Abstract:Several major forces converged to catalyze the formal emergence of a body of knowledge and an organized focus on disorders of the liver in early life. Attendant to the development of a focused clinical subspecialty the pace of patient-and laboratory-based research in the field quickened in parallel to decipher the consequences of genetic or metabolic aberrations on immature liver structure and function. The key research observations that catalyzed the emergence and subsequent rapid growth of Pediatric Hepatolo… Show more
“…Although solid organ transplantation, including liver transplantation, is regarded as one of the most significant advances in medical science, it still faces various challenges such as organ unavailability, postoperative complications, and high costs3334. In the case of pediatric liver transplantation, there are additional problems such as growth retardation due to prolonged steroid exposure, lower physical and psychosocial function after liver transplantation, graft loss, and preoperative malnutrition3536. The identification of successful mechanism-based drugs for the treatment of PFIC3 is necessary to improve the quality of life in pediatric PFIC3 patients.…”
Multidrug resistance 3 (MDR3), encoded by the ATP-binding cassette, subfamily B, member 4 gene (ABCB4), localizes to the canalicular membrane of hepatocytes and translocates phosphatidylcholine from the inner leaflet to the outer leaflet of the canalicular membrane. Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare hepatic disease caused by genetic mutations of ABCB4. In this study, we characterized 8 ABCB4 mutations found in PFIC3 patients, using in vitro molecular assays. First, we examined the transport activity of each mutant by measuring its ATPase activity using paclitaxel or phosphatidylcholine. Then, the pathogenic mechanisms by which these mutations affect MDR3 were examined through immunoblotting, cell surface biotinylation, and immunofluorescence. As a result, three ABCB4 mutants showed significantly reduced transport activity. Among these mutants, one mutation A364V, located in intracellular domains, markedly decreased MDR3 expression on the plasma membrane, while the others did not affect the expression. The expression of MDR3 on the plasma membrane and transport activity of A364V was rescued by a pharmacological chaperone, cyclosporin A. Our study provides the molecular mechanisms of ABCB4 mutations and may contribute to the understanding of PFIC3 pathogenesis and the development of a mutation-specific targeted treatment for PFIC3.
“…Although solid organ transplantation, including liver transplantation, is regarded as one of the most significant advances in medical science, it still faces various challenges such as organ unavailability, postoperative complications, and high costs3334. In the case of pediatric liver transplantation, there are additional problems such as growth retardation due to prolonged steroid exposure, lower physical and psychosocial function after liver transplantation, graft loss, and preoperative malnutrition3536. The identification of successful mechanism-based drugs for the treatment of PFIC3 is necessary to improve the quality of life in pediatric PFIC3 patients.…”
Multidrug resistance 3 (MDR3), encoded by the ATP-binding cassette, subfamily B, member 4 gene (ABCB4), localizes to the canalicular membrane of hepatocytes and translocates phosphatidylcholine from the inner leaflet to the outer leaflet of the canalicular membrane. Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare hepatic disease caused by genetic mutations of ABCB4. In this study, we characterized 8 ABCB4 mutations found in PFIC3 patients, using in vitro molecular assays. First, we examined the transport activity of each mutant by measuring its ATPase activity using paclitaxel or phosphatidylcholine. Then, the pathogenic mechanisms by which these mutations affect MDR3 were examined through immunoblotting, cell surface biotinylation, and immunofluorescence. As a result, three ABCB4 mutants showed significantly reduced transport activity. Among these mutants, one mutation A364V, located in intracellular domains, markedly decreased MDR3 expression on the plasma membrane, while the others did not affect the expression. The expression of MDR3 on the plasma membrane and transport activity of A364V was rescued by a pharmacological chaperone, cyclosporin A. Our study provides the molecular mechanisms of ABCB4 mutations and may contribute to the understanding of PFIC3 pathogenesis and the development of a mutation-specific targeted treatment for PFIC3.
“…29 A limitation of our findings is that the data in the Databook are confined to accredited residencies and specialties, and the proportion of residents entering non-ACGME-accredited fellowship programs is not accounted for. Sources indicate this number is increasing, [30][31][32] and inclusion of these data would show even greater subspecialization rates for graduates of pipeline specialty programs.…”
Background
Recent studies suggest that the supply of primary care physicians and generalist physicians in other specialties may be inadequate to meet the needs of the US population. Data on the numbers and types of physicians-in-training, such as those collected by the Accreditation Council for Graduate Medical Education (ACGME), can be used to help understand variables affecting this supply.
Objective
We assessed trends in the number and type of medical school graduates entering accredited residencies, and the impact those trends could have on the future physician workforce.
Methods
Since 2004, the ACGME has published annually its data on accredited institutions, programs, and residents to help the graduate medical education community understand major trends in residency education, and to help guide graduate medical education policy. We present key results and trends for the period between academic years 2003–2004 and 2012–2013.
Results
The data show that increases in trainees in accredited programs are not uniform across specialties, or the types of medical school from which trainees graduated. In the past 10 years, the growth in residents entering training that culminates in initial board certification (“pipeline” specialties) was 13.0%, the number of trainees entering subspecialty education increased 39.9%. In the past 5 years, there has been a 25.8% increase in the number of osteopathic physicians entering allopathic programs.
Conclusions
These trends portend challenges in absorbing the increasing numbers of allopathic and osteopathic graduates, and US international graduates in accredited programs. The increasing trend in subspecialization appears at odds with the current understanding of the need for generalist physicians.
“…Ever since then, intrahepatic cholestasis has been at the centre of paediatric hepatology, although the focus has been moved to a certain extent from the study of peripheral metabolites to studies of the affects of proteins on the canalicular membrane, the hepatocytic nuclear membrane and lately the intestinal mucosa. Some years ago, at a monothematic meeting held by the American Association for the Study of Liver Diseases, a simplified list of the subtypes of chronic intrahepatic cholestasis was proposed (Table ) . With the help of next‐generation sequencing, and improved biochemical analytical methods such as high‐performance liquid chromatography‐mass spectrometry, the relative number of undiagnosed causes is shrinking, providing hope for innovative causal treatment .…”
Paediatric hepatology dates from the 1970s and it is the youngest of the organ-specific subspecialties. As then there have been impressive achievements in the fields of anatomical, metabolic, immunological and neoplastic diseases, and the advent of modern molecular biology has resulted in a marked increase in exact diagnoses. Liver transplants provided enormous stimulus for the discipline. Due to changing morbidity patterns, the discipline faces new challenges, such as environment-and lifestyle-induced liver diseases, but different forms of chronic viral hepatitis are diminishing. Conclusion: High levels of competence require good clinical research, optimal results and a high degree of centralisation.
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