Mitochondrial Fusion, Fission, and Mitophagy in Cardiac Diseases: Challenges and Therapeutic Opportunities.

Significance: Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged mitochondria is a hallmark of cardiac diseases. Recent Advances: Disruption of quality control systems that maintain mitochondrial number, size, and shape through fission/fusion balance and mitophagy results in dysfunctional mitochondria, defective mitochondrial segregation, impaired cardiac bioenergetics, and excessive oxidative stress. Critical Issues: Pharmacological tools that improve the cardiac pool of healthy mitochondria through inhibition of excessive mitochondrial fission, boosting mitochondrial fusion, or increasing the clearance of damaged mitochondria have emerged as promising approaches to improve the prognosis of heart diseases. Future Directions: There is a reasonable amount of preclinical evidence supporting the effectiveness of molecules targeting mitochondrial fission and fusion to treat cardiac diseases. The current and future challenges are turning these lead molecules into treatments. Clinical studies focusing on acute (i.e., myocardial infarction) and chronic (i.e., heart failure) cardiac diseases are needed to validate the effectiveness of such strategies in improving mitochondrial morphology, metabolism, and cardiac function. Antioxid. Redox Signal. 36, 844-863.

Diagnosis of malignancies in children with musculoskeletal complaints.

CONTEXT: Musculoskeletal complaints may be associated with neoplasias as an initial manifestation of the disease. When these symptoms predominate at the onset of the disease, the differential diagnosis includes several rheumatic diseases. OBJECTIVE: To assess the frequency, clinical features and types of cancer manifested in children presenting with musculoskeletal complaints over a seven-year period. TYPE OF STUDY: Retrospective. SETTING: Discipline of Allergy, Clinical Immunology and Rheumatology, Universidade Federal de São Paulo-Escola Paulista de Medicina. METHODS: The medical records of patients with musculoskeletal complaints and final diagnosis of malignant disease were reviewed. The data collected were: age when symptoms initially presented, age at diagnosis, clinical features presented, laboratory findings, and the initial and final diagnoses. RESULTS: A final diagnosis of cancer was found in nine out of 3,528 patients (0.25%) whose initial symptom was musculoskeletal pain. The mean time between disease onset and final diagnosis was five months. The most common features presented were pauciarticular arthritis or arthralgia involving the large joints. Juvenile rheumatoid arthritis was the most frequent initial diagnosis, in four out of nine patients. Anemia was the most frequent initial hematological change. Six out of eight patients had an increased erythrocyte sedimentation rate. The lactate dehydrogenase level was raised in five out of eight patients. The malignancies found included acute lymphocytic leukemia, acute myeloid leukemia, lymphoma, neuroblastoma and Ewing's sarcoma. DISCUSSION: The frequency of neoplasia in patients with musculoskeletal pain resembled reports in the literature. Consumptive symptoms were not the warning signal in most of our patients. In subsidiary tests, progressive anemia was the most common finding, although the peripheral blood cell count may continue to be normal for weeks or months after symptom onset. CONCLUSION: Malignancy always needs to be ruled out in cases of children with musculoskeletal complaints. Uncharacteristic clinical manifestations and nonspecific laboratory tests may cause difficulty in the final diagnosis, and rigorous investigation should be performed.

Diagnosis of malignancies in children with musculoskeletal complaints

CONTEXTO: As queixas musculoesqueléticas podem estar associadas com neoplasias como uma manifestação inicial da doença em crianças. Quando estes sintomas predominam na apresentação da doença, o diagnóstico diferencial inclui várias doenças reumáticas. OBJETIVOS: Avaliar a freqüência, as características clínicas e os tipos de neoplasias encontrados em crianças encaminhadas ao ambulatório de reumatologia pediátrica com queixas musculoesqueléticas, no período de sete anos. TIPO DE ESTUDO: Retrospectivo. LOCAL: Disciplina de Alergia, Imunologia Clínica e Reumatologia, Departamento de Pediatria, Universidade Federal de São Paulo ù Escola Paulista de Medicina, São Paulo, Brasil. MÉTODOS: Num estudo terciário, foram revisados retrospectivamente os prontuários de crianças com queixas musculoesqueléticas atendidas no ambulatório de reumatologia pediátrica cujo diagnóstico definitivo foi neoplasia. Foram avaliados: idade de início dos sintomas, idade ao diagnóstico da neoplasia, sintomas e sinais iniciais, exames laboratoriais e diagnósticos inicial e definitivo (tipo de neoplasia). RESULTADOS: O diagnóstico definitivo de neoplasia foi encontrado em nove de 3528 pacientes (0,25%) atendidos em nosso ambulatório com queixas musculoesqueléticas. O intervalo médio de tempo entre os sintomas iniciais e o diagnóstico definitivo foi de cinco meses (variação de dois a 18 meses). A apresentação inicial mais freqüente foi artrite e/ou artralgia, de caráter pauciarticular, envolvendo grandes articulações. Artrite reumatóide juvenil foi o diagnóstico inicial em 44,4% dos pacientes (4/9). Na avaliação hematológica inicial, anemia foi a alteração mais freqüente, apenas um paciente apresentou leucocitose e em nenhum paciente foi observada leucopenia. Seis de oito pacientes apresentaram velocidade de hemossedimentação elevada. A desidrogenase láctica estava aumentada em cinco de oito pacientes (63%). Para o diagnóstico definitivo foi necessária a realização de mielograma e/ou biópsia. Os tipos de neoplasias encontrados incluíram leucemia linfóide aguda, leucemia mielóide aguda, linfoma não-Hodgkin, neuroblastoma e tumor de Ewing...

Evaluation of ticarcillin/clavulanic acid versus ceftriaxone plus amikacin for fever and neutropenia in pediatric patients with leukemia and lymphoma.

BACKGROUND: The empirical use of antibiotic treatments is widely accepted as a means to treat cancer patients in chemotherapy who have fever and neutropenia. Intravenous monotherapy, with broad spectrum antibiotics, of patients with a high risk of complications is a possible alternative. METHODS: We conducted a prospective open-label, randomized study of patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy. Patients received either monotherapy with ticarcillin/clavulanic acid (T) or ceftriaxone plus amikacin (C+A). RESULTS: Seventy patients who presented 136 episodes were evaluated, 68 in each arm of the study. The mean neutrophil counts at admission were 217cells/mm(3) (T) and 201cells/mm(3) (C+A). The mean duration of neutropenia was 8.7 days (T) and 7.6 days (C+A). Treatment was successful without the need for modifications in 71% of the episodes in the T group and 81% in the C+A group (p=0.23). Treatment was considered to have failed because of death in two episodes (3%) in the T group and three episodes (4%) in the C+A group, and because of a change in the drug applied in one episode in the T group and two episodes in the C+A group. Overall success was 96% (T) and 93% (C+A). Adverse events that occurred in group T were not related to the drugs used in this study. CONCLUSION: In pediatric and adolescent patients with leukemia or lymphoma, who presented with fever and neutropenia, during chemotherapy, ticarcillin/clavulanic acid was as successful as the combination of ceftriaxone plus amikacin. It should be considered an appropriate option for this group of patients at high risk for infections.

Evaluation of ticarcillin/clavulanic acid versus ceftriaxone plus amikacin for fever and neutropenia in pediatric patients with leukemia and lymphoma

BACKGROUND: The empirical use of antibiotic treatments is widely accepted as a means to treat cancer patients in chemotherapy who have fever and neutropenia. Intravenous monotherapy, with broad spectrum antibiotics, of patients with a high risk of complications is a possible alternative. METHODS: We conducted a prospective open-label, randomized study of patients with lymphoma or leukemia who had fever and neutropenia during chemotherapy. Patients received either monotherapy with ticarcillin/clavulanic acid (T) or ceftriaxone plus amikacin (C+A). RESULTS: Seventy patients who presented 136 episodes were evaluated, 68 in each arm of the study. The mean neutrophil counts at admission were 217cells/mm (T) and 201cells/mm (C+A). The mean duration of neutropenia was 8.7 days (T) and 7.6 days (C+A). Treatment was successful without the need for modifications in 71 percent of the episodes in the T group and 81 percent in the C+A group (p=0.23). Treatment was considered to have failed because of death in two episodes (3 percent) in the T group and three episodes (4 percent) in the C+A group, and because of a change in the drug applied in one episode in the T group and two episodes in the C+A group. Overall success was 96 percent (T) and 93 percent (C+A). Adverse events that occurred in group T were not related to the drugs used in this study. CONCLUSION: In pediatric and adolescent patients with leukemia or lymphoma, who presented with fever and neutropenia, during chemotherapy, ticarcillin/clavulanic acid was as successful as the combination of ceftriaxone plus amikacin. It should be considered an appropriate option for this group of patients at high risk for infections