Developing and validating clinical models to identify candidates for allergic rhinitis pre-exposure prophylaxis.

PURPOSE: Few risk-forecasting models of allergic rhinitis (AR) exist that may aid AR pre-exposure prophylaxis (PrEP) in clinical practice. Therefore, this study aimed to develop and validate an effective clinical model for identifying candidates for AR PrEP using a routine medical questionnaire. METHODS: This study was conducted in 10 Chinese provinces with 13 medical centers (n = 877) between 2019 and 2021. Clinical characteristics and exposure history were collected via face-to-face interviews. Well-trained physicians diagnosed patients with AR based on skin prick test results and clinical performance. The least absolute shrinkage and selection operator model was used to identify potential risk factors for AR, and the logistic regression model was used to construct the risk-forecasting model. Predictive power and model reliability were assessed using area under the receiver operating characteristic curve and calibration curves, respectively. RESULTS: This study diagnosed 625 patients with AR who had positive responses to at least one indoor or outdoor allergen and 460 to at least one outdoor pollen allergen. Two nomograms were established to identify two types of AR with various sensitization patterns. Both models had an area under curve of approximately 0.7 in the development and internal validation datasets. Additionally, our findings found good agreement for the calibration curves of both models. CONCLUSION: Early identification of candidates for AR PrEP using routine medical information may improve the deployment of limited resources and effective health management. Our models showed good performance in predicting AR; therefore, they can serve as potential automatic screening tools to identify AR PrEP candidates.

Effects of resveratrol supplementation on cardiac remodeling in hypertensive patients: a randomized controlled clinical trial.

Resveratrol (RES) has been demonstrated to be protective in the cardiovascular system in animal studies, but the evidence is limited in humans. The purpose of the study was to evaluate the effect of RES supplementation on cardiac remodeling in patients with hypertension. Eighty Subjects were randomly divided into RES group (plus RES 400 mg/d in addition to conventional therapy, n = 43) and control group (conventional therapy, n = 37). The main outcomes of the study were changes within cardiac-remodeling parameters. Secondary outcomes were changes in anthropometric parameters, arterial stiffness parameters and mechanism indices. There was no statistically significant difference between the RES group and control group in terms of baseline characteristics. After 6 months, the RES group had smaller left atrial, lower E/e', higher left ventricular global longitudinal strain and lower biomarkers indicating cardiac fibrosis (expressed by decreases in procollagen type I C-peptide and galectin-3) compared to the control group. However, there was no significant difference in left ventricular structure between the two groups. Although the RES group showed a significant decrease in brachial-ankle pulse wave velocity compared to the pre-intervention value, the difference between the RES and the control groups was not obvious. What's more, compared with the control group, the serum levels of sirtuin3, superoxide dismutase and klotho were significantly increased in the RES group. In conclusion, RES supplementation can alleviate left atrial remodeling, improve left ventricular diastolic function and may alleviate cardiac fibrosis in hypertensive patients, and could be used as an adjunct to conventional therapies of hypertensive heart disease.

Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis.

Male reproductive health is critically worsening around the world. It has been reported that the mycotoxin ZEA causes reproductive toxicity to domestic animals and affects spermatogenesis, thereby inhibiting male reproductive function. Ferroptosis is a newly identified type of programmed cell death that is different from apoptosis and it depends on iron accumulation and lipid peroxidation. Whether ferroptosis is linked to ZEA's detrimental effect on spermatogenesis needs to be further explored. This study clarifies ferroptosis's involvement in ZEA-induced damage on spermatogenesis. The reproductive injury model used in this study was induced by gavaging male mice in the ZEA treatment group with 30 µg/kg of ZEA for five weeks. Results show that ZEA treatment reduced mouse sperm motility and concentration, destroyed the structure of the seminiferous tubules of the testis, damaged the antioxidant defense system, and blocked spermatogenesis. Ferrostatin-1 (Fer-1) inhibition of ferroptosis partially alleviated ZEA-induced oligozoospermia in mice. In addition, ZEA treatment was found to activate a signaling pathway associated with ferroptosis in mouse testis. ZEA also downregulated the expression of Nrf2, SLC7A11, and GPX4, and decreased the protein expression of SLC7A11 and GPX4, resulting in the accumulation of lipid peroxides and an increase in the level of 4-HNE protein in the testis. Importantly, these changes were accompanied by an increase in the relative contents of Fe2+ and Fe3+. Iron accumulation and lipid peroxidation are the causes of ferroptosis in spermatogenic cells, leading to a decrease in sperm motility and concentration. While the administration of Fer-1 at 0.5 and 1 mg/kg also increased the expression of SLC7A11 and GPX4 proteins by upregulating Nrf2 expression, reducing iron accumulation, and reversing ZEA-induced ferroptosis, Fer-1 at 1.5 mg/kg had the best repairing effect for all parameters. In conclusion, ZEA-induced ferroptosis may be mediated by a notable reduction in Nrf2, SLC7A11 and GPX4 expression levels. Overall, ferroptosis is a novel therapeutic target for mitigating ZEA-induced reproductive toxicity.

Gut Microbiota-Testis Axis: FMT Mitigates High-Fat Diet-Diminished Male Fertility via Improving Systemic and Testicular Metabolome.

High-fat diet (HFD)-induced obesity is known to be associated with reduced male fertility and decreased semen quality in humans. HFD-related male infertility is a growing issue worldwide, and it is crucial to overcome this problem to ameliorate the distress of infertile couples. For the first time, we discovered that fecal microbiota transplantation (FMT) of alginate oligosaccharide (AOS)-improved gut microbiota (A10-FMT) ameliorated HFD-decreased semen quality (sperm concentration: 286.1 ± 14.1 versus 217.9 ± 17.4 million/mL; sperm motility: 40.1 ± 0.7% versus 29.0 ± 0.9%), and male fertility (pregnancy rate: 87.4 ± 1.1% versus 70.2 ± 6.1%) by benefiting blood and testicular metabolome. A10-FMT improved HFD-disturbed gut microbiota by increasing gut Bacteroides (colon: 24.9 ± 1.1% versus 8.3 ± 0.6%; cecum: 10.2 ± 0.7% versus 3.6 ± 0.7%) and decreasing Mucispirillum (colon: 0.3 ± 0.1% versus 2.8 ± 0.4%; cecum: 2.3 ± 0.5% versus 6.6 ± 0.7%). A10-FMT benefited gut microbiota to improve liver function by adjusting lipid metabolism to produce n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (blood: 55.5 ± 18.7 versus 20.3 ± 2.4) and docosahexaenoic acid (testis: 121.2 ± 6.2 versus 89.4 ± 6.7), thus ameliorating HFD-impaired testicular microenvironment to rescue spermatogenesis and increase semen quality and fertility. The findings indicated that AOS-improved gut microbiota may be a promising strategy to treat obesity or metabolic issues-related male infertility in the future. IMPORTANCE HFD decreases male fertility via upsetting gut microbiota and transplantation of AOS-benefited gut microbiota (A10-FMT) improves gut microbiota to ameliorate HFD-reduced male fertility. Moreover, A10-FMT improved liver function to benefit the blood metabolome and simultaneously ameliorated the testicular microenvironment to turn the spermatogenesis process on. We demonstrated that AOS-benefited gut microbiota could be applied to treat infertile males with obesity and metabolic issues induced by HFD.

Muscarinic acetylcholine receptor M5 is involved in spermatogenesis through the modification of cell-cell junctions.

Muscarinic acetylcholine receptor (mAChR) antagonists have been reported to decrease male fertility; however, the roles of mAChRs in spermatogenesis and the underlying mechanisms are not understood yet. During spermatogenesis, extensive remodeling between Sertoli cells and/or germ cells interfaces takes place to accommodate the transport of developing germ cells across the blood-testis barrier (BTB) and adluminal compartment. The cell-cell junctions play a vital role in the spermatogenesis process. This study used ICR male mice and spermatogonial cells (C18-4) and Sertoli cells (TM-4). shRNA of control or M5 gene was injected into 5-week-old ICR mice testes. Ten days post-viral grafting, mice were deeply anesthetized with pentobarbital and the testes were collected. One testicle was fresh frozen for RNA-seq analysis or Western blotting (WB). The second testicle was fixed for immunofluorescence staining (IHF). C18-4 or TM-4 cells were treated with shRNA of control or M5 gene. Then, the cells were collected for RNA-seq analysis, WB, or IHF. Knockdown of mAChR M5 disrupted mouse spermatogenesis and damaged the actin-based cytoskeleton and many types of junction proteins in both Sertoli cells and germ cells. M5 knockdown decreased Phldb2 expression in both germ cells and Sertoli cells which suggested that Phldb2 may be involved in cytoskeleton and cell-cell junction formation to regulate spermatogenesis. Our investigation has elucidated a novel role for mAChR M5 in the regulation of spermatogenesis through the interactions of Phldb2 and cell-cell junctions. M5 may be an attractive future therapeutic target in the treatment of male reproductive disorders.

Giant Paraganglioma Complicated With Catecholamine Crisis and Catecholamine Cardiomyopathy: A Case Report and Review of the Literature.

Background: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors which overproduce catecholamines. Heart failure and myocardial infarction caused by paraganglioma complicated with catecholamine crisis are the most common causes of death in PPGL patients before surgery. When giant paraganglioma is complicated with catecholamine crisis, treatment brooks no delay. Case Summary: A 49-year-old man had episodic sweating, tachycardia with irregular pulse, and headaches 5 days before, and then showed up with chest pain and wheezing for 1 day. Meanwhile, he developed symptoms of recurrent severe abdominal pain and loss of consciousness, and his blood pressure was severely unstable (from 70/40 to 300/200 mmHg). First, the electrocardiogram showed ventricular tachycardia, and then we noticed the waves of ST-segment elevation, but we did not find significant abnormalities in coronary angiography. Abdominal CT and MRI revealed a giant lesion with bleeding or infection in the retroperitoneal adrenal area. These imaging findings were confirmed during surgery, and there was vascular adhesion between the retroperitoneal tumor and the inferior vena cava and left and right renal vein. After the successful resection of the tumor, postoperative pathology confirmed paraganglioma, and the patient pulled through and was discharged quickly. Discussion: This is a rare case of giant paraganglioma complicated with catecholamine crisis and catecholamine cardiomyopathy. We can diagnosis this disease greatly by elevated norepinephrine, and it is a gold biochemical standard at present. Standard treatment is surgical resection, which is effective in treating this rare neuroendocrine tumor.

Impact of siRNA targeting of ß-catenin on differentiation of rat neural stem cells and gene expression of Ngn1 and BMP4 following in vitro hypoxic-ischemic brain damage.

The aim of the present study was to investigate the possible damage-repair mechanisms of neural stem cells (NSCs) following hypoxic-ischemic brain damage (HIBD). NSCs obtained from Sprague Dawley rats were treated with tissue homogenate from normal or HIBD tissue, and ß­catenin expression was silenced using siRNA. The differentiation of NSCs was observed by immunofluorescence, and semiquantitative reverse transcription­polymerase chain reaction and western blot analysis were applied to detect the mRNA and protein expression levels of Ngn1 and BMP4 in the NSCs. Compared with control NSCs, culture with brain tissue homogenate significantly increased the differentiation of NSCs into neurons and oligodendrocytes (P<0.05), whereas differentiation into astrocytes was significantly reduced (P<0.05). Compared with negative control­transfected cells, knockdown of ß­catenin expression significantly decreased the differentiation of NSCs into neurons and oligodendrocytes (P<0.01), whereas the percentage of NSCs differentiated into astrocytes was significantly increased (P<0.01). Compared with control NSCs, the mRNA and protein expression levels of Ngn1 were significantly increased (P<0.01) and BMP4 levels were significantly reduced (P<0.01) by exposure of the cells to brain tissue homogenate. Compared with the negative control plasmid­transfected NSCs, the levels of Ngn1 mRNA and protein were significantly reduced by ß­catenin siRNA (P<0.01), whereas BMP4 levels were significantly increased (P<0.01). In summary, the damaged brain tissues in HIBD may promote NSCs to differentiate into neurons for self­repair processes. ß­Catenin, BMP4 and Ngn1 may be important for the coordination of NSC proliferation and differentiation following HIBD.

[Correlation between insulin resistance and myocardial injury in critically ill children].

OBJECTIVE: To study the relationship between insulin resistance and myocardial injury in children with critical diseases in light of the fact that such children usually suffer from noticeable insulin resistance and myocardial injury. METHODS: Sixty-three children with critical diseases who were admitted between March 2010 and June 2011 were enrolled to comprise a case group. Fasting blood glucose, serum insulin, myocardial enzyme, and troponin I (CTnI) levels were measured. The insulin resistance index (HOMA-IR) was calculated. The children were classified into two groups: insulin resistance (HOMA-IR>1.0; n=30) and non-insulin resistance (HOMA-IR≤1.0; n=33). Thirty healthy children served as the control group. RESULTS: HOMA-IR, lactate dehydrogenase (LDH), aspartate aminotransferaseaspartate transaminase (AST), creatine kinase (CK), isoenzymes of creating kinase (CK-MB), α-hydroxybuty rate dehydrogenase (α-HBDH) and CTnI in the insulin resistance group were higher than those in the non-insulin resistance and the control groups (all P<0.05). The non-insulin resistance group also showed obviously higher levels in terms of LDH, AST, CK, CK-MB, α-HBDH, and CTnI than the control group (P<0.05). In the insulin resistance group, there exists a positive correlation between HOMA-IR and such indicators as LDH, CK, CK-MB, AST, α-HBDH and CTnI (r=0.697, 0.739, 0.781, 0.642, 0.381, 0.792 respectively; all P<0.05). CONCLUSIONS: Insulin resistance makes myocardial injury more serious; HOMA-IR can serve as a forecast indicator for the degree of myocardial injury.

[Efficacy of sublingual immunotherapy in children with dust mite allergic asthma].

OBJECTIVE: To compare the efficacy of sublingual immunotherapy (SLIT) combined with inhaled corticosteroids (ICS) versus ICS alone in children with mild and moderate dust mite allergic asthma. METHODS: Thirty-two children with mild and moderate dust mite allergic asthma were randomly divided into two groups: SLIT+ICS (n=18) and ICS alone (n=14). A total of 30 children completed the one year clinical observation . The amount of ICS administration, the day and night symptom scores, skin-prick test and pulmonary function test results, serum specific immunoglobulin E (sIgE) and G4 (sIgG4) levels and visual analog scale (VAS) scores were compared between the two groups. RESULTS: By the end of one year the SLIT+ICS group had significantly decreased amount of ICS administration than the ICS alone group. Compared with the ICS alone group, the day and night symptom scores decreased, FEF25-75% increased significantly, and serum sIgE levels and VAS scores were significantly reduced in the SLIT+ICS group. There were no statistical differences in the skin-prick test results, and FEV1 and sIgG4 levels between the two groups. No severe adverse events occurred in both groups during the follow-up period. CONCLUSIONS: SLIT combined with ICS may produce a better efficacy than ICS alone in the improvement of day and night symptoms, pulmonary function and VAS scores in children with dust mite-allergic asthma.