RESUMO
A man in his early twenties with obesity was found dead in his apartment. The deceased was found naked and surrounded by empty bottles of electrolytes. An autopsy performed approximately 6 days postmortem and gross inspection revealed the absence of injury and no apparent extrinsic cause of death. It was decided to dissect to investigate the cause of death. The deceased had become morbidly obese (weight, 98 kg; height, 160 cm; body mass index, 38.3). Shortly before his death, he presented at a clinic complaining of gastric discomfort and heartburn, but other than hypertension (155/91 mmHg) no specific abnormality was found. He was normothermic (36.6â), and his blood oxygen saturation was normal (97%). Postmortem computed tomography of the thorax revealed a mediastinal mass obstructing the trachea, an upper-airway obstruction, and a narrowed thoracic cavity due to upward compression by an enlarged fatty liver. Autopsy confirmed that the tracheal mass was fatty tissue within the thymus and that upward pressure from an enlarged fatty liver had compressed the thoracic cavity. The deceased likely developed nocturnal chronic hypoxia because of compression by the mediastinal fat mass as well as intermittent hypoxia because of obstructive sleep apnea when lying supine. Chronic and intermittent hypoxia, diabetes, and obesity activate the sympathetic nervous system, increasing the risk of hypertension, heart failure, and arrhythmias. Histological findings showed pulmonary congestion and edema, reflecting heart failure as well as myocardial fragmentation and waving, showing hyper-contraction and hyper-relaxation, respectively. Hypertension, feeling overheated, and myocardial hyper-contraction can be explained as sympathetic nerve over-activation. Intra-cardiac coagulation and a renal cortical pallor suggested subacute death from cardiogenic shock due to heart failure. Postmortem computed tomography before autopsy detected airway obstruction and revealed the cause and pathophysiology of unexpected death in a young man with morbid obesity. Therefore, this could be a potentially useful clinical practice for determining the cause of death postmortem.
RESUMO
The Wilms' tumor gene WT1 consists of 10 exons and encodes a zinc finger transcription factor. There are four major WT1 isoforms resulting from alternative splicing at two sites, exon 5 (17AA) and exon 9 (KTS). All major WT1 isoforms are overexpressed in leukemia and solid tumors and play oncogenic roles such as inhibition of apoptosis, and promotion of cell proliferation, migration and invasion. In the present study, a novel alternatively spliced WT1 isoform that had an extended exon 4 (designated as exon 4a) with an additional 153 bp (designated as 4a sequence) at the 3' end was identified and designated as an Ex4a(+)WT1 isoform. The insertion of exon 4a resulted in the introduction of premature translational stop codons in the reading frame in exon 4a and production of C-terminal truncated WT1 proteins lacking zinc finger DNA-binding domain. Overexpression of the truncated Ex4a(+)WT1 isoform inhibited the major WT1-mediated transcriptional activation of anti-apoptotic Bcl-xL gene promoter and induced mitochondrial damage and apoptosis. Conversely, suppression of the Ex4a(+)WT1 isoform by Ex4a-specific siRNA attenuated apoptosis. These results indicated that the Ex4a(+)WT1 isoform exerted dominant negative effects on anti-apoptotic function of major WT1 isoforms. Ex4a(+)WT1 isoform was endogenously expressed as a minor isoform in myeloid leukemia and solid tumor cells and increased regardless of decrease in major WT1 isoforms during apoptosis, suggesting the dominant negative effects on anti-apoptotic function of major WT1 isoforms. These results indicated that Ex4a(+)WT1 isoform had an important physiological function that regulated oncogenic function of major WT1 isoforms.