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Background: Thrombotic microangiopathy (TMA) is a rare side effect of interferon-beta (IFN-β) therapy. The clinical characteristics of IFN-β-induced TMA are unknown. Objectives: To explore the clinical characteristics of IFN-β-induced TMA and provide reference for the prevention of TMA. Design: Articles on IFN-β-induced TMA were collected by searching the literature in relevant Chinese and English databases from inception to 31 July 2023. Methods: Data in the articles were extracted and analyzed retrospectively. Results: Forty-seven patients, with a median age of 41 years (range 22, 66), were included in the analysis. The median time to the diagnosis of IFN-β-induced TMA was 8 years (range 0.1–30) after administration. The main clinical symptoms were neurological symptoms (51.1%), hypertension (78.7%), dyspnea (19.1%), edema (19.1%), asthenia/fatigue (19.1%), and digestive symptoms (17.0%). Most patients presented with hemolytic anemia (76.6%), thrombocytopenia (63.8%), and acute kidney injury (70.2%). All patients stopped IFN-β and received plasma exchange therapy (53.2%), systemic steroids (46.8%), antihypertensive therapy (46.8%), eculizumab (12.8%), and rituximab (12.8%). Kidney damage was not completely reversible; 40.4% of patients achieved renal function and hematology remission, 27.7% developed chronic kidney disease, 25.5% developed end-stage renal disease, and 2.1% died. Conclusion: IFN-β-induced TMA is a rare but serious complication that can be life-threatening. It may occur after many years of IFN-β therapy, and patients taking IFN-β should be monitored for symptoms such as headache and hypertension. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a rare but life-threatening adverse event with pembrolizumab. What is known about pembrolizumab-induced MG is largely based on case reports. This analysis collected pembrolizumab-induced MG cases from Chinese and English databases published from September 1, 2014, to June 30, 2022. Demographic and clinical information of the patients, management, and outcome data were collected and analyzed. Sixty-five patients with a median age of 73 years (range 30–86), including 43 male patients (66.2%), were included. Eight patients (12.3%) with prior MG experienced worsening symptoms after receiving pembrolizumab. The median time to the onset of MG was four weeks (range 0.7–27). The most common symptoms were ptosis (81.5%, 53 patients), diplopia (50.8%, 33 patients), dyspnea (44.6%, 29 patients), trunk or peripheral weakness (43.1%, 28 patients), and dysphagia (30.8%, 20 patients). Concurrent myositis and myocarditis occurred in 13 (20.0%) and 17 patients (26.2%). Pembrolizumab was discontinued in 63 patients (96.9%). Forty-four patients (67.7%) received combination therapies based on steroids (intravenous immune globulin, plasmapheresis, or immunosuppressants). Twenty-seven patients (41.5%) had symptoms completely recovered. Fourteen patients (21.5%) died from immunotoxicity or primary cancers. Clinicians should consider the possibility of pembrolizumab-induced MG, especially during the first eight weeks of therapy. Patients should be treated as early as possible, regardless of the severity of the initial symptoms. Considering an increasing number of reported cases with pembrolizumab induced MG, clinicians need to be more aware of this phenomenon. Pembrolizumab induced MG treatment usually occurs within 8 weeks after administration. The primary treatment for pembrolizumab induced MG is steroids. Other treatments include intravenous immunoglobulin, plasmapheresis, and immunomodulators such as rituximab and cyclosporine [ABSTRACT FROM AUTHOR]

It is well known that the lipotoxic mechanism of palmitic acid (PA), a main constituent of triglyceride, is dependent on reactive oxygen species (ROS). Recently, it has also been reported that PA is an autophagy inducer. However, the causal association and underlying mechanism of induced autophagy and ROS in PA toxicity remain unclear. The present study demonstrates for the first time that PA-induced autophagy enhances ROS generation via activating the calcium ion/protein kinase Cα/nicotinamide adenine dinucleotide phosphate oxidase 4 (Ca2+/PKCα/NOX4) pathway in human umbilical vein endothelial cells (HUVECs). It was revealed that PA treatment resulted in a significant increase in ROS generation and autophagic activity, leading to endothelial dysfunction as indicated by downregulated nitric oxide synthesis, decreased capillary-like structure formation and damaged cell repair capability. Furthermore, PA effectively activated the Ca2+/PKCα/NOX4 pathway, which is indicative of upregulated cytosolic Ca2+ levels, activated PKCα and increased NOX4 protein expression. 3-Methyladenine was then used to inhibit autophagy, which significantly reduced PA-induced ROS generation and blocked the Ca2+/PKCα/NOX4 pathway. The endothelial dysfunction caused by PA was ameliorated by downregulating ROS generation using a NOX4 inhibitor. In conclusion, PA-induced autophagy contributes to endothelial dysfunction by increasing oxidative stress via the Ca2+/PKCα/NOX4 pathway in HUVECs. [ABSTRACT FROM AUTHOR]

The dipeptidyl peptidase 4 inhibitor vildagliptin (VLD), a widely used anti‐diabetic drug, exerts favourable effects on vascular endothelium in diabetes. We determined for the first time the improving effects of VLD on mitochondrial dysfunction in diabetic mice and human umbilical vein endothelial cells (HUVECs) cultured under hyperglycaemic conditions, and further explored the mechanism behind the anti‐diabetic activity. Mitochondrial ROS (mtROS) production was detected by fluorescent microscope and flow cytometry. Mitochondrial DNA damage and ATP synthesis were analysed by real time PCR and ATPlite assay, respectively. Mitochondrial network stained with MitoTracker Red to identify mitochondrial fragmentation was visualized under confocal microscopy. The expression levels of dynamin‐related proteins (Drp1 and Fis1) were determined by immunoblotting. We found that VLD significantly reduced mtROS production and mitochondrial DNA damage, but enhanced ATP synthesis in endothelium under diabetic conditions. Moreover, VLD reduced the expression of Drp1 and Fis1, blocked Drp1 translocation into mitochondria, and blunted mitochondrial fragmentation induced by hyperglycaemia. As a result, mitochondrial dysfunction was alleviated and mitochondrial morphology was restored by VLD. Additionally, VLD promoted the phosphorylation of AMPK and its target acetyl‐CoA carboxylase in the setting of high glucose, and AMPK activation led to a decreased expression and activation of Drp1. In conclusion, VLD improves endothelial mitochondrial dysfunction in diabetes, possibly through inhibiting Drp1‐mediated mitochondrial fission in an AMPK‐dependent manner. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) contributes to dysfunction of endothelial cells via its receptor, Fn14. However, its role in the production of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS) and the subsequent decrease in nitric oxide (NO) in endothelial cells remains unclear. In this study, the effect of TWEAK/Fn14 on generation of ROS, mtROS and NO in endothelial cells and its potential mechanism was investigated. Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK with Fn14 small interfering (si)RNA or negative control RNA. It was demonstrated that TWEAK induced the production of ROS and mtROS in HUVECs, which were detected by fluorescent microscope, and flow cytometry. In addition, TWEAK decreased the generation of NO as indicated using the Nitric Oxide Assay kit. Furthermore, TWEAK aggravated mtDNA damage as measured by quantitative polymerase chain reaction analysis. Inhibition of Fn14 by Fn14 siRNA decreased TWEAK-induced ROS and mtROS production, as well as mtDNA damage, while it increased the production of NO in endothelial cells. In addition, TWEAK inhibited the expression of active AMP-activated protein kinase (AMPK) and its downstream protein peroxisome proliferator-activated receptor-γ coactivator-1a (PGC-1a) and manganese superoxide dismutase (MnSOD). Notably, Fn14 siRNA enhanced the expression of the aforementioned proteins. Taken together, TWEAK/Fn14 contributes to endothelial dysfunction through modulation of ROS and mtROS. In addition, the underlying mechanism is implicated in the AMPK/PGC-1a/MnSOD signaling pathway. [ABSTRACT FROM AUTHOR]

Objectives: Trimethylamine oxide (TMAO) is a metabolite of intestinal flora and is known to promote the progression of atherosclerotic plaques. However, how TMAO works, including its effect on vascular endothelial cells, is not fully understood. This study aims to explore the biological role of TMAO in human umbilical vein endothelial cells (HUVECs) and the underlying mechanism., Methods: Cell pyroptosis and the loss of plasma membrane integrity were induced under TMAO stimulation in HUVECs. The plasma membrane integrity of the cells was measured by Hoechst 33342/propidium iodide (PI) staining and lactate dehydrogenase leakage assay, and the changes in cell morphology were observed by atomic force microscope. The expression of proteins related to pyroptosis was determined by Western blotting or immunofluorescence. Mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) activity in HUVECs was measured by the ALDH2 activity assay kit, and the level of reactive oxygen species (ROS) was detected by fluorescent probe DCFH-DA., Results: TMAO induced pyroptotic cell death, manifesting by the presence of propidium iodide-positive cells, the leakage of lactate dehydrogenase, the production of N-terminal gasdermin D (GSDMD-N), and the formation of plasma membrane pores. Moreover, TMAO induced elevated expression of inflammasome components, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 in cells. TMAO significantly inhibited ALDH2 activity and increased intracellular ROS production. However, the activation of ALDH2 by pharmacological manipulation attenuated TMAO-induced inflammasome activation and GSDMD-N production., Conclusions: TMAO induces pyroptosis of vascular endothelial cells through the ALDH2/ROS/NLRP3/GSDMD signaling pathway, which may be a potential therapeutic target for improving the treatment of atherosclerosis.

Objective: To carry out cyto- and molecular genetic testing for a child featuring facial dysmorphism and attention deficit and hyperactive disorder., Methods: The child was subjected to routine peripheral blood lymphocyte chromosomal karyotyping, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array) analyses., Results: The child's facial dysmorphism included low-set ears, curly ear auricle, protuberance of eyebrow arch, nostril notch, short and flat philtrum and thin upper lip. SNP-array revealed that he has carried a 4.883 Mb deletion at 2q37. His chromosomal karyotype was ultimately determined as 45, XY, der(2;21) (2pter→ 2q37.3::21p13→ 21p10::20p10→ 20pter), der(20) (21qter→ 21q10::20q10→ 20qter)., Conclusion: A rare case of 2q37 deletion syndrome involving three chromosomes was discovered. Combined use of various cyto- and molecular genetic techniques is crucial for the diagnosis of chromosomal abnormalities with complex structures.

Treatment-induced neuropathy is an distinct, acute form of neuropathic pain which often occur shortly after initiation of intensive glycemic control and is characterized by excruciating neuropathic pain. It is a rare form of diabetic neuropathy and easy to be misdiagnosed. Clinical characteristics were analyzed based on two cases of treatment-induced neuropathy in diabetes accepted by the Third Xiangya Hospital of Central South University. It is proposed that strict glycemic control may lead to the occurrence of the disease. At Present, the pathogenesis is still unclear. Besides, the morbidity is much higher than we expected. It is important to improve the doctors awareness of this disease and avoid the the disease through carful glycemic control.

It is well known that the lipotoxic mechanism of palmitic acid (PA), a main constituent of triglyceride, is dependent on reactive oxygen species (ROS). Recently, it has also been reported that PA is an autophagy inducer. However, the causal association and underlying mechanism of induced autophagy and ROS in PA toxicity remain unclear. The present study demonstrates for the first time that PA-induced autophagy enhances ROS generation via activating the calcium ion/protein kinase Cα/nicotinamide adenine dinucleotide phosphate oxidase 4 (Ca 2+ /PKCα/NOX4) pathway in human umbilical vein endothelial cells (HUVECs). It was revealed that PA treatment resulted in a significant increase in ROS generation and autophagic activity, leading to endothelial dysfunction as indicated by downregulated nitric oxide synthesis, decreased capillary-like structure formation and damaged cell repair capability. Furthermore, PA effectively activated the Ca 2+ /PKCα/NOX4 pathway, which is indicative of upregulated cytosolic Ca 2+ levels, activated PKCα and increased NOX4 protein expression. 3-Methyladenine was then used to inhibit autophagy, which significantly reduced PA-induced ROS generation and blocked the Ca 2+ /PKCα/NOX4 pathway. The endothelial dysfunction caused by PA was ameliorated by downregulating ROS generation using a NOX4 inhibitor. In conclusion, PA-induced autophagy contributes to endothelial dysfunction by increasing oxidative stress via the Ca 2+ /PKCα/NOX4 pathway in HUVECs.

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder characterized by hypogonadotropic hypogonadism and olfactory dysfunction. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS), have been identified in a few KS patients with additional developmental defects including hearing loss. However, the understanding of SOX10 mutation associates with KS and other clinical consequences remains fragmentary. A 30-year-old Chinese male patient presented with no pubertal sex development when he was at the age of twelve years. Additionally, he showed anosmia, sensory deafness, and blue irises. Last year, he developed clinical symptoms of hyperthyroidism with a fast heartbeat, heat intolerance and weight loss. Blood examinations revealed low levels of FSH, LH, and testosterone. Thyroid function showed high levels of FT3, FT4 and extremely low level of TSH. Molecular analysis detected a de novo (c.565G>T/p.E189X) mutation in SOX10, which has previously been reported in a patient with WS4 (WS with Hirschsprung). The mutation was predicted to be probably damaging. These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS. Importantly, our result implies that the same SOX10 mutation can underlie both typical KS and WS, while the correlation between SOX10 and hyperthyroidism still needs to be clarified in the future., (© 2018 by the Association of Clinical Scientists, Inc.)

Only a few previous studies have demonstrated an association between resistance to thyroid hormone (RTH) and thyroid cancer. The current study presents the case of a 67-year-old female who was referred to the Third Xiangya Hospital of Central South University with an enlargement of the neck that had grown gradually over two years and subsequently, rapidly enlarged over the two months prior to admission, alongside a slight sensation of shortness of breath. Laboratory data revealed a significantly increased level of thyroid-stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine, free thyroxine, thyroprotein and thyroglobulin antibody; however, the levels of thyroperoxidase and TSH receptor antibody were within the normal ranges. A thyroid hormone suppression test revealed a TSH reduction of 32%, Magnetic resonance imaging of the pituitary gland was negative for abnormalities. The patient's thyroid pathology revealed a non-Hodgkin's lymphoma of the thyroid. CHOP + nimustine chemotherapy significantly reduced the clinical symptoms. The genetic analysis revealed a novel point mutation of the thyroid hormone receptor β (THRB) gene in exon 10 (g1680 G to A) in the 3'-untranslated region of the patient. To the best of our knowledge, this is the first case report of RTH with thyroid non-Hodgkin's lymphoma, which involved a mutation (g1680 G to A) in exon 10 of THRB.