Pathophysiology最新文献

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Background: Cause of death analysis is fundamental to forensic pathology. We present the case of a 9½-year-old girl with a genetically confirmed diagnosis of Dravet syndrome who died in her sleep with no evidence of motor seizure. She also had a lifelong history of recurrent pneumonias and, along with her family, had tested positive for COVID-19 10 days before death. Methods: Long-term clinical history of Dravet Syndrome and respiratory infections were obtained from patient's medical charts and radiology reports. A Rapid-Antigen Test was used to confirm SARS-CoV2 infection days prior to death. At autopsy, brain, heart and lung tissues were obtained. Paraffin-embedded tissues were double-stained with H&E, and immunohistochemically stained using various antibodies. Results: Autopsy revealed evidence of previous seizure activity in the brain and cellular interstitial thickening in the lung. The brain showed edema and fibrillary gliosis without neuronal loss in neocortex and hippocampus. The lung showed inflammatory interstitial thickening with histiocytes, megakaryocytes, B-lymphocytes, and T-lymphocytes, including helper/suppressor cells and cytotoxic T-lymphocytes. Diffuse alveolar damage was observed as alveolar flooding with proteinaceous fluid. Conclusions: The cause of death may be attributed to Sudden Unexpected Death in Epilepsy (SUDEP) in Dravet syndrome, sudden death in viral pneumonia, or some combination of the two. When two independent risk factors for sudden unexpected death are identified due to co-pathology, it may not be possible to determine a single cause of death beyond a reasonable doubt.

Background/Objectives: Duchenne muscular dystrophy (DMD) is a genetic disease characterized by a lack of dystrophin caused by mutations in the DMD gene, and some minor cases are due to decreased levels of dystrophin, leading to muscle weakness and motor impairment. Creatine supplementation has demonstrated several benefits for the muscle, such as increased strength, enhanced tissue repair, and improved ATP resynthesis. This preliminary study aimed to investigate the effects of creatine on the gastrocnemius muscle in dystrophy muscle (MDX) and healthy C57BL/10 mice. Methods: Twenty MDX and C57Bl/10 mice were organized into groups and supplemented or not with creatine in a dosage of 0.3 mg for 8 weeks. Gastrocnemius tissue was analyzed using histomorphology and histomorphometric techniques. Results: The results demonstrated potential anti-inflammatory effects of creatine, with less observation of inflammatory infiltrates, the preservation of intramuscular glycogen, and reduction in tissue fibrosis in supplemented animals. Conclusions: These findings suggest that creatine may enhance tissue function and slow the progression of DMD. However, further research, with more analysis, is needed to elucidate molecular mechanisms underlying creatine's effects on reducing mononuclear leukocytes and its role in mitigating tissue fibrosis.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the liver is not defined. Therefore, this study aimed to evaluate the effects of ERα overexpression, specifically in the liver in mice fed a high-fat diet (HFD). Methods: Male C57BL/6J mice were divided into four groups, vehicle fed with regular chow (RC) (RC-Vehicle); vehicle fed an HFD (HFD-Vehicle); AAV-treated fed with RC (RC-AAV); and AAV-treated fed an HFD (HFD-AAV), for 6 weeks (8-10 mice per group). AAV was administered intravenously to induce ERα overexpression. Results: We demonstrate that overexpression of ERα in RC-fed mice reduces body fat (28%). These mice show increased oxygen consumption in cultured primary hepatocytes, both in basal (19%) and maximal respiration (34%). In HFD-fed mice, we showed a decrease in hepatic TAG content (43%) associated with improved hepatic insulin sensitivity (145%). Conclusions: From this perspective, our results prove that hepatic ERα signaling is responsible for some of the metabolic protective effects of estrogen in mice. Overexpression of ERα improves hepatocyte mitochondrial function, consequently reducing hepatic lipid accumulation and protecting animals from hepatic steatosis and hepatic insulin resistance. Further investigations will be needed to determine the exact molecular mechanism by which ERα improves hepatic metabolic health.

Background: A dysregulated proinflammatory microenvironment is considered one of the reasons why current therapies of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) do not secure disease control. Therefore, the development of BCR-ABL1-independent therapies is encouraged. Renalase (RNLS) is a multifunctional protein that exhibits both enzymatic and non-enzymatic cytokine-like properties, along with potent anti-inflammatory and anti-apoptotic effects. It is expressed in various tissues, including tumors. Methods: We investigated the levels of RNLS in the blood of CML patients in the chronic phase, treatment naïve patients, and those in remission under TKI treatment (either imatinib or nilotinib) and compared them to healthy individuals. Results: Renalase concentration was markedly decreased in treatment-naive CML patients compared to other groups (p = 0.000), while lower levels in the TKI group were not statistically significant compared to controls. The levels correlated negatively with the total leukocyte and neutrophil count (p < 0.05), while a positive correlation was present with CRP levels in treatment naïve patients. Conclusions: Dynamic regulation of RNLS expression and activity is coupled with transcription factors NF-κB and STAT3. Interpretation of our results might rely on differential requirements of activated STATs (STAT3/5) during CML clone development and maintenance, including the observation of RNLS rise upon TKI introduction. Overall, our research provides new insights into the field of hematological malignancies. Unlike other malignancies studied, RNLS plasma levels are significantly decreased in CML. In future perspectives, RNLS could potentially serve as a diagnostic, prognostic, or therapeutic option for these patients.

Chronic Kidney Disease of Unknown Etiology (CKDu) is a worldwide hidden health threat that is associated with progressive loss of kidney functions without showing any initial symptoms until reaching end-stage renal failure, eventually leading to death. It is a growing health problem in Asia, Central America, Africa, and the Middle East, with identified hotspots. CKDu disease mainly affects young men in rural farming communities, while its etiology is not related to hypertension, kidney stones, diabetes, or other known causes. The main suspected causal factors are heat-stress, dehydration, exposure to agrochemicals, heavy metals and use of hard water, infections, mycotoxins, nephrotoxic agents, altitude, and genetic factors. This review gives an overview of CKDu and sheds light on its medical history, geographic distribution, and worldwide prevalence. It also summarizes the suspected causal factors, their proposed mechanisms of action, as well as the main methods used in the CKDu prior detection and surveillance. In addition, mitigation measures to reduce the burden of CKDu are also discussed. Further investigation utilizing more robust study designs would provide a better understanding of the risk factors linked to CKDu and their comparison between affected regions.

Post-Traumatic Stress Disorder (PTSD) is a multifaceted psychiatric disorder triggered by traumatic events, leading to prolonged psychological distress and varied symptoms. Rat models have been extensively used to explore the biological, behavioral, and neurochemical underpinnings of PTSD. This review critically examines the strengths and limitations of commonly used rat models, such as single prolonged stress (SPS), stress-re-stress (S-R), and predator-based paradigms, in replicating human PTSD pathology. While these models provide valuable insights into neuroendocrine responses, genetic predispositions, and potential therapeutic targets, they face challenges in capturing the full complexity of PTSD, particularly in terms of ethological relevance and translational validity. We assess the degree to which these models mimic the neurobiological and behavioral aspects of human PTSD, highlighting areas where they succeed and where they fall short. This review also discusses future directions in refining these models to improve their utility for translational research, aiming to bridge the gap between preclinical findings and clinical applications.

Histomorphometric measurements of the wall thickness and internal diameter of the macrovessels of the chorionic villi of placentas from pregnancies complicated by preeclampsia or fetal growth restriction in comparison with normotensive pregnancy.

Methods: The research included placentas from singleton pregnancies complicated by preeclampsia and/or fetal growth restriction, women delivered in medical institutions in Karaganda city (Kazakhstan). Placentas were divided into three groups: PE (n = 59), isolated FGR (n = 24), and PE with FGR (n = 41). The control group consisted of normotensive pregnancies, compared by gestation period. Placental examination and selection of placental tissue fragments were carried out in accordance with the consensus recommendations of the Amsterdam Placental Workshop Group. The sections were stained with hematoxylin and eosin and Masson trichrome. Morphometric measurements were performed using ImageJ software version 1.52p.

Results: Our data showed that, in the PE group, there was a significant decrease in the wall thickness of the proximal and distal vessels with an increase in internal diameter compared with the control group (p < 0.01). In the PE + FGR group, there was a thickening of the wall of the proximal part of the vessels with a decrease in their lumen and a decrease in the wall thickness of the vessels with an increase in the lumen in the distal part compared with the control group (p < 0.01).

Conclusions: Two histopatterns of placental macrovessels in preeclampsia were revealed: the histophenotype of diffuse (proximal and distal) ectatic macroangiopathy with a thin vascular wall with a decrease in the thickness of the muscle layer and the histophenotype of proximal fibromuscular sclerosis with vascular obliteration/spasm and distal ectatic macroangiopathy. We believe that significant structural differences in vascular remodeling may reflect the different temporal and spatial nature of the pathological factor. Future research is needed to investigate the associations between histopatterns of placental vascular remodeling in preeclampsia and long-term perinatal/maternal outcomes.

Aim: To investigate the anti-inflammatory, antioxidant, and diabetic wound healing properties of the novel topical formulation [Ferulic acid-loaded nanoemulgel (DLMGO-G)]. Methods: Ferulic acid nanoemulsion developed with lemongrass oil is investigated in diabetic wound healing. Further nanoemulsion is incorporated into 1% carbopol^® 934 to obtain the DLMGO-G. Nanoemulsion was characterized for particle size, and polydispersity index (PDI) was obtained by Malvern Zetasizer (Zetasizer Nano ZS, Malvern, AL, USA), and morphology by TEM (JEM 1400, JOEL, Akishima, Japan). Furthermore, in vitro cell line and in vivo studies were carried out. Results: The developed nanoemulsion showed a globule size of 28.04 ± 0.23 nm and PDI of 0.07 ± 0.01. The morphology of nanoformulations by TEM confirmed the spherical and uniform nature. Further, the nanoformulation in in vitro cell line experiments revealed that the IC50 value was increased by 1.52 times compared to the drug solution. The treatment groups have shown that fibroblast morphologies were spindle-shaped, suggesting that nanoformulation was compatible with the cells and developed normally on nanoformulation. It also reduced ROS with improved internalization more than the control group. The in vitro wound healing model also revealed that nanoformulation had better wound healing activity. In the in vivo diabetic wound studies on male SD rats, the levels of inflammatory markers such as TNF-α, IL-6, IL-22, and IL-1β declined significantly when treated with DLMGO-G. IL-10 levels significantly increased compared to the diseased group, and MMP-9 levels were remarkably decreased compared to the diseased group. Furthermore, histopathological studies showed the regeneration and granulation of tissues. Conclusions: Thus, these findings indicate that FA-loaded nanoemulgel greatly accelerates the healing of wounds in diabetic rats.

Background/objectives: Vitamin D (VD) deficiency has been associated with increased risk of gestational disorders affecting the endocrine system, immune system, and neurodevelopment in offspring. Recent studies have focused on the interaction between toxic elements and micronutrients during pregnancy. This review analyzes the potential relationships between VD levels and heavy metals in pregnant women and their offspring.

Methods: A systematic review was conducted according to PRISMA 2020 guidelines, using databases such as PubMed, ScienceDirect, Cochrane Library, and Google Scholar. Boolean operators 'AND' and 'OR' were applied with terms like 'pregnancy', 'vitamin D', 'heavy metals', and 'newborns'.

Results: From 4688 articles, 14 studies were selected based on relevance and quality. These studies measured the levels of metals like lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), in biological samples including maternal blood, umbilical cord blood, placenta tissue, and meconium during different stages of pregnancy, showing an inverse relationship between VD deficiency and heavy metal concentrations, which could be related to the incidence of preterm birth.

Conclusions: The review highlights the importance of maintaining adequate VD levels during pregnancy, suggesting that sufficient VD may mitigate the adverse effects of heavy metal exposure, potentially reducing pregnancy-related complications.