Metabolic Dysfunction-Associated Steatohepatitis Detected by Neutrophilic Crown-Like Structures in Morbidly Obese Patients: A Multicenter and Clinicopathological Study.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), and closely associated with a high risk of liver-related morbidity and mortality. Although enhanced neutrophil infiltration of the liver is a histological hallmark of MASH, the morphological pattern of hepatic neutrophils and their relevance to the definition of MASH remain unknown. This clinicopathological study aimed to determine the association of neutrophilic crown-like structures (CLSs) in liver biopsies and evaluate their relevance to the histological diagnosis of MASH. A total of 483 morbidly obese adults who underwent bariatric surgery were recruited. Neutrophilic CLSs in liver biopsies were detected by immunohistochemistry for neutrophil elastase and proteinase 3. All participants were classified into 4 histological subgroups: no MASLD (118, 24.4%), MASLD (76, 15.7%), borderline MASH (185, 38.3%), and definite MASH (104, 21.5%). In the discovery cohort (n = 379), the frequency of neutrophilic CLSs increased in line with the severity of liver disease. The number of neutrophilic CLSs was positively correlated with established histological characteristics of MASH. At a cutoff value of <0.3 per 20× microscopic field, the number of neutrophilic CLSs yielded a robust diagnostic accuracy to discriminate no MASLD and MASLD from borderline MASH and definite MASH; a cutoff at >1.3 per 20× microscopic field exhibited a statistically significant accuracy to distinguish definite MASH from other groups (no MASLD, MASLD, and borderline MASH). The significance of neutrophilic CLSs in identifying borderline MASH and definite MASH was confirmed in an external validation cohort (n = 104). The frequency of neutrophilic CLSs was significantly higher than that of macrophagic CLSs. In conclusion, neutrophilic CLSs in the liver represent a typical histological characteristic of MASH and may serve as a promising indicator to improve the diagnostic accuracy of MASH during histological assessment of liver biopsies.

A case report of anti-GAD65 antibody-positive autoimmune encephalitis in children associated with autoimmune polyendocrine syndrome type-II and literature review.

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

Identification and multicentric validation of soluble CDCP1 as a robust serological biomarker for risk stratification of NASH in obese Chinese.

The definitive diagnosis of non-alcoholic steatohepatitis (NASH) currently relies on invasive and labor-intensive liver biopsy. Here, we identified soluble CUB domain-containing protein 1 (sCDCP1) as a top-ranked non-invasive biomarker for NASH using Olink-based proteomics in 238 obese individuals with liver biopsies. Both the circulating concentration and hepatic mRNA abundance of sCDCP1 were significantly elevated in patients with NASH and correlated closely with each histological feature of NASH. In the pooled multicenter validation cohort, sCDCP1 as a standalone biomarker achieved an area under the receiver operating characteristic (AUROC) of 0.838 (95% confidence interval [CI] 0.789-0.887) for diagnosing NASH, which is better than those achieved with cytokeratin-18 and other non-invasive tests. Furthermore, the C-DAG model established by the combination of sCDCP1 with diabetes, aspartate aminotransferase (AST), and gender accurately rules in and rules out both NASH and fibrotic NASH (gray zones <20%). Thus, sCDCP1-based non-invasive tests can be potentially implemented for screening and early diagnosis of NASH and for ruling out low-risk individuals to avoid unnecessary liver biopsies.

Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2.

Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (Ldha), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1ß (IL-1ß). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1ß was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.

Beta-klotho in type 2 diabetes mellitus: From pathophysiology to therapeutic strategies.

Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), ß-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of ß-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of ß-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target ß-Klotho and/or the ß-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of ß-Klotho-based therapies.

COVID-19 and metabolic comorbidities: An update on emerging evidences for optimal therapies.

Type 2 diabetes mellitus, obesity, hypertension, and other associated metabolic complications have been demonstrated as a crucial contributor to the enhanced morbidity and mortality of patients with coronavirus disease 2019 (COVID-19). Data on the interplay between metabolic comorbidities and the outcomes in patients with COVID-19 have been emerging and rapidly increasing. This implies a mechanistic link between metabolic diseases and COVID-19 resulting in the exacerbation of the condition. Nonetheless, new evidences are emerging to support insulin-mediated aggressive glucose-lowering treatment as a possible trigger of high mortality rate in diabetic COVID-19 patients, putting the clinician in a confounding and difficult dilemma for the treatment of COVID-19 patients with metabolic comorbidities. Thus, this review discusses the pathophysiological link among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), metabolic complications, and severe inflammation in COVID-19 development, especially in those with multi-organ injuries. We discuss the influence of several routinely used drugs in COVID-19 patients, including anti-inflammatory and anti-coagulant drugs, antidiabetic drugs, renin-angiotensin-aldosterone system inhibitors. Especially, we provide a balanced overview on the clinical application of glucose-lowering drugs (insulin and metformin), angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers. Although there is insufficient evidence from clinical or basic research to comprehensively reveal the mechanistic link between adverse outcomes in COVID-19 and metabolic comorbidities, it is hoped that the update in the current review may help to better outline the optimal strategies for clinical management of COVID-19 patients with metabolic comorbidities.

Observe Impact Modified Guipitang Administration Combined with Hot Pressing of Traditional Chinese Medicine on Rehabilitation in Patients with Deficiency of Qi and Blood Syndrome Breast Cancer Postoperative / 中国实验方剂学杂志

Objective:To observe the rehabilitation effect of modified Guipitang administration combined with traditional Chinese medicine （TCM） hot pressing in patients with deficiency of Qi and blood syndrome breast cancer postoperative， and investigate its effect on immune function and tumor markers. Method:One hundred and fifty-four patients were divided into observation group （77 cases） and control group （77 cases） by random number table. Two groups were given comprehensive treatment measures after operation. Patients in control group additionally took Bazhen granules orally， 8 g/time， 2 times/day， for eight weeks. Patients in observation group additionally took Guipitang orally for syndrome differentiation， 1 dose/day for eight weeks. The chest， shoulders and upper limbs of the affected side were hot-pressed with TCM， 20 min/time， 2 times/ day， 5 days a week， the first 4 weeks. The occurrence of lymphedema， subcutaneous fluid， poor skin flap growth， sleep disturbance， shoulder joint dysfunction， etc. Were recorded in both groups. Before and after treatment， the scores of European organization for research and treatment of cancer quality of life questionnaire core-30（EORTC QLQ-30）， and scores of cancer-induced fatigue and Qi and blood deficiency were graded. T lymphocyte subsets （CD3⁺， CD4⁺， CD8⁺ levels and CD4⁺/CD8⁺）， regulatory T cells （Treg）， inhibitory T cells （Ts）， cytotoxic T cells （Tc）， human growth differentiation factor 3 （GDF3）， serum carbohydrate antigen 153 （CA153）， carcinoembryonic antigen （CEA） and human epidermal growth factor -2 （HER-2） levels were detected before and after treatment. Result:After treatment， the observation group incidence of lymphedema， subcutaneous effusion， poor skin flap growth， sleep disturbance and shoulder joint dysfunction was 8（10.39%）， 9（11.69%）， 11（14.29%）， 25（32.47%） and 8 （10.39%） respectively in the observation group， all lower than 18（23.38%）， 20（25.97%）， 23（29.87%）， 46（59.74%） and 19（24.68%） in the control group（<italic>P</italic><0.05， <italic>P</italic><0.01）. The scores of overall quality of life and function scores in the observation group were higher than those in the control group （<italic>P</italic><0.01）， hile symptom score was lower than that in the control group （<italic>P</italic><0.01）. The scores of cancer-induced fatigue deficiency of Qi and blood syndrome in the observation group were lower than those in the control group （<italic>P</italic><0.01）. The Tc， CD3⁺， CD4⁺， CD4⁺/CD8⁺ levels in the observation group were higher than those of the control group （<italic>P</italic><0.01）， while the Treg， Ts， CD8⁺ levels were lower than those in the control group （<italic>P</italic><0.01）. The GDF3， CA153， CEA， HER-2 levels in the observation group were lower than those in the control group （<italic>P</italic><0.01）. Conclusion:On the basis of conventional comprehensive interventions of western medicine， Guipitang combined with TCM hot pressing for breast cancer patients after surgery can reduce postoperative complications， reduce fatigue， postoperative symptoms and TCM syndromes. Besides， it can enhance the immune function of the body， improve the quality of life， promote postoperative recovery， and inhibit the expression of tumor markers， thus improving the prognosis of patients.

Complete genome of a unicellular parasite (Antonospora locustae) and transcriptional interactions with its host locust.

Microsporidia are a large group of unicellular parasites that infect insects and mammals. The simpler life cycle of microsporidia in insects provides a model system for understanding their evolution and molecular interactions with their hosts. However, no complete genome is available for insect-parasitic microsporidian species. The complete genome of Antonospora locustae, a microsporidian parasite that obligately infects insects, is reported here. The genome size of A. locustae is 3 170 203 nucleotides, composed of 17 chromosomes onto which a total of 1857 annotated genes have been mapped and detailed. A unique feature of the A. locustae genome is the presence of an ultra-low GC region of approximately 25 kb on 16 of the 17 chromosomes, in which the average GC content is only 20 %. Transcription profiling indicated that the ultra-low GC region of the parasite could be associated with differential regulation of host defences in the fat body to promote the parasite's survival and propagation. Phylogenetic gene analysis showed that A. locustae, and the microsporidian family in general, is likely at an evolutionarily transitional position between prokaryotes and eukaryotes, and that it evolved independently. Transcriptomic analysis showed that A. locustae can systematically inhibit the locust phenoloxidase PPO, TCA and glyoxylate cycles, and PPAR pathways to escape melanization, and can activate host energy transfer pathways to support its reproduction in the fat body, which is an insect energy-producing organ. Our study provides a platform and model for studies of the molecular mechanisms of microsporidium-host interactions in an energy-producing organ and for understanding the evolution of microsporidia.

Kinetics and model development of iohexol degradation during UV/H2O2 and UV/S2O82- oxidation.

The degradation rates and kinetics of one commonly used iodinated contrast medium, iohexol, were investigated and compared during ultraviolet (UV) photolysis, UV/H2O2 and UV/S2O82- advanced oxidation processes (AOPs). Results indicate that the iohexol degradation rate increased in the order of UV/H2O2 < UV irradiation < UV/S2O82- and followed pseudo-first-order kinetics. Increasing persulfate concentration significantly increased iohexol degradation rate, whereas increasing H2O2 concentration caused reverse effect. Radical scavenging test results show that UV photolysis, OH and radicals all contributed to iohexol degradation during UV/S2O82-, but OH was the main contributor during UV/H2O2 and was consumed by excess H2O2. The kinetic models of iohexol degradation by both AOPs were developed, and the reaction rate constants with OH and were calculated as 5.73 (±0.02) × 108 and 3.91 (±0.01) × 1010 M-1 s-1, respectively. Iohexol degradation rate remained stable at pH 5-9 during UV irradiation and UV/H2O2, but gradually decreased at pH 5-7 and remained stable at pH 7-9 during UV/S2O82-. The presence of anions displayed inhibitory effects on iohexol degradation during UV/S2O82- in the order of Cl- >HCO3- ≫ SO42-. UV/S2O82- AOP exhibited high degradation efficiency and stability on the basis of UV irradiation, which can be applied as a promising degradation method for iohexol. UV/S2O82- AOP can effectively mineralize iohexol to CO2 but promoted the generation of toxic iodoform (CHI3), and the subsequent chlorination had the potential to reduce the content of disinfection by-products; therefore, further evaluation of possible environmental hazards is warranted.

Enzymatic gene expression by Pleurotus tuoliensis (Bailinggu): differential regulation under low temperature induction conditions.

Pleurotus tuoliensis is a valuable, rare and edible mushroom that is been commercially cultivated and is rapidly developing in China markets. Low temperatures are required to induces primordia initiation for the successful production of fruiting bodies (basidiomes) during commercial cultivation. In this work, we investigated the enzymatic activities and performed transcription profiling analysis of enzymatic genes under different low temperature conditions. The results suggest that the enzymatic activities and transcription levels decrease or increase significantly at 4 and 13 °C. Lacc10 and mnp6 seems to play a dominant role during nutrition growth. Furthermore, the expression of laccase and peroxidase genes was highly correlated to the detected extracellular enzymatic activity. Cold stress genes expression profiles were upregulated under 4 °C/13 °C (3 days), while only the Hsp70 gene was downregulated (at the stage of fruiting bodies production) at 13 °C (12 days). Our results showed that the transcriptional regulation of laccase and ligninolytic peroxidase genes plays an important role in the fruiting bodies of Bailinggu under low temperature induction (4 °C). Induction at low temperatures was a highly important cultivation condition in Bailinggu.

[Spatial pattern of Sitodiplosis mosellana and its egg parasitoids mixed population].

Geostatistis methods were adopted to analyze the spatial pattern of Sitodiplosis mosellana (Diptera: Cecidomyiidae) at its different development periods and of its egg parasitoids mixed population (Tetrastichus sp. and Platygaster error; Hymoneptera: Eulophidae and Platygastridae). The aggregated spatial arrangements for S. mosellana cocoon, adult, and larva and for egg parasitoids mixed population could be well described by spherical model, spherical-exponential model, linear sill model, and spherical-exponential model, respectively. The spatial dependence range of S. mosellana cocoon, adult at initial emergence period, adult at peak emergence period, and larva, and of egg parasitoids mixed population was 53.6, 190.6, 154.1, 4.2 and 280.3 m, and the aggregation intensity was 30.5%, 95.6%, 96.3%, 14.9% and 95.3%, respectively. The simulated maps of the spatial distribution produced by Kriging model could intuitively analyze the dynamic changes of S. mosellana at its different development periods and of egg parasitoids mixed population from the two aspects of time and space.