Risk factors of neonatal stroke from different origins: a systematic review and meta-analysis.

Given the persistent ambiguity regarding the etiology of neonatal stroke across diverse origins, our objective was to conduct a comprehensive evaluation of both qualitative and quantitative risk factors. An exhaustive search of eight databases was executed to amass all pertinent observational studies concerning risk factors for neonatal stroke from various origins. Subsequent to independent screening, data extraction, and bias assessment by two researchers, a meta-analysis was conducted utilizing RevMan and Stata software. Nineteen studies, encompassing a total of 30 factors, were incorporated into this analysis. Beyond established risk factors, our investigation unveiled gestational diabetes (OR, 5.51; P < 0.00001), a history of infertility (OR, 2.44; P < 0.05), placenta previa (OR, 3.92; P = 0.02), postdates (OR, 2.07; P = 0.01), preterm labor (OR, 2.32; P < 0.00001), premature rupture of membranes (OR, 3.02; P = 0.007), a prolonged second stage of labor (OR, 3.94; P < 0.00001), and chorioamnionitis (OR, 4.35; P < 0.00001) as potential risk factors for neonatal cerebral arterial ischemic stroke. Additionally, postdates (OR, 4.31; P = 0.003), preterm labor (OR, 1.60; P < 0.00001), an abnormal CTG tracing (OR, 9.32; P < 0.0001), cesarean section (OR, 4.29; P = 0.0004), male gender (OR, 1.73; P = 0.02), and vaginal delivery (OR, 1.39; P < 0.00001) were associated with an elevated risk for neonatal hemorrhagic stroke. CONCLUSIONS: This study provides a succinct overview and comparative analysis of maternal, perinatal, and additional risk factors associated with neonatal cerebral artery ischemic stroke and neonatal hemorrhagic stroke, furnishing critical insights for healthcare practitioners involved in the diagnosis and prevention of neonatal stroke. This research also broadens the conceptual framework for future investigations. WHAT IS KNOWN: • Research indicates that prenatal, perinatal, and neonatal risk factors can elevate the risk of neonatal arterial ischemic stroke (NAIS). However, the risk factors for neonatal cerebral arterial ischemic stroke remain contentious, and those for neonatal hemorrhagic stroke (NHS) and neonatal cerebral venous sinus thrombosis (CVST) are still not well-defined. WHAT IS NEW: • This study is the inaugural comprehensive review and meta-analysis encompassing 19 studies that explore maternal, perinatal, and various risk factors linked to neonatal stroke of differing etiologies. Notably, our analysis elucidates eight risk factors associated with NAIS: gestational diabetes mellitus, a history of infertility, placenta previa, postdates, preterm birth, premature rupture of membranes, a prolonged second stage of labor, and chorioamnionitis. Furthermore, we identify six risk factors correlated with NHS: postdates, preterm birth, an abnormal CTG, the method of delivery, male gender, and vaginal delivery. Additionally, our systematic review delineates risk factors associated with CVST.

Risk factors for infant hearing loss: a meta-analysis.

Hearing loss is a common disability in infants that significantly impacts their cognitive, language, and literacy development. This study aimed to systematically assess the risk factors for the early identification and intervention in infant hearing loss. Databases were searched for meta-analyses of observational studies until November 2023. The quality assessment was performed using the Cochrane risk of bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of the evidence. A meta-analysis identified 14 risk factors significantly associated with infant hearing loss. According to the GRADE approach, there were four factors with moderate-certainty evidence (low birth weight(LBW), congenital anomalies, craniofacial anomalies, intracranial hemorrhages), seven factors with low-certainty evidence (ototoxic medications, family history of hearing loss, mechanical ventilation > 5 days, intrauterine infection, admission to neonatal intensive care unit (NICU) > 5 days, mechanical ventilation and asphyxia) and six with extremely-low-certainty evidence (very low birth weight < 1500 g (VLBW), hyperbilirubinemia, sepsis or meningitis, male sex, premature birth, small for gestational age (SGA)). Nevertheless, no significant association was found between infant hearing loss and factors such as small for gestational age (SGA), male sex, and premature birth (P > 0.05).  Conclusion: The identification of these 14 interrelated risk factors can prove advantageous in clinical practice, as these findings could guide hearing screening and parental counseling. Furthermore, prospective research could be conducted to develop risk-based scoring systems based on these factors. What is Known: • Infant hearing loss is a worldwide issue. • Risk factors for this condition are debated. What is New: • This is the first meta-analysis to comprehensively evaluate perinatal and postnatal risk factors for hearing loss in infants. • Intracranial hemorrhage, mechanical ventilation, and low birth weight are associated with infant hearing loss. However, no evidence of an association was found between premature birth, being small for gestational age, or male sex and hearing loss.

GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy.

Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-ß1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.

[Research progress on the mechanism of comorbidities of vestibular migraine and sleep disorders].

Vestibular migraine （VM） is one of the common vestibular diseases characterized by recurrent vertigo and migraine. Studies have shown that the sleep structure of VM patients is similar to that of migraine patients, and they have a common pathophysiological pathogenesis. There is a strong correlation between VM and the clinical symptoms of sleep disorders. Sleep disorders can trigger VM. On the contrary, VM can affect sleep regulatory centers and lead to structural sleep disorders. In addition, there is a common relationship between VM and sleep disorders in neuroanatomy, neurotransmitters and neural pathways. A correct understanding of the relationship between vestibular migraine and sleep disorders can provide some help for clinical diagnosis and treatment. This article reviews the relationship between vestibular migraine and the pathogenesis of sleep disorders.

D609 inhibition of phosphatidylcholine-specific phospholipase C attenuates prolonged insulin stimulation-mediated GLUT4 downregulation in 3T3-L1 adipocytes.

Glucose uptake is stimulated by insulin via stimulation of glucose transporter 4 (GLUT4) translocation to the plasma membrane from intracellular compartments in adipose tissue and muscles. Insulin stimulation for prolonged periods depletes GLUT4 protein, particularly in highly insulin-responsive GLUT4 storage vesicles. This depletion mainly occurs via H2O2-mediated retromer inhibition. However, the post-receptor mechanism of insulin activation of oxidative stress remains unknown. Here, we show that phosphatidylcholine-specific phospholipase C (PC-PLC) plays an important role in insulin-mediated downregulation of GLUT4. In the study, 3T3-L1 adipocytes were exposed to a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate (D609), for 30 min prior to the stimulation with 500 nM insulin for 4 h, weakening the depletion of GLUT4. D609 also prevents insulin-driven H2O2 generation in 3T3-L1 adipocytes. Exogenous PC-PLC and its product, phosphocholine (PCho), also caused GLUT4 depletion and promoted H2O2 generation in 3T3-L1 adipocytes. Furthermore, insulin-mediated the increase in the cellular membrane PC-PLC activity was observed in Amplex Red assays. These results suggested that PC-PLC plays an important role in insulin-mediated downregulation of GLUT4 and that PCho may serve as a signaling molecule.

Xp11 translocation renal cell carcinoma with morphological features mimicking multilocular cystic renal neoplasm of low malignant potential: a series of six cases with molecular analysis.

AIMS: Xp11 translocation renal cell carcinoma (RCC) is a distinctive subtype of RCC with TFE3 (Transcription Factor Binding to IGHM Enhancer 3) gene rearrangement. The gross features in most Xp11 translocation RCCs closely resemble clear cell RCCs. In this study, we report six cases of Xp11 translocation RCCs with a unique multicystic architecture, reminiscent of multilocular cystic renal cell neoplasm of low malignant potential (MCRN-LMP). METHODS AND RESULTS: Microscopically, the renal mass was well circumscribed with multilocular cystic architecture. The cyst walls and septa were mostly lined by a single layer of cells with clear cytoplasm and low-grade nuclei, reminiscent of MCRN-LMP. Psammoma bodies were detected in four cases. One particular patient was misdiagnosed with benign cysts in local hospitals and led to second operation. Tumour cells were settled according to the track of the first surgical procedure. TFE3 fluorescence in situ hybridization (FISH) assay confirmed the diagnosis of Xp11 translocation RCCs. FISH and RNA sequencing analyses confirmed MED15-TFE3 gene fusion in all six cases. Respective patients were alive, without any recent evidence of disease recurrence and/or metastasis. CONCLUSIONS: Here, we introduce a relatively inertia-variant of Xp11 translocation RCC which mimics MCRN-LMP. The distinctive morphological condition is linked to MED15-TFE3 gene fusion. In fact, renal neoplasms with morphological features of MCRN-LMP, especially those containing psammoma bodies, should be routinely evaluated for evidence of TFE3 gene rearrangements.

Inhibition of BAG-1 induced SH-SY5Y cell apoptosis without affecting Hsp70 expression.

OBJECTIVE: To further explore the role of BCL-2 associated anthanogen-1 (BAG-1) in neuronal apoptosis and whether the effect of BAG-1 depends on heat shock protein 70 (HSP70). METHODS: RNA interference (RNAi) technology was used to inhibit the expression of BAG-1 in SH-SY5Y cells. Hypoxia-reoxygenation injury model in the SH-SY5Y cells was established. Cell Counting Kit-8 (CCK-8) was performed for cell viability. Annexin V-APC/7-AAD double-staining followed by flow cytometry was used to measure cell apoptosis. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis were used to detect the messenger RNA (mRNA) and protein expression of genes, respectively. RESULTS: BAG-1 gene silencing decreased SH-SY5Y cell viability and promoted SH-SY5Y cell apoptosis after hypoxia-reoxygenation. However, the down-regulation of BAG-1 had no effect on the mRNA and protein expression of HSP70. CONCLUSION: BAG-1 could protect SH-SY5Y cells from the hypoxia-reoxygenation injury without affecting HSP70 expression.

Complement C3 exacerbates renal interstitial fibrosis by facilitating the M1 macrophage phenotype in a mouse model of unilateral ureteral obstruction.

The impact of the renal microenvironment on macrophage phenotype determination can contribute to the progression or resolution of renal fibrosis. Although the complement proteins affect macrophage polarization, whether complement component 3 (C3) can induce macrophage polarization and regulate renal interstitial fibrosis remains undetermined. In the present study, we investigated the contribution of C3 on macrophage polarization and renal fibrosis in C3-deficient mice with unilateral ureteral obstruction and bone marrow-derived macrophages. C3-deficient mice exhibited attenuated renal fibrosis and ameliorated peritubular capillary rarefaction. Lack of C3 contributed to M2 macrophage polarization, increased IL-10 and VEGF164, and decreased TNF-α and soluble VEGF receptor 1 expression in the obstructed kidneys at the early stages of unilateral ureteral obstruction. C3a facilitated LPS-induced M1 polarization and inflammatory factor production in bone marrow-derived macrophages in vitro, accompanied by increased ERK, NF-κB, and STAT1 phosphorylation. The ERK-specific inhibitor PD98059 inhibited the phosphorylation of ERK, NF-κB, and STAT1 and attenuated M1 polarization-related inflammatory factor production. Furthermore, the culture supernatant from M1 macrophages and C3a-treated M2 macrophages were more detrimental to angiogenesis compared with M2 macrophage supernatants. Thus, complement C3 exacerbates renal interstitial fibrosis by facilitating macrophage M1 polarization, promoting proinflammatory cytokine expression, and deteriorating peritubular capillary rarefaction in the kidney.

The role of podocyte damage in the etiology of ischemia-reperfusion acute kidney injury and post-injury fibrosis.

BACKGROUND: To establish a model of chronic renal fibrosis following acute kidney injury (AKI) in BALB/c mice and to observe the effect of AKI on podocyte injury and chronic fibrosis of the kidney. Additional aims included using the model to explore the role of podocyte injury in AKI and post-injury fibrosis. METHODS: Fifty BALB/C mice were randomly divided into control group (Ctr), sham group (sham), AKI 20 group (renal ischemia, 20 min reperfusion), AKI 30 group (renal ischemia, 30 min reperfusion) and AKI 40 group (renal ischemia, 40 min reperfusion). Mice serum and 24-h urine were collected on the 8th, 9th, 10th, 14th, and 28th days for urinary protein, serum creatinine (Scr) and blood urea nitrogen (BUN) analysis. HE staining, transmission electron microscopy (TEM), Masson staining, Q-PCR, Western Blot and immunohistochemistry were applied. RESULTS: Serum Scr and BUN levels across all AKI groups at the 9th day were significantly higher (P < 0.05) than controls, with higher reperfusion groups maintaining that increase up to 28 days (P < 0.05). Compared with Ctr group, the urinary protein of the AKI 40 group significantly rose on the 9th day (P < 0.05), normalizing immediately on the 10th day (P < 0.05). In contrast, the AKI 30 group rose significantly on the 14th day (P < 0.05) maintaining elevated levels for two weeks (P < 0.05). HE staining demonstrated ischemia-dependent renal tissue damage was aggravated in the mild to aggravated AKI groups. Mesangial proliferation, glomerulosclerosis, and tubulointerstitial pathology were also significantly increased in these groups (P < 0.05). Masson staining further showed that glomerular, renal tubular, and interstitial collagen were increased by ischemia in a time-dependent manner. Transmission EM additionally that podocytes of the mild to severe AKI groups displayed extensive fusion, exfoliation and GBM exposure. Synaptopodin, Nephrin, and CD2AP mRNA and protein expression demonstrated ischemic time-dependent decreases, while the TRPC6 was increased. There was a significant difference in the levels of Synaptopodin, Nephrin, CD2AP, and TRPC6 between the mild and severe AKI groups (P < 0.05). CONCLUSIONS: 1) During the AKI process mice podocyte injury, proteinuria and the subsequent progression into chronic renal fibrosis is observed.2) Podocyte injury may be one of the causes of ischemia-reperfusion acute kidney injury and post-injury fibrosis.

Diagnosing pituitary adenoma in unstained sections based on multiphoton microscopy.

PURPOSE: If we can find a new method that can achieve rapid diagnosis of adenoma during operation, it will help surgeon shorten the operation time and enhance the treatment efficacy. This study discusses the feasibility of multiphoton microscopy (MPM) in diagnosing pituitary adenoma. METHOD: MPM, based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) is performed for the diagnosis of pituitary adenoma in unstained sections. RESULTS: Our results show that MPM can reveal the variation of reticulin fiber by SHG signals of collagen, combined with the measurement of area of acinus, thickness of collagen fiber and collagen percentage. MPM can further reflect the change of meshwork in normal pituitary and hyperplasia quantitatively. And the characteristics of typical growth patterns of pituitary adenoma are demonstrated by the overlay of SHG and TPEF images. What's more, we can identify the boundary of normal pituitary, hyperplasia and adenoma from MPM images. And the experiment also results verify the feasibility of this method in frozen sections. CONCLUSION: These results indicated that MPM can make a diagnosis of pituitary adenoma by the morphological changes without routine pathological processing including hematoxylin-eosin (H&E) staining and other special staining. Therefore, this technique is expected to help diagnosis of pituitary adenoma during operation.

[Protective effect of BAG-1L mediated by lentivirus in human neuroblastoma cells induced by hypoxia].

OBJECTIVE: To investigate the protective effects of lentivirus mediated Bcl-2-associated athanogene 1L (BAG-1L) over-expression on human neuroblastoma cells (SH-SY5Y) induced by hypoxia/re-oxygenation, and to study its effect on the phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT) pathway. METHODS: SH-SY5Y cells were cultured in vitro, and the cells at logarithmic phase were collected, and they were divided into recombined lentiviral infection group [infected by lentivirus containing BAG-1L and green fluorescent protein (GFP) gene], vector control group (infected by lentivirus containing GFP without BAG-1L gene) and cell control group (non-infection). Western Blot was used to detect the expression of BAG-1L in target cells after infection for 48 hours. SH-SY5Y cells were subjected to hypoxia for 8 hours and re-oxygenation for 24 hours, then the cell counting kit-8 (CCK-8) was used to detect the cell activity, and the apoptosis was detected by flow cytometry after allophycocyanin labeled annexin V/7-amino actinomycin D (Annexin V-APC/7-AAD) staining. Western Blot was used to detect the protein expressions of BAG-1L, heat shock protein 70 (HSP70), AKT and phosphorylated AKT (p-AKT). RESULTS: After infection for 48 hours, exogenous BAG-1L protein bands were observed in recombined lentiviral infection group, but not observed in cell control group and vector control group. After hypoxia/re-oxygenation treatment, the cell viability in recombined lentiviral infection group was significantly higher than that in cell control group and vector control group (A value: 0.689±0.036 vs. 0.425±0.013, 0.400±0.012), apoptosis was significantly decreased [apoptosis rate: (26.97±1.82)% vs. (36.60±1.45)%, (35.77±3.74)%], the protein levels of BAG-1L, HSP70 and p-AKT were significantly increased [BAG-1L protein (gray value): 2.405±0.167 vs. 0.529±0.141, 0.601±0.099; HSP70 protein (gray value): 0.997±0.123 vs. 0.634±0.091, 0.584±0.106; p-AKT protein (gray value): 1.234±0.118 vs. 0.661±0.210, 0.712±0.199, all P < 0.01], but the protein level of AKT was slightly increased (gray value: 1.103±0.269 vs. 0.646±0.188, 0.791±0.326) without statistically significant differences (both P > 0.05). There was no significant difference in all parameters between cell control group and vector control group (all P > 0.05). CONCLUSIONS: Lentivirus mediated BAG-1L gene over-expression can protect nerve cells against hypoxic injury and apoptosis, and the protective effect may be related to the activation increase of pathway on PI3K/AKT.

Hirudin promotes angiogenesis by modulating the cross-talk between p38 MAPK and ERK in rat ischemic skin flap tissue.

Hirudin's ability to increase angiogenesis in ischemic flap tissue and improve the flaps survival has been demonstrated in our previous studies. However, the knowledge about hirudin functional role in angiogenesis is still limited. In the present study, we investigate the effects of locally injected hirudin on the expression of VEGF, endostatin and thrombospondin-1 (TSP-1) using rat model. Caudally based dorsal skin flaps were created and were treated with hirudin or normal saline. Result showed that the flap survival was improved by hirudin treatment relative to the control. Treatment of flaps with hirudin exerted significant angiogenic effect as evidenced by increased VEGF expression and reduced endostatin and TSP-1 production (p<0.01), and promoted neovascularization (microvascular density, p<0.01). Moreover, hirudin treatment increased the ERK1/2 phosphorylation, while attenuated the phosphorylation of p38 MAPK, and the addition of thrombin could reverse these effects of hirudin on ERK1/2 and p38 MAPK activity. The MEK inhibitor blocked the hirudin-induced VEGF expression, and the p38 MAPK inhibitor attenuated the thrombin-induced TSP-1 expression. Furthermore, a specific inhibitor of p38 MAPK activates ERK1/2 in ischemic flaps, suggesting that cross-talk between p38 MAPK and ERK might exist in rat ischemic flap tissue. Moreover, either the hirudin or SCH79797 (PAR1 antagonist) could attenuate the p38 MAPK phosphorylation and increases the ERK1/2 phosphorylation, indicating that the cross-talk between p38 MAPK and ERK1/2 modulated by thrombin/PAR1 signaling may participate in the process of hirudin-stimulated ERK1/2 signaling. In conclusion, these observations suggest that hirudin exerts its angiogenesis effect by regulating the expression of angiogenic and antiangiogenic factors via a cross-talk of p38 MAPK-ERK pathway.