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Abstract Background Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma‐associated HLH (LA‐HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA‐HLH in the elderly population. Methods We retrospectively analyzed a multicenter cohort of elderly patients with LA‐HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed. Results A total of 173 elderly patients with LA‐HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B‐cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p 1407 U/L), and a higher creatinine level (>96.8 μmol/L) were independent predictors of decreased overall survival and 60‐day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60‐day survival of elderly patients with LA‐HLH. Conclusions LA‐HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA‐HLH.

Abstract Depression has become one of the most common mental illnesses in the world. For better prediction and diagnosis, methods of automatic depression recognition based on speech signal are constantly proposed and updated, with a transition from the early traditional methods based on hand‐crafted features to the application of architectures of deep learning. This paper systematically and precisely outlines the most prominent and up‐to‐date research of automatic depression recognition by intelligent speech signal processing so far. Furthermore, methods for acoustic feature extraction, algorithms for classification and regression, as well as end to end deep models are investigated and analysed. Finally, general trends are summarised and key unresolved issues are identified to be considered in future studies of automatic speech depression recognition.

Background Nitric oxide (NO) is the most important vasodilator secreted by vascular endothelial cells, and its abnormal synthesis is involved in the development of cardiovascular disease. The prenatal period is a critical time for development and largely determines lifelong vascular health in offspring. Given the high incidence and severity of gestational hypoxia in mid‐late pregnancy, it is urgent to further explore whether it affects the long‐term synthesis of NO in offspring vascular endothelial cells. Methods and Results Pregnant Sprague–Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. The thoracic aortas of fetal and adult male offspring were isolated for experiments. Gestational hypoxia significantly reduces the NO‐dependent vasodilation mediated by acetylcholine in both the fetal and adult offspring thoracic aorta rings. Meanwhile, acetylcholine‐induced NO synthesis is impaired in vascular endothelial cells from hypoxic offspring thoracic aortas. We demonstrate that gestational hypoxic offspring exhibit a reduced endothelial NO synthesis capacity, primarily due to increased expression of NADPH oxidase 2 and enhanced reactive oxygen species. Additionally, gestational hypoxic offspring show elevated levels of miR‐155‐5p in vascular endothelial cells, which is associated with increased expression of NADPH oxidase 2 and reactive oxygen species generation, as well as impaired NO synthesis. Conclusions The present study is the first to demonstrate that gestational hypoxia impairs endothelial NO synthesis via the miR‐155‐5p/NADPH oxidase 2/reactive oxygen species axis in offspring vessels. These novel findings indicate that the detrimental effects of gestational hypoxia on fetal vascular function can persist into adulthood, providing new insights into the development of vascular diseases.

Abstract Introduction Ferroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood–brain barrier (BBB) disruption followed by secondary iron‐loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron‐dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke–induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats. Methods We conducted the subcutaneous injection of 1.3 mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion–reperfusion (MCAO‐R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, 68Ga‐citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis‐related indexes. Results CSO treatment could significantly ameliorate MCAO‐R‐induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up‐regulated anti‐ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down‐regulating ferroptosis‐related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment. Conclusion CSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.

Abstract Background The rapidly increasing case reports revealed that neuronal intranuclear inclusion disease (NIID) had concomitant other system symptoms besides nervous system symptoms. In this study, we systematically evaluated the symptoms, signs, auxiliary examination, and pathological changes in different systems in NIID patients. Methods NIID patients were confirmed by examining GGC repeats in the NOTCH2NLC gene. Clinical data of NIID patients including symptoms, signs, and auxiliary examinations were collected for analysis. Ubiquitin and p62 were detected in different tissues from previous surgical samples. Results Fifty‐one NIID patients from 17 families were included in this study. Except neurological symptoms, clinical manifestations from other systems were very notable and diverse. The proportions of different system symptoms were 88.2% in nervous system, 78.4% in respiratory system, 72.5% in circulatory system, 72.5% in locomotor system, 66.7% in urinary system, 64.7% in digestive system, 61.5% in reproductive system, and 50.0% in endocrine system. In addition, other common symptoms included sexual dysfunction (43.1%), pupil constriction (56.9%), blurred vision (51.0%), and hearing loss (23.5%). Ubiquitin and p62‐positive cells were found in different tissues and systems in 24 NIID patients with previous surgery. Initial symptoms of NIID and median onset age in different systems also revealed system heterogeneity of NIID. Interpretation For the first time, we systematically demonstrated that NIID is a heterogeneous and systemic neurodegenerative disease by providing clinical and pathological evidence. In addition to the nervous system, the clinical symptomatic and pathological spectrum of NIID has been extended to almost all systems.

Background Stroke is a sexually dimorphic disease and a leading cause of death and disability. Estrogen replacement therapy (ERT) confers beneficial neuroprotective effects if administered within a widely accepted time window called the “critical period.” However, very few studies have explored the idea of modulating the critical period to enable long‐term post‐menopausal women to regain more benefits from estrogen therapy. Here, motivated by previous findings that electroacupuncture could both alter estrogen metabolism and induce significant tolerance against stroke, it was explored whether EA could restore estrogen's neuroprotection against cerebral ischemia in long‐term ovariectomized (OVX) rats. Methods We implemented 1 week(w)‐EA pretreatment on OVX‐10w or OVX‐20w rats, and tested the expression of estrogen receptors, and detected the ERT's neuroprotection against stroke induced by middle cerebral artery occlusion (MCAO). Results We found that the expression levels of phospho‐ERα‐S118 and estrogen receptor β (ERβ) in the striatum of OVX‐10w rats were significantly decreased and ERT's neuroprotection was abolished in the OVX‐10w rats. However, EA‐1w pretreatment could significantly recover the expression levels of phospho‐ERα‐S118 and ERβ, and also restored the neuroprotective effects of ERT in OVX‐10w rats. However, EA‐1w pretreatment could not restore the expression of estrogen receptors and ERT's neuroprotection in OVX‐20w rats. Conclusion Taken together, our study indicates that EA may be an easy intervention that can restore the efficacy of estrogen therapy during the “critical period,” which has the potential to improve the stroke outcomes of an enormous number of long‐term post‐menopausal women. However, the time‐sensitive influences for how EA and estrogen metabolism interact with each other should be considered.

Background Antenatal intrauterine fetal hypoxia is a common pregnancy complication that has profound adverse effects on an individual's vascular health later in life. Pulmonary arteries are sensitive to hypoxia, but adverse effects of antenatal hypoxia on pulmonary vasoreactivities in the offspring remain unknown. This study aimed to determine the effects and related mechanisms of antenatal hypoxia on pulmonary artery functions in adult male offspring. Methods and Results Pregnant Sprague‐Dawley rats were housed in a normoxic or hypoxic (10.5% O2) chamber from gestation days 10 to 20. Male offspring were euthanized at 16 weeks old (adult offspring). Pulmonary arteries were collected for vascular function, electrophysiology, target gene expression, and promoter methylation studies. In pulmonary artery rings, contractions to serotonin hydrochloride, angiotensin II, or phenylephrine were reduced in the antenatal hypoxic offspring, which resulted from inactivated L‐type Ca2+ channels. In pulmonary artery smooth muscle cells, the basal whole‐cell Ca2+ currents, as well as vasoconstrictor‐induced Ca2+ transients were significantly reduced in antenatal hypoxic offspring. In addition, increased promoter methylations within L‐type Ca2+ channel subunit alpha1 C were compatible with its reduced expressions. Conclusions This study indicated that antenatal hypoxia programmed long‐lasting vascular hypocontractility in the male offspring that is linked to decreases of L‐type Ca2+ channel subunit alpha1 C in the pulmonary arteries. Antenatal hypoxia resulted in pulmonary artery adverse outcomes in postnatal offspring, was strongly associated with reprogrammed L‐type Ca2+ channel subunit alpha1 C expression via a DNA methylation‐mediated epigenetic mechanism, advancing understanding toward the effect of antenatal hypoxia in early life on long‐term vascular health.

Background Magnesium sulfate (MgSO4) has been used as a common therapy for preeclampsia and eclampsia for many years. MgSO4 decreases peripheral vascular resistance so as to reduce maternal blood pressure. Whether placental blood vessels react to MgSO4 in the same patterns as that in maternal vessels is largely unknown. Methods and Results This study compared placental vessels (PV) versus nonplacental vessels (non‐PV) in human and animal models. MgSO4‐caused vascular dilation was significantly weaker in PV than that in non‐PV. Prostaglandin I2 synthetase affected MgSO4‐mediated vasodilatation in PV, not in umbilical vessels, while cyclooxygenase did not influence MgSO4‐induced relaxation in both PV and non‐PV. Mg2+‐caused vasodilatation was mainly through calcium channels. In PV, calcium channel activities were significantly weaker in PV than that in non‐PV. Relative mRNA expression of CACNA1D, CACNB2, and CACNB3 was significantly higher in PV than those in umbilical vessels, despite the fact that the expression of CACNA1F was less in PV. The contractile phenotype of smooth muscle cell marker (CALD1) was less and the synthetic phenotype (MYH10) was more in PV than that in UV. Conclusions These results demonstrated that PV were characterized by much weaker responses to MgSO4 compared with nonplacental vessels. The difference was related to weaker calcium channel activity and minor contractile phenotype smooth muscle cells in PV, providing important information for further understanding treatments with MgSO4 in preeclampsia.

BackgroundHypoxia during pregnancy could cause abnormal development and lead to increased risks of vascular diseases in adults. This study determined angiotensin II (AII)‐mediated vascular dysfunction in offspring middle cerebral arteries (MCA). Methods and ResultsPregnant rats were subjected to hypoxia. Vascular tension in offspring MCA by AII with or without inhibitors, calcium channel activities, and endoplasmic reticulum calcium stores were tested. Whole‐cell patch clamping was used to investigate voltage‐dependent calcium channel currents. mRNA expression was tested using quantitative real‐time polymerase chain reaction. AII‐mediated MCA constriction was greater in male offspring exposed to prenatal hypoxia. AT1 and AT2 receptors were involved in the altered AII‐mediated vasoconstriction. Prenatal hypoxia increased baseline activities of L‐type calcium channel currents in MCA smooth muscle cells. However, calcium currents stimulated by AII were not significantly changed, whereas nifedipine inhibited AII‐mediated vasoconstrictions in the MCA. Activities of IP3/ryanodine receptor–operated calcium channels, endoplasmic reticulum calcium stores, and sarcoendoplasmic reticulum membrane Ca2+‐ATPase were increased. Prenatal hypoxia also caused dysfunction of vasodilatation via the endothelium NO synthase. The mRNA expressions of AT1A, AT1B, AT2R, Cav1.2α1C, Cav3.2α1H, and ryanodine receptor RyR2 were increased in the prenatal‐hypoxia group. ConclusionsHypoxia in pregnancy could induce dysfunction in both contraction and dilation in the offspring MCA. AII‐increased constriction in the prenatal‐hypoxia group was not mainly dependent on the L‐type and T‐type calcium channels; it might predominantly rely on the AII receptors, IP3/ryanodine receptors, and the endoplasmic reticulum calcium store as well as calcium ATPase.