Search

Mitochondrial diseases are rare genetic disorders caused by dysfunction of the respiratory chain in mitochondria (RCD). They manifest themselves with multi-organ damage and a very diverse phenotype. Symptoms often begin in childhood and early childhood. Diagnostics requires the cooperation of many specialists (including pathologist, geneticist, biochemist). The diagnostic material that is valuable from the pathologist's point of view is the brain and muscle. The following disease entities were discussed: Leigh disease, MELAS, Alpers disease and mitochondrial DNA deletions. [ABSTRACT FROM AUTHOR]

Dysferlinopathies are rare disorders of muscle that present two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. They are caused by mutations in the gene encoding the skeletal muscle protein dysferlin, which is involved in muscle repair. The clinical presentation of the disease is rather uncharacteristic, and molecular genetic testing is long-lasting; thus muscle biopsy may be essential in the diagnostic process. Histology itself reveals non-specific changes, but a variety of currently available muscle protein immunostains may be very helpful. We present a 19-year-old girl with epilepsy and elevated creatine phosphokinase (CPK) concentration. Due to increased CPK, myopathy was suspected and muscle biopsy was performed. Light microscopy showed no distinctive myopathic changes, and electron microscopy showed no abnormalities. Extended immunohistochemistry, performed much later, showed complete absence of dysferlin immunostaining. Based on that result, the diagnosis of LGMD2B was made, with subsequent genetic testing to be done. Two known pathogenic variants were found in the DYSF gene, confirming the diagnosis of LGMD2B and allowing proper genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is currently a treatment of choice in patients with end-stage liver disease. Acute cellular rejection (ACR), antibody-mediated rejection (AMR), and chronic rejection (ChR) are major causes of graft injury. Therefore, new markers predicting graft rejection are investigating. Apoptosis has been recently proposed as one of the mechanisms contributing to liver fibrosis in liver grafts. Coarse needle liver biopsy is still a gold standard in monitoring post-transplant pathologies. The aim of this study was to assess the utility of immunohistochemical (IHC) staining for M30 (cytokeratin 18), as a prognostic marker of rejection in pediatric recipients of liver transplant and predicting marker of liver fibrosis and worse follow-up., Methods: The study enrolled 55 biopsies from 55 patients aged 2.37 to 18.9 years (median 13.87 years) who underwent protocolar liver biopsies taken 1-17 years after liver transplantation (median 8.36 years). The control group (positive control group) consisted of 26 biopsies from 16 patients in whom acute ACR was diagnosed. IHC staining for M30 (cytokeratin 18) and histochemical Azan staining were performed in all liver specimens. The following changes were re-evaluated in each specimen: features of ACR (the severity was assessed using RAI/Rejection Activity Index/Scale, which ranges from 3-9 points and include 3 histopathological changes suggestive of rejection), AMR or ChR; severity of fibrosis (Ishak Scale); presence of cholestasis and steatosis. Clinical parameters including laboratory tests of liver function (AST, ALT, GGTP, bilirubin) were also evaluated., Results: M30 expression correlated with presence of acute cellular rejection. However, no relationship was found between M30 expression and severity of fibrosis., Conclusions: M30 staining, marker of apoptosis, seems to be a promising marker predicting acute cellular rejection.

Inflammatory bowel diseases (IBD) are chronic intestinal conditions of multifactorial aetiology including genetic susceptibility, immunological impairment, dysbiosis, and environmental factors. The diagnosis is based on both clinical and endoscopic features, wherein histopathological evaluation remains a gold diagnostic standard. However, fast, reliable, and non-invasive biological markers have been used for years for diagnosis as well as for disease activity monitoring. Currently, commonly used faecal calprotectin is the only biomarker approved and recommended by the European Crohn's and Colitis Organization (ECCO). Nonetheless, other biological markers discriminating between functional and organic bowel conditions have been widely studied. Therefore, the aim of this manuscript was to review new potential biomarkers of inflammation in IBD. The aim of this study was to review currently available biomarkers of intestinal inflammation and increased gut permeability in IBD., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Termedia.)

Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP + ), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN 4 ) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN 4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN 4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN 4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN 4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN 4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN 4 -induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN 4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN 4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN 4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN 4 in the prevention/treatment of NAFLD., Competing Interests: Declaration of competing interest Paulo J. Oliveira and Fernanda Borges are cofounders of the CNC-UP spin-off company MitoTAG (Coimbra, Portugal). This spin-off had no involvement in the data collection, analysis and interpretation, manuscript writing, and the decision to submit the manuscript for publication., (Copyright © 2022. Published by Elsevier B.V.)

Competing Interests: The authors declare no conflict of interest.

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., Competing Interests: The authors declare no conflict of interest.

Introduction: The clinical efficacy of infliximab (IFX) for induction of remission in both adults and children with active Crohn's disease (CD) has been well documented. Recently, so-called "deep remission" defined as mucosal healing has become the ultimate endpoint of the most recent therapeutic advances for CD. However, endoscopic evidence of mucosal healing is not necessarily associated with histological evidence of suppression of inflammation., Aim: Since data on that issue are limited, especially in the paediatric population, the aim of this study was to assess the impact of induction therapy with IFX on deep microscopic remission in paediatric patients with CD., Material and Methods: Fifty-six children (32 boys and 24 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. Colonoscopy and gastroscopy with sample collection were performed in all patients before and after three injections of IFX. 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 previously described numerical scoring system., Results: Thirty-nine (69.6%) patients reached clinical remission (PCDAI ≤ 10). When comparing data at baseline and at week 10, a significant decrease was observed in median PCDAI, and in SES-CD score between the initial and control colonoscopies. We also reported a decrease in histological scale. However, the difference was not statistically significant ( p = 0.63). Three (5.4%) patients had a score of zero in the control histological examination. The correlation was found only between histological score and SES-CD score. Clinical remission correlated better with mucosal healing expressed by a decrease in SES-CD score than with microscopic changes., Conclusions: Biological therapy with infliximab enables mucosal healing in paediatric patients with CD, which is not necessarily associated with histological evidence of suppression of inflammation. Mucosal healing correlates better than microscopic healing with clinical remission., Competing Interests: The authors declare no conflict of interest.

Aim: To verify the impact of induction therapy with infliximab (IFX) on mucosal healing in children with ulcerative colitis (UC)., Methods: The study included all UC pediatric patients treated with IFX at our center over the last 10 years. The data were collected from patients' medical charts and analyzed retrospectively. A total of 16 patients with UC underwent colonoscopy with sample collection before and after three IFX injections. Pediatric Ulcerative Colitis Activity Index (PUCAI) was used to assess the clinical condition; endoscopic features were classified according to the Baron scale; and histological changes were evaluated according to the protocol of The British Society of Gastroenterology and Geboes Index. Clinical response was defined as a ≥ 20-point reduction in PUCAI index, and clinical remission as PUCAI index < 10 points. Endoscopic mucosal remission was defined as completely normal (score 0) on the Baron scale. Histological remission was defined as grade 0 in the Geboes Index. To assess correlation between variables, Spearman's rank correlation coefficient was used., Results: Clinical remission (PUCAI < 10) at week 8 was achieved in 68.75% of investigated subjects. Endoscopic mucosal remission at week 8 (Baron 0) was observed in 12.5% of patients. Histological remission (Geboes 0) after induction therapy with IFX was noticed in 18.75% cases. A general histological improvement, expressed by normal surface and crypt architecture, number of crypts, and lamina propria cellularity, was observed in six (37.5%) patients; there was no improvement in nine (56.25%) individuals, and worsening was observed in one (3.75%) case. Changes were not related to UC location. A reduction of inflammatory process was observed in 10 (62.5%) patients; there were no changes in four (25%) individuals, and the inflammation became more severe in two (12.5 %) cases. Simultaneous clinical, endoscopic and histological improvement of parameters assessing disease activity at week 8 was noticed in six (37.5%) patients. 55.5% of investigated patients with normal mucosa seen on endoscopy showed no inflammation on histology. A Baron score of 2 and 3 showed a good correlation with histology results (78.2% of patients with a Geboes Index ≥ 3)., Conclusion: IFX has a positive histological effect in more than one-third of UC patients. IFX reduces intestinal inflammation and improves clinical condition.