Quarterly Journal of Medicine最新文献

Accurate annotation of coding regions in RNAs is essential for understanding gene translation. We developed a deep neural network to directly predict and analyze translation initiation and termination sites from RNA sequences. Trained with human transcripts, our model learned hidden rules of translation control and achieved a near perfect prediction of canonical translation sites across entire human transcriptome. Surprisingly, this model revealed a new role of codon usage in regulating translation termination, which was experimentally validated. We also identified thousands of new open reading frames in mRNAs or lncRNAs, some of which were confirmed experimentally. The model trained with human mRNAs achieved high prediction accuracy of canonical translation sites in all eukaryotes and good prediction in polycistronic transcripts from prokaryotes or RNA viruses, suggesting a high degree of conservation in translation control. Collectively, we present a general and efficient deep learning model for RNA translation, generating new insights into the complexity of translation regulation.

Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.

Microscopic haematuria is a common clinical finding, with reported prevalences of up to 22%. The role of renal biopsy in the investigation of this condition is still debated. Currently urological investigation including cystourethroscopy is often regarded as adequate. We investigated 165 patients (94 male, 71 female; mean age 37.5 years, range 10-71) referred with isolated microscopic haematuria, using renal biopsy and cystourethroscopy. All patients were normotensive with normal serum creatinine, no proteinuria, sterile urine and a normal IVU. Renal biopsy abnormalities were found in 77/165 (46.6%): IgA nephropathy (49), global or segmental mesangial proliferative glomerulonephritis without IgA deposits (16), thin membrane nephropathy (7), vascular changes suggestive of hypertension (3), interstitial nephritis (1), and membranous nephropathy (1). Only five abnormalities were found on cystourethroscopy (cystitis 3, urethral stricture 1, bladder stone 1). Two patients with cystitis also had IgA nephropathy. Biopsy abnormalities were commonest under the age of 20 (69.2%), but 40% of biopsies were abnormal even in the seventh decade of life. Because renal biopsy abnormalities are very frequent in patients with isolated haematuria, renal biopsy is indicated in patients over 45 years of age if renal imaging and cystoscopy are normal. In those under 45 years, renal biopsy should replace cystoscopy as the investigation to follow normal renal imaging.

Cryptococcal meningitis is a common cause of chronic meningitis in Papua New Guinea, affecting apparently immunocompetent people. The majority of infections are believed to be due to Cryptococcus neoformans var. gattii. We have reviewed the records of 49 Melanesian adults who presented with proven cryptococcal meningitis to the University teaching hospital in Port Moresby, and compare our findings with other published studies of cryptococcal meningitis in the tropics and sub-tropics. None of the patients had an obvious cause of immunosuppression. Visual disturbances and fundoscopic changes of papilloedema or papillitis were particularly common. The in-hospital case fatality rate for patients treated with amphotericin B and flucytosine was 22.4%. Of the fully treated patients, 31% became completely blind before being discharged from hospital. Therapy directly aimed at reducing intracranial pressure may improve outcome.

Disturbance in the vitamin D/parathyroid hormone (PTH) axis may be important in the pathogenesis of glucose intolerance and insulin resistance in uraemia. To investigate possible relationships between hyperparathyroidism, intracellular free calcium ([Ca2+]i), and glucose tolerance in chronic renal failure, we measured serum intact PTH (I-PTH) by two-site immunometric assay, platelet [Ca2+]i using the fluorescent indicator fura-2, and plasma glucose and insulin after 14 h overnight fast and at 30, 60 and 120 min following a 75 g oral glucose load, in 18 chronic haemodialysis patients with elevated serum I-PTH. Calcitriol (1 microgram) was administered parenterally at the end of each dialysis session for four weeks. This significantly decreased serum I-PTH (p < 0.001) and platelet [Ca2+]i (p < 0.01). Uraemic patients initially showed marked glucose intolerance, with increased area below the glucose curve compared to healthy controls, but after 4 weeks of calcitriol treatment, this effect was significantly decreased, and there was a significant rise in the area under the insulin curve after glucose load. The insulinogenic index also increased significantly after calcitriol treatment. These data suggest that calcitriol treatment of haemodialysis patient with secondary hyperparathyroidism is associated with increased insulin secretion in response to glucose challenge, and that this change is linked to the decrease in intracellular free calcium.