformina (30 tabletas de 500mg) secundario a intento autolítico. La paciente se presentó somnolienta, con ruidos hidroaéreos aumentados, y relajación de esfínteres. Los controles gasométricos mostraron cifras de lactato en ascenso, llegando a valores de hasta 19,5 mmol/L. Paciente requirió ventilación mecánica invasiva motivo por el cual, ingresó al servicio de Terapia Intensiva para manejo de fallo multiorgánico, se inició tratamiento sustitutivo renal con ciclos prolongados. Paciente fue dada de alta del servicio de terapia intensiva en su quinto día de hospitalización y continuó su tratamiento multidisciplinar a cargo del servicio de medicina interna. Conclusiones: La metformina al ser un medicamento ampliamente usado a nivel mundial, todo servicio de emergencias debería estar preparado para identificar los casos de intoxicación por este fármaco. Dentro de las intervenciones se incluye: fluidoterapia, drogas vasoactivas, soporte ventilatorio invasivo, bicarbonato de sodio y terapia de reemplazo renal; todas ellas se brindaron a nuestra paciente con resultados exitosos.

Metformin is a medicine used as first-line treatment in type 2 diabetes mellitus, its mechanism of action includes among others: preventing the production of hepatic glucose, decreases the transport of glucose at intestinal level. One of its adverse effects is lactic acidosis, especially when its used in autolytic attempts. Mortality in these patients is still high despite modern treatment with renal replacement therapy. Case presentation: We present the case of a 16-year-old female patient who entered the emergency service due to metformin poisoning (30 tablets of 500mg) secondary to autolytic attempt. The patient was drowsy, with increased hydroaereal noises, and relaxation of sphincters. Gasometric controls showed rising lactate figures, reaching values of up to 19.5 mmol/L. Patient required invasive mechanical ventilation which is why, entered the intensive therapy service for management of multiorgan failure, renal replacement treatment was initiated with prolonged cycles. Patient was discharged from intensive care on her fifth day of hospitalization and continued her treatment in charge of the internal medicine service. Conclusions: Metformin being a widely used medicine worldwide, every emergency service should be prepared to identify cases of this drug. Interventions include: fluid therapy, vasoactive drugs, invasive ventilatory support, sodium bicarbonate, and renal replacement therapy; All of them were provided to our patient with successful results.

Clinical and genetic analysis of a case of dihydrolipoamide dehydrogenase deficiency caused by novel variant of DLD gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of a patient with dihydrolipoamide dehydrogenase deficiency.@*METHODS@#Potential variants of the DLD gene were detected by whole exome sequencing and verified by Sanger sequencing.@*RESULTS@#Compound heterozygous variants, c.704_705delTT (p.Leu235Argfs*8) and c.1058T>C (p.Ile353Thr), were detected in the DLD gene. The c.1058T>C (p.Ile353Thr) variant was derived from his mother and known to be pathogenic. The c.704_705delTT (p.Leu235Argfs*8) variant was derived from his father and was unreported previously.@*CONCLUSION@#The compound heterozygous variants of c.704_705delTT (p.Leu235Argfs*8) and c.1058T>C (p.Ile353Thr) of the DLD gene probably underlay the disease in this patient. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.

Levetiracetam administration is correlated with lower mortality in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: a retrospective study / 中华医学杂志(英文版)

BACKGROUND@#Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS.@*METHODS@#A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures (n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients.@*RESULTS@#LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group (n = 48) was lower than that of the non-LEV group (n = 54; mean ± standard deviation, 2.79 ± 1.47 vs. 3.83 ± 1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0-1) between the groups (P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15-0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08-0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ = 4.29, P = 0.04).@*CONCLUSIONS@#The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.

A case of telbivudine-related fatal lactic acidosis and multiple organ dysfunction syndrome / 中南大学学报(医学版)

The incidence of telbivudine-related adverse reactions has been gradually increased. The increased levels of muscle enzymes and blood lactate are common. In this case, a 23-year-old male patient with long-term oral telbivudine had a rare serious adverse reaction. The main clinical manifestations were progressive myalgia, gradually progressed to mental disorder, and together with multiple organ dysfunction, in which the level of blood lactate was increased significantly and metabolic acidosis was extremely severe. Blood purification and sodium bicarbonate were given to correct acidosis, while ceftazidime was used to prevent infection. Telbivudine was discontinued, and tenofovir disoproxil fumarate and liver protective drug were used. The patient was discharged with a better health condition. Such patients are easily misdiagnosed as neuromuscular diseases in the early stage, which might delay the treatment and worsen medical conditions. Clinicians need to be cautious and obtain an early identification to avoid misdiagnosis.

Twenty-one-year follow-up of variable onset MELAS syndrome with heteroplasmic nt3243A>G mtDNA mutation: A case report

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder of which m.3243A>G is the most commonly associated mutation, resulting in an inability to meet the energy requirements of various organs. MELAS poses a diagnostic challenge owing to its multiple organ involvement and great clinical variability due to its heteroplasmic nature. We report three cases from a family who were initially misdiagnosed with myasthenia gravis or undiagnosed. Although there is no optimal consensus treatment approach for patients with MELAS because of the disease's heterogeneity, our 21-year-long therapy regimen of l-arginine, l-carnitine, and coenzyme Q10 supplementation combined with dietary management appeared to provide noticeable protection from the symptoms and complications. Prompt early diagnosis is important, as optimal multidisciplinary management and early intervention may improve outcomes.

Acidosis láctica por metformina. Reporte de dos casos / Metformin lactic acidosis. Report of two cases

RESUMEN La metformina es uno de los medicamentos más utilizados como primera línea para control de la diabetes mellitus tipo 2; tiene un papel benéfico en la mortalidad cardiovascular y bajo riesgo de producir hipoglucemia; sin embargo, no está exenta de efectos adversos, de los cuales, el más temido es la acidosis láctica, cuya incidencia es de 7,4 casos por 100.000 usuarios del medicamento por año. Los principales factores de riesgo para desarrollar dicha complicación son la insuficiencia renal aguda o crónica, la falla cardíaca, la enfermedad hepática y el uso concomitante de medicamentos que bloquean la cadena respiratoria de la mitocondria. El tratamiento incluye la reanimación hídrica, el soporte y, en algunos casos, el bicarbonato. La terapia de reemplazo renal ha sido exitosa en estos pacientes, pero las indicaciones para hacerla aún no son claras porque la metformina es una molécula parcialmente dializable y se requiere hemodiálisis prolongada para reducir suficientemente sus niveles. A pesar del tratamiento intensivo, la mortalidad asociada a esta complicación continúa siendo muy alta. El diagnóstico temprano y el tratamiento oportuno son fundamentales para mejorar el pronóstico.

SUMMARY Metformin lactic acidosis. Report of two cases Metformin is recommended as a first-line treatment for patients with diabetes mellitus type 2; it has a cardiovascular protective effect, and low risk of hypoglycemia. However, a severe but infrequent complication of its use is lactic acidosis, which has high morbidity and mortality rates. The estimated incidence of metformin lactic acidosis is 7,4 cases per 100.000 patients per year. Main risk factors are acute or chronic renal disease, congestive heart failure, hepatic failure, and concomitant use of drugs that affect metformin clearance or energy metabolism. Treatment includes hydration with crystalloids, support measures, and intravenous bicarbonate. Renal replacement therapy has been successful for treating metformin-associated lactic acidosis, but there are still no clear indications for it, because metformin is a partially dialyzable molecule and prolonged hemodialysis is required to reduce its levels sufficiently. Despite current treatment, mortality remains high. Early diagnosis and prompt multidisciplinary support are essential to improve outcome in these patients.

Importância da transfaunação no tratamento da acidose láctica ruminal aguda induzida em cabras e ovelhas / Value of transfaunation for the treatment of induced ruminal lactic acidosis in goats and sheep

O objetivo deste trabalho foi avaliar a importância da transfaunação no tratamento e recuperação de cabras e ovelhas com acidose lática ruminal aguda (ALRA) induzida experimentalmente. Seis cabras (41,2±5,6kg) e seis ovelhas (46,8±4,57kg), não gestantes e não lactantes, receberam 15g de sacarose por quilo de peso corporal para indução da enfermidade. A ALRA foi induzida duas vezes em cada animal, com intervalo de 30 dias após recuperação total da primeira indução. Os procedimentos terapêuticos consistiram na remoção do conteúdo ruminal líquido por lavagem e sifonamento com auxílio de sondagem esofágica, e na correção da acidose metabólica com soluções eletrolíticas, contendo lactato ou bicarbonato de sódio, infundidas por via intravenosa. A transfaunação fez parte de apenas um dos tratamentos de cada animal e consistiu na administração por sondagem esofágica de 2L de suco ruminal de um bovino sadio. A recuperação completa foi avaliada por exames físicos e exames do suco ruminal realizados até quatro dias após os procedimentos terapêuticos. A eficácia dos protocolos de tratamento, com ou sem transfaunação, foi comparada. O protocolo de indução foi efetivo em induzir a enfermidade e as cabras e ovelhas apresentaram sinais clínicos de intensidade máxima (apatia, atonia ruminal, distensão abdominal, diarreia de consistência pastosa a líquida e desidratação moderada) 16 horas após a administração intrarruminal de sacarose, sem distinção entre as espécies. Neste momento, as características do suco ruminal mostraram-se semelhantes aos quadros típicos de ALRA. A frequência de movimentos ruminais se normalizou no terceiro dia após os procedimentos terapêuticos, sem diferença entre as espécies, e independente de terem recebido a transfaunação ou não. A transferência de suco ruminal também não acelerou a recuperação do apetite, que foi considerado normal somente no quarto dia após os procedimentos terapêuticos, em ambas as espécies. Em relação ao líquido ruminal, quando receberam a transfaunação, os caprinos e ovinos apresentaram recuperação das características de cor, odor e consistência mais rapidamente do que quando não receberam. A atividade fermentativa da microbiota ruminal não sofreu influência da transfaunação e se normalizou dois e três dias após os procedimentos terapêuticos nas ovelhas e cabras, respectivamente. A transfaunação promoveu o retorno mais rápido da população de protozoários ruminais, que já foram observados 24 horas após os procedimentos terapêuticos, em ambas as espécies. Quando os animais não receberam a transfaunação, o retorno dos protozoários só ocorreu no segundo dia após os procedimentos terapêuticos. A recuperação completa dos animais estudados ocorreu em até quatro dias, independente da realização da transfaunação ou não. Conclui-se que a transferência de suco ruminal não pode ser considerada medida crucial para o tratamento e convalescença de caprinos e ovinos acometidos por de ALRA.(AU)

The aim of this study was to evaluate the value of transfaunation in the treatment and recovery of goats and sheep with acute rumen lactic acidosis (ARLA) experimentally induced. Six goats (41.2±5.6kg) and six sheep (46.8±4.57kg), non-pregnant and non-lactating, received 15g of sucrose per kilogram of body weight for the disease induction. The ARLA was induced in each animal twice with an interval of 30 days after full recovery of the first induction. Therapeutic procedures consisted in removal of the rumen fluid content by washing and siphoning with an esophageal tube and correction of metabolic acidosis with intravenous electrolyte solutions containing sodium lactate or sodium bicarbonate. The transfaunation was part of only one of each animal treatment and consisted in administration of two liters of rumen fluid colleted from a healthy cow. Complete recovery was assessed by physical examinations and rumen fluid examinations up to four days after therapeutic procedures. The efficacy of treatment protocols, with or without transfaunation was compared. The protocol used was effective in induce the disease and goats and sheep showed clinical signs of maximum intensity (apathy, rumen stasis, abdominal distension, diarrhea and moderate dehydration) 16 hours after the intraruminal administration of sucrose. At this moment, the characteristics of ruminal fluid were similar to the typical ARLA. The frequency of ruminal movements became normal on the third day after therapeutic procedures, with no difference between species, and regardless transfaunation. The ruminal fluid transfer did not accelerate the recovery of appetite, considered normal only on the fourth day after treatment in both species. When transfauntation was received, goats and sheep showed recovery of characteristics of color, odor and consistency faster than when they did not receive. The fermentative activity of the rumen microbiota was not impacted by transfaunation and normalized two and three days after therapeutic procedures in sheep and goats, respectively. The transfaunation promoted faster return of the protozoa population, which was observed 24 hours after therapeutic procedures in both species. When the animals did not receive transfaunation, the protozoa returns occurred only on the second day after therapeutic procedures. Full recovery of the animals occurred within four days, regardless of transfaunation. In conclusion, the ruminal fluid transfer can not be considered crucial for the treatment and convalescence of goats and sheep affected by ARLA.(AU)