Adalimumab for endoscopic and histopathological mucosal healing in paediatric patients with moderate to severe Crohn's disease

Abstract Introduction: Deep remission, defined as clinical remission with mucosal healing (MH), with anti-tumor necrosis factor (TNF)-α agents is a new target for therapy in Crohn's disease (CD). Provided that the efficacy of infliximab (IFX) for induction of MH in CD has been demonstrated, there are much less data for adalimumab (ADA), and none concerning MH on histopathological examination. Aim: To assess the impact of biological therapy with ADA on both endoscopic and histopathological MH in paediatric patients with CD. Material and methods: Twenty-three children (10 boys and 13 girls) aged 13.0 ±9.3 years with moderate to severely active CD diagnosed at the mean age of 5.5 ±0.83 years were included into the study. Seven (30.4%) patients had been previously treated with infliximab and switched to ADA due to intolerance or loss of response. Colonoscopy and gastroscopy with sample collection were performed in all patients before and after induction treatment with ADA. Clinical activity of the disease was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI), and the endoscopic activity was scored using the Simple Endoscopic Score (SES-CD). Histological changes were evaluated by a self-adapted numerical scoring system. Results: Four (17.4%) patients reached clinical remission (PCDAI ≤ 10). When comparing data at baseline and at a week after ADA treatment, a significant decrease was observed in median PCDAI and in SES-CD score between the initial and control colonoscopies. We reported a decrease in histological scale, which was not statistically significant. A correlation was found between PCDAI and SES-CD score. Conclusions: Biological therapy with ADA has a positive impact on endoscopic mucosal healing in paediatric patients with CD, which is not associated with histological evidence of suppression of inflammation. Endoscopic MH correlates better than microscopic one with clinical remission

Case Report: Adenosine kinase deficiency diagnosed 10 years after liver transplantation: Novel phenotypic insights

Adenosine kinase (ADK) deficiency is a rare inborn error of methionine and adenosine metabolism. So far, a total of 27 patients with ADK deficiency have been reported. Here, we describe the first Polish patient diagnosed with ADK deficiency, aiming to highlight the clinical presentation of disease, emphasize diagnostic difficulties, and report the long-term follow-up. Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine. A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy. The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency. Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine

Is there a common cause for paediatric Cushing’s disease?

Introduction: According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing’s disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children’s Memorial Health Institute (CMHI). Material and methods: Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42–17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. Results: The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 μg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. Conclusion: The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing’s disease, as previously reported

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD

Giant Intrapericardial Myxoma Adjacent to the Left Main Coronary Artery

A 62-years-old woman was admitted to the hospital because of chronic cough, expectoration of thick mucus, hoarseness and tightness in the precordial area. Computed Tomography (CT) examination revealed the presence of a giant intrapericardial tumor with the dimensions of 80 × 38 × 32 mm. It was located anteriorly and laterally to the left atrium, posteriorly to the pulmonary trunk and the ascending aorta. This hypodense change modeled the left atrium without evidence of invasion. CT coronary angiography and 3-dimensional reconstruction were applied to enable precise planning of cardiac surgery. CT evaluation confirmed that it is possible to remove the tumor without damage to the adjacent left main coronary artery. The patient underwent cardiac surgery with sternotomy and cardiopulmonary bypass. A cohesive, smooth, vascularized tumor pedunculated to the left atrial epicardium was visualized. The location and dimensions corresponded to those determined by CT scan examination. The entire tumor was successfully dissected together with adjacent adipose and fibrous tissue. Histological evaluation revealed the presence of myxoid cells, blood vessels, degenerative changes, and microcalcifications embedded in profuse hyalinized stroma. Those histological features enabled identification of the intrapericardial tumor as a myxoma. Follow-up CT examination did not demonstrate any signs of recurrence of the myxoma. According to our knowledge, a myxoma located inside the pericardial sac has never been described before

Detection of new potentially pathogenic mutations in two patients with primary pigmented nodular adrenocortical disease (PPNAD) — case reports with literature review

Introduction: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of ACTH-independent Cushing’s syndrome (CS). Half of patients with PPNAD are sporadic cases and the other half familial.Material and methods: We present two patients with PPNAD confirmed by genetic analysis.Results: In both patients there were no abnormal findings on diagnostic imaging of both adrenals and heart. Patients underwent bilateral two-stage adrenalectomy. Histopathological examination confirmed PPNAD. Genetic testing showed the following mutations in the PRKAR1A gene coding for the regulatory subunit type 1A of the protein kinase A enzyme: c.125dupG (patient 1) and c.15dupT (patient 2). Both these defects lead to inactivation of the PRKAR1A protein and are consequently causative of PPNAD in these patients.Conclusions: The novel mutations presented in this article are considered to be pathogenic for PPNAD.

p66Shc Aging Protein in Control of Fibroblasts Cell Fate

Reactive oxygen species (ROS) are wieldy accepted as one of the main factors of the aging process. These highly reactive compounds modify nucleic acids, proteins and lipids and affect the functionality of mitochondria in the first case and ultimately of the cell. Any agent or genetic modification that affects ROS production and detoxification can be expected to influence longevity. On the other hand, genetic manipulations leading to increased longevity can be expected to involve cellular changes that affect ROS metabolism. The 66-kDa isoform of the growth factor adaptor Shc (p66Shc) has been recognized as a relevant factor to the oxygen radical theory of aging. The most recent data indicate that p66Shc protein regulates life span in mammals and its phosphorylation on serine 36 is important for the initiation of cell death upon oxidative stress. Moreover, there is strong evidence that apart from aging, p66Shc may be implicated in many oxidative stress-associated pathologies, such as diabetes, mitochondrial and neurodegenerative disorders and tumorigenesis. This article summarizes recent knowledge about the role of p66Shc in aging and senescence and how this protein can influence ROS production and detoxification, focusing on studies performed on skin and skin fibroblasts