Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Genetic landscape of pediatric acute liver failure of indeterminate origin

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Özne, eğitim, hakikat

Bu makale. PAIDEIA dergisinin Theory of Knowledge bölümünden alınmıştır.İnsan kültüründe ve toplumda birbirine karıştırılan iki süreç gelişir. Hegel'e göre, ilki her bireyde evrensel bilgi ve deneyimin gelişmesidir, çünkü bireyler tam olarak olmaları gereken şeylerle doğmazlar. İkincisi, birey ve bireyin bilinçliliğin de biricik ve tek formda evrensel bilgi ve deneyimin öznelleştirilmesidir. Felsefe tarihinde bu iki sürecin analiz edilmesi, bilen özne, hakikat, eğitim ve paideia nın birbirine bağlı olduğunu gösterir. Başkaları için kaygılanma ve onları yönetme yeteneklerini geliştiren hermeneutik "kendine bakma" ilkesi, bütünlüğünde bu özellikleri içinde bulunduran ve paideia özelliğini belirleyen geleneklerden birisini betimler. Bu prensip Sokratesçi, Platoncu, Epikürosçu ve Stoacı gelenek tarafından geliştirildi ve cogito 'ya doğru giden düşüncesiyle Descartes tarafından gerçekleştirildi. "Kendine bakma" 17.yy' da bilimsel bilgiyi elde etme koşulu olarak düşünüldü; ama daha sonraları egotizm ve bireycilik olarak nitelendirildi ve kendini kavrama ile yer değiştirdi. Foucault, modern hermeneutik yetişme kavramının temeli olarak ilk anlamında "kendine bakma" ilkesinin tekrar gözden geçirilmesi için gereklilikleri kanıtlar. Böylece "yol gösteren" ya da "özel öğretmen" olarak felsefenin rolü, süreci gözden geçirmektir

Partial Hepatectomy for the Resistant Fasciola Hepatica Infection in a Child.

Fascioliasis is an emerging and important chronic parasitic disease caused by two trematode liver fluke species: Fasciola hepatica (F. hepatica) and Fasciola gigantica (F. gigantica) infecting several herbivorous mammals including cattle, goats, sheep, and humans. We report a 9-year-old girl who suffered from F. hepatica infection and underwent right hepatectomy because of increasing abdominal pain resistant to anthelmintic chemotherapy. When anthelmintic drug treatment is not effective and abdominal pain persists, surgical resection including hepatectomy should be kept in mind for resistant F. hepatica infection

Deriving effective vaccine allocation strategies for pandemic influenza: Comparison of an agent-based simulation and a compartmental model.

Individuals are prioritized based on their risk profiles when allocating limited vaccine stocks during an influenza pandemic. Computationally expensive but realistic agent-based simulations and fast but stylized compartmental models are typically used to derive effective vaccine allocation strategies. A detailed comparison of these two approaches, however, is often omitted. We derive age-specific vaccine allocation strategies to mitigate a pandemic influenza outbreak in Seattle by applying derivative-free optimization to an agent-based simulation and also to a compartmental model. We compare the strategies derived by these two approaches under various infection aggressiveness and vaccine coverage scenarios. We observe that both approaches primarily vaccinate school children, however they may allocate the remaining vaccines in different ways. The vaccine allocation strategies derived by using the agent-based simulation are associated with up to 70% decrease in total cost and 34% reduction in the number of infections compared to the strategies derived by using the compartmental model. Nevertheless, the latter approach may still be competitive for very low and/or very high infection aggressiveness. Our results provide insights about potential differences between the vaccine allocation strategies derived by using agent-based simulations and those derived by using compartmental models

Consensus statement on diagnosis, treatment and follow-up of cow’s milk protein allergy among infants and children in Turkey

The present paper aims to provide experts' consensus on diagnosis and management of cow's milk protein allergy (CMPA) among infants and children in Turkey, based on review of available evidence-based guidelines, publications and experts' clinical experience. The experts agreed that CMPA diagnosis should be based on symptomatic evaluation and diagnostic elimination diet as followed by implementation of an open challenge test after disappearance of symptoms and confirmation of CMPA diagnosis in re-appearance of symptoms. For breastfed infants, differential diagnosis involves withdrawal of cow's milk-containing products from the mother's diet, while calcium supplements and appropriate dietary advice are given to mothers to prevent nutritional deficiency. For infants not breastfed exclusively, cow's milk-based formula and any complementary food containing cow's milk protein (CMP) should be avoided. The first line treatment should be extensively hydrolyzed formula (eHF) with use of amino acid-based formula (AAF) in severe cases such as anaphylaxis, enteropathy, eosinophilic esophagitis and food protein induced enterocolitis along with cases of multiple system involvement, multiple food allergies and intolerance to eHF. Introduction of supplementary foods should not be delayed in CMPA, while should be made one by one in small amounts and only after the infant is at least 17 weeks of age. Infants who are at-risk can be identified by family history of atopic disease. Exclusive breastfeeding for 4-6 months (17-27 weeks) is recommended as the best method of infant allergy prevention. There is no evidence that modifying the mother's diet during pregnancy and/or breast-feeding and delaying solid or even potentially allergic foods beyond 4-6 months in infants may be protective against allergy among at-risk infants. When exclusive breastfeeding is not possible, at-risk infants should get a partially or extensively hydrolyzed formula (pHF or eHF) to prevent allergy until risk evaluation by a health professional. In conclusion, the present consensus statement provides recommendations regarding diagnosis, prevention and management of CMPA in infants and children in Turkey, and thus expected to guide physicians to optimize their approach to CMPA and decrease burden of the disease on infants and their caregivers

A new therapeutic combination for osteosarcoma: Gemcitabine and Clofazimine co-loaded liposomal formulation

Osteosarcoma is the most common cancer in bone. Drug resistance is a challenge of current treatments that needs to be improved with novel treatment strategies. In this research, a new dual drug delivery system was developed with Gemcitabine (GEM) and Clofazimine (CLF) co-loaded liposome formulations. GEM is a well-known anticancer agent and CLF is a leprostatic and anti-inflammatory drug recently recognized as effective on cancer. GEM and CLF co-loaded liposomal formulation was achieved with compartmentalization as hydrophilic GEM being in core and lipophilic CLF sequestering in lipid-bilayer. Liposomes had high encapsulation efficiency (above 90%, GEM and above 80%, CLF). CLF release was enhanced while GEM release was slowed down in coloaded liposomes compared to single cases. GEM/CLF co-loaded liposomes significantly enhanced cytotoxicity than GEM or CLF loaded liposomes on osteosarcoma cell line. CLF and GEM had synergistic effect (CI < 1). Results of flow cytometry showed higher apoptotic cell ratio, caspase-3 activity, mitochondrial membrane depolarized cells' ratio for GEM/CLF co-loaded liposome treatments than other liposomes. Cytotoxicity of CLF on bone cancer cells and also its synergistic effect with GEM on osteosarcoma is reported for the first time with this study. CLF's loading with GEM into liposome was also a new approach for enhancement of anticancer effect on Saos-2 cells. Therefore, GEM/CLF co-loaded liposomal delivery system is proposed as a novel approach for treatment of osteosarcoma

Urgent operation improves weakness in cauda equina syndrome due to lumbar disc herniation

WOS: 000499639000003PubMed: 31663070Objectives: This study aims to examine the effect of surgical timing on the sphincter function and improvement of motor function in patients with cauda equine syndrome (CES) due to lumbar disc herniation (LDH). Patients and methods: Between January 2005 and December 2013, a total of 33 patients (18 males, 15 females; mean age 48.6 +/- 2.2 years, range, 24 to 73 years) who underwent lumbar spinal surgery and were diagnosed with CES due to LDH were retrospectively analyzed. Data including demographics, muscle weakness, sensory deficit, sphincter control, LDH level, time from the initiation of symptoms to admission, and time to surgery were documented. The latest muscle weakness, sensory deficits, and sphincter control were also recorded. The patients were divided into two groups according to the rate of muscle strength improvement and data including age, sex, and operation time were compared. Results: The weakness remained unchanged in 11 (33.3%), improved in 13 (39.4%), and returned to normal in nine (27.3%) patients. Sphincter control resolved in five patients. Sensory loss resolved in two patients. While admission duration was shorter in the group with improved muscle strength (p=0.02), there was no significant difference in the time to surgery (p=0.63). Logistic regression analyses revealed that only the admission within 0 to 24 hours was significant for the muscle strength improvement (regression coeeficient [B]=2.83, standard error [SE]=0.86, p=0.006). Conclusion: A significant improvement in the motor strength can be achieved in patients with CES who are operated within 24 hours. On the other hand, patients with CES should be received surgery immediately when first seen, regardless of the time, since the muscle strength is slightly improved