OCEANIA: real-world study of ovarian cancer treatment patterns across multiple lines of therapy in Argentina and Brazil.

Aim: To evaluate real-world data on treatment patterns in Argentina and Brazil in patients with ovarian cancer. Methods: This study evaluated de-identified antineoplastic exposure data from a private healthcare provider in Argentina and health claims database (Orizon) in Brazil from 2010 to 2019 and 2015 to 2020, respectively. Results: Platinum-based chemotherapy was the most common first-line therapy (Argentina: n =311 [87.6%]; Brazil: n = 1142 [79.3%]). The proportion of patients receiving platinum-based chemotherapy declined across both populations from first- to second-line, while use of non-platinum-based, targeted, and hormone therapies increased. Duration of platinum-based treatment and time to next treatment decreased from first- to fourth-line. Conclusion: There is an unmet need for effective therapies that can prolong time to next treatment in ovarian cancer in Argentina and Brazil.

[Box: see text].

Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity.

5-aminolevulinic acid (5-ALA) is the first precursor of the heme biosynthesis pathway, accumulated in acute intermittent porphyria (AIP), an inherited metabolic disease characterized by porphobilinogen deaminase deficiency. An increased incidence of hepatocellular carcinoma (HCC) has been reported as a long-term manifestation in symptomatic AIP patients. 5-ALA is an α-aminoketone prone to oxidation, yielding reactive oxygen species and 4,5-dioxovaleric acid. A high concentration of 5-ALA presents deleterious pro-oxidant potential. It can induce apoptosis, DNA damage, mitochondrial dysfunction, and altered expression of carcinogenesis-related proteins. Several hypotheses of the increased risk of HCC rely on the harmful effect of elevated 5-ALA in the liver of AIP patients, which could promote a pro-carcinogenic environment. We investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to 5-ALA 25 mM for 2 h and 24 h using DNA microarray. Distinct transcriptome profiles were observed. 5-ALA '25 mM-2h' upregulated 10 genes associated with oxidative stress response and carcinogenesis. Enrichment analysis of differentially expressed genes by KEGG, Reactome, MetaCore™, and Gene Ontology, showed that 5-ALA '25 mM-24h' enriched pathways involved in drug detoxification, oxidative stress, DNA damage, cell death/survival, cell cycle, and mitochondria dysfunction corroborating the pro-oxidant properties of 5-ALA. Furthermore, our results disclosed other possible processes such as senescence, immune responses, endoplasmic reticulum stress, and also some putative effectors, such as sequestosome, osteopontin, and lon peptidase 1. This study provided additional knowledge about molecular mechanisms of 5-ALA toxicity which is essential to a deeper understanding of AIP and HCC pathophysiology. Furthermore, our findings can contribute to improving the efficacy of current therapies and the development of novel biomarkers and targets for diagnosis, prognosis, and therapeutic strategies for AHP/AIP and associated HCC.

Transcriptome profile analysis reveals putative molecular mechanisms of 5-aminolevulinic acid toxicity

5-aminolevulinic acid (5-ALA) is the first precursor of the heme biosynthesis pathway, accumulated in acute intermittent porphyria (AIP), an inherited metabolic disease characterized by porphobilinogen deaminase deficiency. An increased incidence of hepatocellular carcinoma (HCC) has been reported as a long-term manifestation in symptomatic AIP patients. 5-ALA is an α-aminoketone prone to oxidation, yielding reactive oxygen species and 4,5-dioxovaleric acid. A high concentration of 5-ALA presents deleterious pro-oxidant potential. It can induce apoptosis, DNA damage, mitochondrial dysfunction, and altered expression of carcinogenesis-related proteins. Several hypotheses of the increased risk of HCC rely on the harmful effect of elevated 5-ALA in the liver of AIP patients, which could promote a pro-carcinogenic environment. We investigated the global transcriptional changes and perturbed molecular pathways in HepG2 cells following exposure to 5-ALA 25 mM for 2 h and 24 h using DNA microarray. Distinct transcriptome profiles were observed. 5-ALA ’25 mM-2h′ upregulated 10 genes associated with oxidative stress response and carcinogenesis. Enrichment analysis of differentially expressed genes by KEGG, Reactome, MetaCore™, and Gene Ontology, showed that 5-ALA ‘25 mM-24h’ enriched pathways involved in drug detoxification, oxidative stress, DNA damage, cell death/survival, cell cycle, and mitochondria dysfunction corroborating the pro-oxidant properties of 5-ALA. Furthermore, our results disclosed other possible processes such as senescence, immune responses, endoplasmic reticulum stress, and also some putative effectors, such as sequestosome, osteopontin, and lon peptidase 1. This study provided additional knowledge about molecular mechanisms of 5-ALA toxicity which is essential to a deeper understanding of AIP and HCC pathophysiology. Furthermore, our findings can contribute to improving the efficacy of current therapies and the development of novel biomarkers and targets for diagnosis, prognosis, and therapeutic strategies for AHP/AIP and associated HCC.

Influence of creep deformation on sub-regional lumbar spine motion during manual lifting.

Prolonged or repetitive spine flexion induces creep deformation of posterior spine tissues allowing for increased intervertebral motion beyond 'normal' limits, which may influence sub-regional (intersegmental) spine motion during subsequent manual lifting tasks. Using spine skin-surface kinematics, intersegmental lumbar spine motion was recorded over 20 minutes of prolonged static spine flexion and a subsequent manual lifting task (2 lifts every 3 minutes, 30 minutes total) in 14 participants. Results demonstrated that mid to lower lumbar intersegmental levels (i.e. L2/L3 to L4/L5) experienced the greatest overall creep deformation and range of motion during both prolonged flexion and manual lifting; however, overall range of motion during manual lifting was unaffected. Additionally, creep deformation did not completely recover within 30 minutes. Future work should continue to investigate the influence of this residual creep, as well as how overall creep deformation impacts spine neuromuscular control and stability, and ultimately the development of low back disorders. Practitioner summary: Mid to lower lumbar spine levels (i.e. L2/L3 to L4/L5) experienced the greatest creep deformation and range of motion during both prolonged flexion and manual lifting. Repeated lifting following prolonged flexion may limit creep recovery; however, overall lifting kinematic motion remained unchanged.

Effect of 5-aminolevulinic acid on the expression of carcinogenesis-related proteins in cultured primary hepatocytes

Acute intermittent porphyria (AIP) is a heme pathway disorder caused by a decrease in the activity and synthesis of porphobilinogen deaminase. Thus, the first heme precursor 5-aminolevulinic acid (ALA) accumulates in the liver. Reactive oxygen species (ROS) resulting from ALA oxidation may be correlated to a higher incidence of hepatocellular carcinoma (HCC) in AIP patients. However, the molecular mechanisms of this relationship have not been thoroughly elucidated to date. In this study, we investigated the effect of increasing levels of ALA on the expression of proteins related to DNA repair, oxidative stress, apoptosis, proliferation and lipid metabolism. Primary rat hepatocytes were isolated by the collagenase perfusion method, lipoperoxidation was evaluated by a TBA fluorimetric assay and Western blotting was used to assess protein abundance. The data showed that ALA treatment promoted a dose-dependent increase of p53 expression, downregulation of Bcl-2, HMG-CoA reductase and OGG1 and an increase in lipoperoxidation. There was no alteration in the expression of the transcription factor NF-?B, catalase and superoxide dismutase. ALA oxidation products induced protein regulation patterns, suggesting the interconnection of cellular processes, such as the intrinsic pathway of apoptosis, redox homeostasis, cell proliferation, lipid metabolism and DNA repair. This study helps to elucidate the molecular mechanisms of hepatotoxicity mediated by ALA pro-oxidant effects and supports the hypothesis that ALA accumulation correlates with a higher incidence of hepatic carcinogenic events.

Training adolescents with type 1 diabetes to carbohydrate counting without parents' help / Capacitação de adolescentes com diabetes tipo 1 para a contagem de carboidratos sem a ajuda dos pais

ABSTRACT Objective: To develop and evaluate the effectiveness of a nutrition education program to enable adolescents with type 1 diabetes to count carbohydrates without the parents' help. Methods: Nineteen adolescents with type 1 diabetes from a diabetes center participated in four fortnightly meetings of one hour, with lectures and discussions about healthy nutrition, importance of nutrients for blood glucose, portion sizes, food replacements, and carbohydrate counting therapy. All meetings ended with exercises to check the learning. Adolescents were followed for one year after the intervention. Results: All participants were 100% successful in all the steps of the program and started carbohydrate counting in the main meals. Nutritional status and total daily insulin doses before and after the study did not differ. After 12 months, 68% of the adolescents counted carbohydrates at all times, 16% did so in extra snacks, and 16% were suspended from the new therapy. Eighty percent of the parents were satisfied with the program, believing teenagers were trained in the new therapy. Conclusion: A short nutrition education program successfully trained adolescents to count carbohydrates without the parents' help.

RESUMO Objetivo: Desenvolver e avaliar a eficácia de um programa de educação nutricional para capacitar adolescentes com diabetes tipo 1 na contagem de carboidratos sem ajuda dos pais. Métodos: Dezenove adolescentes com diabetes tipo 1 de um centro de diabetes participaram de quatro encontros quinzenais de uma hora, com palestras e discussões sobre alimentação saudável, importância dos nutrientes na glicemia, tamanho das porções, substituições de alimentos e contagem de carboidratos. Todos os encontros foram finalizados com exercícios para verificar o aprendizado. Os adolescentes foram acompanhados por um ano após a intervenção. Resultados: Todos os pacientes tiveram 100% de sucesso em todas as etapas do programa e começaram a contagem de carboidratos nas refeições principais. Não houve diferença no estado nutricional e doses totais diárias de insulina antes e depois do estudo. Após 12 meses, 68% dos adolescentes contavam carboidratos em todas as refeições, 16% nos lanches extras, e 16% tinham interrompido a nova terapia. Oitenta por cento dos pais estavam satisfeitos com o programa e acreditavam que os adolescentes estavam capacitados para nova terapia. Conclusão: Após um programa de educação nutricional, de curta duração, foi possível capacitar adolescentes na contagem de carboidratos sem a presença constante dos pais.

Seasonality of dizziness and vertigo in a tropical region.

Vertigo and dizziness are among the most common medical complaints in the emergency room, and are associated with a considerable personal and health care burden. Scarce and conflicting reports indicate those symptoms may present a seasonal distribution. This study aimed at investigating the existence of a seasonal distribution of vertigo/dizziness in a tropical region, and the correlations of these findings with climatic variables. The charts of all patients consecutively admitted between 2009 and 2012 in the emergency room of a Brazilian general hospital were reviewed. A total of 4920 cases containing these terms were sorted from a sample of 276,076 emergency records. Seasonality was assessed using Cosinor Analysis. Pearson's correlations were performed between the incidence of consultations, considering separately dizziness and vertigo and each of the predictor climatic variables of that index month. Significant seasonal patterns were observed for dizziness and vertigo in the emergency room. Vertigo was more frequent in late winter-spring, negatively correlating to humidity (r = -0.374; p = 0.013) and rainfall (r = -0.334; p = 0.020). Dizziness peaked on summer months, and positively correlated to average temperatures (r = 0.520; p < 0.001) and rainfall (r = 0.297; p = 0.040), but negatively to atmospheric pressure (r = -0.424; p = 0.003). The different seasonal patterns evidenced for dizziness and vertigo indicate possible distinct underlying mechanisms of how seasons may influence the occurrence of those symptoms.

[Continuous subcutaneous insulin infusion in type 1 diabetic during pregnancy: case report and literature review]. / Infusão de insulina subcutânea contínua em gestante com diabetes tipo 1: relato de caso e revisão da literatura.

The type 1 diabetic patient pregnancy is subjected to various attempts to obtain good glycemic control, since the pre-conception period throughout the gestation. Continuous subcutaneous insulin infusion (CSII) is a therapeutic tool to achieve the glycemic targets. Here it is presented the case of a Type 1 diabetic woman, who was not under multiple insulin daily injections therapy, and whose insulin therapy started on CSII during the second trimester of gestation, obtaining successful therapeutic outcome.

Infusão de insulina subcutânea contínua em gestante com diabetes tipo 1: relato de caso e revisão da literatura / Continuous subcutaneous insulin infusion in type 1 diabetic during pregnancy: case report and literature review

A gestação em portadoras de diabetes tipo 1 é alvo de múltiplas tentativas para o bom controle glicêmico desde o período pré-concepcional, com a terapia com infusão de insulina subcutânea contínua apresentando opção terapêutica adicional na tentativa de alcançar as metas glicêmicas. Apresentamos o caso de uma paciente com diabetes tipo 1, não controlada com múltiplas injeções diárias, cuja instalação da bomba de insulina ocorreu durante o segundo trimestre de gestação, com sucesso terapêutico.

The type 1 diabetic patient pregnancy is subjected to various attempts to obtain good glycemic control, since the pre-conception period throughout the gestation. Continuous subcutaneous insulin infusion (CSII) is a therapeutic tool to achieve the glycemic targets. Here it is presented the case of a Type 1 diabetic woman, who was not under multiple insulin daily injections therapy, and whose insulin therapy started on CSII during the second trimester of gestation, obtaining successful therapeutic outcome.

[Diabetes ketoacidosis associated with Guillan-Barré syndrome]. / Cetoacidose diabética associada com síndrome de Guillain-Barré: relato de caso.

Guillain-Barré syndrome (GBS) is a disorder caused by exaggerated immune response to infectious process. Diabetes Melito (DM) is not recognized as one cause of this inflammatory polyradiculoneuropathy with just a few cases of this association been described in the literature so far. We report here the case of a 44 years-old female patient admitted with a history of polyuria, polydipsia, weight loss, asthenia, hyperglycemia (562 mg/dL) and ketoacidosis without any infectious focus. The patient progressed with poliradiculopathy, respiratory insufficiency and liquoric alteration completing the picture of Guillain-Barré syndrome. The patient fully recovered from the neurologic deficit and then stopped with insulin therapy.

Cetoacidose diabética associada com síndrome de Guillain-Barré: relato de caso / Diabetes ketoacidosis associated with Guillan-Barré syndrome

A síndrome de Guillain-Barré (GBS) é uma desordem causada por exacerbada resposta imune aos processos infecciosos. O diabetes melito (DM) não é reconhecido como uma causa desta polirradiculopatia inflamatória, com poucos casos relatados na literatura sobre tal associação. Apresentamos um caso de uma paciente do sexo feminino, 44 anos, admitida com história recente de poliúria, polidipsia, perda de peso e astenia, glicemia de 562 mg/dL, em cetoacidose, sem foco infeccioso. Posteriormente desenvolveu quadro de polirradiculopatia, insuficiência respiratória e alteração liquórica compondo o quadro de GBS. No presente relato, a paciente recuperou-se plenamente do déficit neurológico, assim como da hiperglicemia, configurando quadro de diabetes tipo 2, com tendência à cetoacidose, evoluindo sem insulino-dependência.

Guillain-Barré syndrome (GBS) is a disorder caused by exaggerated immune response to infectious process. Diabetes Melito (DM) is not recognized as one cause of this inflammatory polyradiculoneuropathy with just a few cases of this association been described in the literature so far. We report here the case of a 44 years-old female patient admitted with a history of polyuria, polydipsia, weight loss, asthenia, hyperglycemia (562 mg/dL) and ketoacidosis without any infectious focus. The patient progressed with poliradiculopathy, respiratory insufficiency and liquoric alteration completing the picture of Guillain-Barré syndrome. The patient fully recovered from the neurologic deficit and then stopped with insulin therapy.

[Diabetes mellitus associated with atypical antipsychotic medications: case report and review of the literature]. / Diabetes mellitus associado com drogas antipsicóticas atípicas: relato de caso e revisão da literatura.

Since the introduction of atypical antipsychotic medications, starting with clozapine in 1990, many studies have associated these drugs with the development of diabetes among other metabolic disorders, as well as with the onset of the disease as ketoacidosis. We report the case of a 28-year-old patient with schizophrenia who was admitted with diabetic acidosis 1 month after the beginning of clozapine therapy. No weight gain was reported and the patient maintains satisfactory glycemia levels with no treatment required after discontinuation of the drug. The literature on this subject and cases reported so far are reviewed, including the association of other atypical antipsychotic drugs also involved in endocrine disorders. The objective of this report is to raise the awareness of physicians treating psychiatric patients to the possibility of new-onset diabetes during therapy with atypical antipsychotic drugs and to emphasize the necessity for increased vigilance and close metabolic follow-up of these patients.

Diabetes mellitus associado com drogas antipsicóticas atípicas: relato de caso e revisão da literatura / Diabetes mellitus associated with atypical antipsychotic medications: case report and review of the literature

Desde a introdução das medicações antipsicóticas atípicas, iniciando com a clozapina, em 1990, muitos relatos associam essas drogas ao desenvolvimento de diabetes mellitus, entre outros distúrbios metabólicos, assim como abertura da doença como cetoacidose. Relatamos o caso de um paciente de 28 anos, com esquizofrenia, admitido em cetoacidose diabética 1 mês após início da terapia com clozapina, sem relação com ganho de peso, mantendo-se com níveis satisfatórios de glicemia, sem tratamento, após suspensão da droga. Revisamos o assunto, com outros casos relatados até o momento, incluindo a associação de outros antipsicóticos atípicos igualmente envolvidos em distúrbios endócrinos. Objetivamos, com o relato deste caso, aumentar a atenção dos clínicos envolvidos no tratamento dos pacientes portadores de distúrbios psiquiátricos para a possibilidade do surgimento de diabetes durante a terapia, e enfatizar a necessidade de aumento da vigilância e do acompanhamento metabólico desses pacientes.

Since the introduction of atypical antipsychotic medications, starting with clozapine in 1990, many studies have associated these drugs with the development of diabetes among other metabolic disorders, as well as with the onset of the disease as ketoacidosis. We report the case of a 28-year-old patient with schizophrenia who was admitted with diabetic acidosis 1 month after the beginning of clozapine therapy. No weight gain was reported and the patient maintains satisfactory glycemia levels with no treatment required after discontinuation of the drug. The literature on this subject and cases reported so far are reviewed, including the association of other atypical antipsychotic drugs also involved in endocrine disorders. The objective of this report is to raise the awareness of physicians treating psychiatric patients to the possibility of new-onset diabetes during therapy with atypical antipsychotic drugs and to emphasize the necessity for increased vigilance and close metabolic follow-up of these patients.

HELLP síndrome associada à síndrome de Cushing: relato de dois casos / HELLP syndrome associated to Cushing's syndrome: report of two cases

A gravidez associada à síndrome de Cushing (SC) é quadro raro e está relacionada com hipertensão arterial severa em 64,6 por cento dos casos, além de infertilidade e abortamento em 75 por cento das pacientes com SC. Quando ocorre a gravidez, a causa mais freqüente do hipercortisolismo é o adenoma adrenal produtor de cortisol. Uma das principais complicações da hipertensão arterial na gravidez é a HELLP síndrome. Os autores relatam dois casos de gestação em paciente portadora de síndrome de Cushing, que evoluíram com quadro súbito e severo de HELLP síndrome e conseqüente progressão para o óbito fetal. O primeiro caso foi ocasionado por adenoma adrenal e o segundo, por um carcinoma de supra-renal. A gestação associada à síndrome de Cushing predispõe a situações ameaçadoras à vida, como a HELLP síndrome, devendo-se dar atenção especial à paciente nesses casos. O diagnóstico precoce permite o tratamento específico em tempo hábil, tentando reduzir a alta morbi-mortalidade nesses casos.

[HELLP syndrome associated to Cushing's syndrome--report of two cases]. / HELLP síndrome associada à síndrome de Cushing--relato de dois casos.

Pregnancy is a rare occurrence in Cushing's syndrome (CS) and it is associated with severe arterial hypertension in 64.6% of cases; infertility and abortion occur in 75% of patients with CS. In the event of a pregnancy in CS the etiology of hypercortisolism is the cortisol-producing adrenal adenoma in most cases. A most severe complication of high blood pressure in pregnancy is the HELLP syndrome. We report two cases of pregnancy in patients with CS, who developed a severe, sudden and early situation of HELLP syndrome which progressed to fetal death. The first was caused by an adrenal adenoma and the second by an adrenal carcinoma. Pregnancy due to CS can lead to a serious life-threatening situation, like the HELLP syndrome. Special attention should be paid when pregnancy is associated to CS. Early diagnosis leads to specific treatment, in an attempt to reduce de high morbid-mortality in these cases.