Structural insight into the ZFAND1-p97 interaction involved in stress granule clearance.

Arsenite-induced stress granule (SG) formation can be cleared by the ubiquitin-proteasome system aided by the ATP-dependent unfoldase p97. ZFAND1 participates in this pathway by recruiting p97 to trigger SG clearance. ZFAND1 contains two An1-type zinc finger domains (ZF1 and ZF2), followed by a ubiquitin-like domain (UBL); but their structures are not experimentally determined. To shed light on the structural basis of the ZFAND1-p97 interaction, we determined the atomic structures of the individual domains of ZFAND1 by solution-state NMR spectroscopy and X-ray crystallography. We further characterized the interaction between ZFAND1 and p97 by methyl NMR spectroscopy and cryo-EM. 15N spin relaxation dynamics analysis indicated independent domain motions for ZF1, ZF2, and UBL. The crystal structure and NMR structure of UBL showed a conserved ß-grasp fold homologous to ubiquitin and other UBLs. Nevertheless, the UBL of ZFAND1 contains an additional N-terminal helix that adopts different conformations in the crystalline and solution states. ZFAND1 uses the C-terminal UBL to bind to p97, evidenced by the pronounced line-broadening of the UBL domain during the p97 titration monitored by methyl NMR spectroscopy. ZFAND1 binding induces pronounced conformational heterogeneity in the N-terminal domain of p97, leading to a partial loss of the cryo-EM density of the N-terminal domain of p97. In conclusion, this work paved the way for a better understanding of the interplay between p97 and ZFAND1 in the context of SG clearance.

Intermittent hypoxia exacerbates metabolic dysfunction-associated fatty liver disease by aggravating hepatic copper deficiency-induced ferroptosis.

Intermittent hypoxia (IH) is an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Copper deficiency can disrupt redox homeostasis, iron, and lipid metabolism. Here, we investigated whether hepatic copper deficiency plays a role in IH-associated MAFLD and explored the underlying mechanism(s). Male C57BL/6 mice were fed a western-type diet with adequate copper (CuA) or marginally deficient copper (CuD) and were exposed separately to room air (RA) or IH. Hepatic histology, plasma biomarkers, copper-iron status, and oxidative stress were assessed. An in vitro HepG2 cell lipotoxicity model and proteomic analysis were used to elucidate the specific targets involved. We observed that there were no differences in hepatic phenotypes between CuA-fed and CuD-fed mice under RA. However, in IH exposure, CuD-fed mice showed more pronounced hepatic steatosis, liver injury, and oxidative stress than CuA-fed mice. IH induced copper accumulation in the brain and heart and exacerbated hepatic copper deficiency and secondary iron deposition. In vitro, CuD-treated cells with IH exposure showed elevated levels of lipid accumulation, oxidative stress, and ferroptosis susceptibility. Proteomic analysis identified 360 upregulated and 359 downregulated differentially expressed proteins between CuA and CuD groups under IH; these proteins were mainly enriched in citrate cycle, oxidative phosphorylation, fatty acid metabolism, the peroxisome proliferator-activated receptor (PPAR)α pathway, and ferroptosis. In IH exposure, CuD significantly upregulated the ferroptosis-promoting factor arachidonyl-CoA synthetase long chain family member (ACSL)4. ACSL4 knockdown markedly eliminated CuD-induced ferroptosis and lipid accumulation in IH exposure. In conculsion, IH can lead to reduced hepatic copper reserves and secondary iron deposition, thereby inducing ferroptosis and subsequent MAFLD progression. Insufficient dietary copper may worsen IH-associated MAFLD.

Comparison of efficacy of nadroparin and fondaparinux sodium for prevention of deep vein thromboembolism in lower extremities after total hip arthroplasty and total knee arthroplasty: a retrospective study of 592 patients.

OBJECTIVES: To compare the efficacy of nadroparin and fondaparinux sodium for prevention of deep vein thromboembolism (DVT) in lower extremities after total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: A total of 592 patients were enrolled in the study. Clinical data of patients who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA) in our hospital from December 2021 to September 2022 were retrospectively collected, which mainly included patients' general information, surgery-related information, and DVT-related information. The patients were categorized into the nadroparin group(n = 278) and the fondaparinux sodium group(n = 314) according to the types of anticoagulants used. Anticoagulant therapy began 12-24 h after operation and continued until discharge. DVT prevalence between two groups was compared. The Statistical Package for Social Sciences (SPSS) software version 25 (SPSS, Armonk, NY, USA) was used for statistical analysis. RESULTS: The prevalence of DVT in the nadroparin group and the fondaparinux sodium group was 8.3% (23/278) and 15.0% (47/314), respectively(p = 0.012). Statistical analysis showed that nadroparin group showed a lower prevalence of thrombosis than fondaparinux group (OR = 1.952, P = 0.012). Subgroup analyses showed that nadroparin group had a lower prevalence of DVT than fondaparinux group in some special patients groups such as female patients (OR = 2.258, P = 0.007), patients who are 65-79 years old (OR = 2.796, P = 0.004), patients with hypertension (OR = 2.237, P = 0.042), patients who underwent TKA (OR = 2.091, P = 0.011), and patients who underwent combined spinal-epidural anesthesia (OR = 2.490, P = 0.003) (P < 0.05). CONCLUSION: Nadroparin may have an advantage over fondaparinux sodium in preventing DVT in lower extremities after THA and TKA.

Exploring the effect of disc displacement on the risk and severity of condylar erosion in adult temporomandibular disorder patients: A CBCT and MRI study.

OBJECTIVE: The objective of the study was to investigate the relationship between types of disc displacement (DD) diagnosed by magnetic resonance imaging (MRI), and the risk (presence or absence) and severity of condylar erosion (CE) graded using cone-beam computed tomography (CBCT) in adult Temporomandibular disorders (TMD) patients. METHODS: A total of 353 TMD patients (283 females, 70 males) underwent MRI scans to categorise DD as normal (NA), anterior displacement with reduction (ADDR), or anterior displacement without reduction (ADDNR). CE severity was graded on a scale of 0-3 (absence, mild, moderate or severe) using CBCT. To establish the plausibility and cut-off points for CE diagnosis, the severity of CE was then further divided into three classifications: Grade 0 versus 1 + 2 + 3; Grades 0 + 1 versus 2 + 3; Grades 0 + 1 + 2 versus 3. Logistic regression analysis was performed, adjusting for age, gender and joint correlation. RESULTS: ADDNR significantly increased the risk of CE compared with NA (OR = 10.04, 95% CI: [6.41, 15.73]) and showed a significant increase in CE severity across all classifications (ORs = 10.04-18.95). The effects of ADDNR were significant in both genders (p < .001) and had a greater impact in females. ADDR was predominantly associated with mild CE. CONCLUSIONS: ADDNR significantly increased the risk and severity of CE independent of gender when compared to NA, whereas ADDR was mainly associated with mild CE. Slight cortical discontinuity may represent a subclinical diagnosis requiring further investigation.

Identification of Endothelial Cell Protein C Receptor by Urinary Proteomics as Novel Prognostic Marker in Non-Recovery Kidney Injury.

Acute kidney injury is a common and complex complication that has high morality and the risk for chronic kidney disease among survivors. The accuracy of current AKI biomarkers can be affected by water retention and diuretics. Therefore, we aimed to identify a urinary non-recovery marker of acute kidney injury in patients with acute decompensated heart failure. We used the isobaric tag for relative and absolute quantification technology to find a relevant marker protein that could divide patients into control, acute kidney injury with recovery, and acute kidney injury without recovery groups. An enzyme-linked immunosorbent assay of the endothelial cell protein C receptor (EPCR) was used to verify the results. We found that the EPCR was a usable marker for non-recovery renal failure in our setting with the area under the receiver operating characteristics 0.776 ± 0.065; 95%CI: 0.648-0.905, (p < 0.001). Further validation is needed to explore this possibility in different situations.

Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient.

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-ß42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-ß42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-ß at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aß-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aß-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.

MRI susceptibility artefacts caused by orthodontic wire.

OBJECTIVES: To evaluate magnetic susceptibility artefacts produced by orthodontic wires on MRI and the influence of wire properties and MRI image sequences on the magnitude of the artefact. METHODS: Arch form orthodontic wires [four stainless steels (SS), one cobalt chromium (CC) alloy, 13 titanium (Ti) alloys] were embedded in a polyester phantom, and scanned using a 1.5-T superconducting magnet scanner with an eight-channel phased-array coil. All wires were scanned with T1-weighted spin echo (SE) and gradient echo (GRE) sequences according to the American Society for Testing and Materials (ASTM) F2119-07 standard. The phantom was also scanned other eight sequences. Artefacts were measured using the ASTM F2119-07 definition and OsiriX software. Artefact volume was analyzed according to metal composition, wire length, number of wires, wire thickness, and imaging sequence as factors. RESULTS: With SE/GRE, black/white artefacts volumes from all SS wires were significantly larger than those produced by CC and Ti wires (P < 0.01). With the GRE, the black artefacts volume was highest with the SS wires. With the SE, the black artefacts volume was small, whereas white artefacts were noticeable. The cranio-caudal extent of the artefacts was significantly longer with SS wires (P < 0.01). Although a direct relationship of wire length, number of wires and wire thickness with artefact volume was noted, these factors did not influence artefact extension in the cranio-caudal direction. CONCLUSIONS: Ferromagnetic/paramagnetic orthodontic wires create artefacts due to local alteration of magnetic field homogeneity. The SS-type wires produced the largest artefacts followed by CC and Ti.

Characteristics of and Outcomes After Dialysis-Treated Acute Kidney Injury, 2009-2018: A Taiwanese Multicenter Study.

RATIONALE & OBJECTIVE: Dialysis-treated acute kidney injury (AKI) is increasingly common in intensive care units (ICUs) and is associated with poor outcomes. Few studies have explored the temporal trends in severity of acute illness at dialysis initiation, indications for dialysis, and their association with patient outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 9,535 adult patients admitted to the ICU who received their first dialysis treatment from Chang Gung Memorial Hospital system in Taiwan from 2009 through 2018. EXPOSURE: Calendar year. OUTCOMES: ICU mortality and dialysis treatment at discharge among hospital survivors. ANALYTICAL APPROACH: The temporal trends during the study period were investigated using test statistics suited for continuous or categorical data. The association between the study year and the risk of mortality was analyzed using multivariable Cox regression with adjustment for relevant clinical variables, including the severity of acute illness, defined by Sequential Organ Failure Assessment (SOFA) score. RESULTS: The mean SOFA score at dialysis initiation decreased slightly from 14.0 in 2009 to 13.6 in 2018. There was no significant trend in the number of indications for dialysis initiation that were fulfilled over time. Observed ICU mortality decreased over time, and the curve appeared to be reverse J-shaped, with a substantial decrease from 56.1% in 2009 to 46.3% in 2015 and a slight increase afterward. The risk of mortality was significantly reduced from 2013 to 2018 compared with 2009 in adjusted models. The decreasing trend in ICU mortality over time remained significant. There was an increase in dialysis treatment at discharge among survivors, mainly in patients with estimated glomerular filtration rate<60mL/min/1.73m2, from 36.8% in 2009 to 43.9% in 2018. LIMITATIONS: Residual confounding from unmeasured factors over time such as severity of comorbidities, detailed medication interventions, and delivered dialysis dose. CONCLUSIONS: We observed reductions in mortality among ICU patients with dialysis-treated acute kidney injury between 2009 and 2018, even after adjusting for dialysis indication and severity of illness at dialysis initiation. However, dialysis treatment at discharge among survivors has increased over time, mainly in patients with preexisting kidney disease. PLAIN-LANGUAGE SUMMARY: The current medical management of severe acute kidney injury (AKI) is primarily limited to supportive care and kidney replacement therapy if indicated, leading to perceptions that outcomes among intensive care unit (ICU) patients with dialysis-treated AKI have not improved. In this multicenter retrospective study of ICU patients with dialysis-treated AKI between 2009 and 2018 in Taiwan, patient mortality decreased over time despite increasing comorbidities. Moreover, the decreasing linear trends remained significant even when considering severity of acute illness at dialysis initiation, which was based on physiologic and laboratory measurements seldom evaluated in previous studies. Further research should explore the basis for these improvements.

The neural basis of pain during labor.

Characterizing a labor pain-related neural signature is a key prerequisite for devising optimized pharmacologic and nonpharmacologic labor pain relief methods. The aim of this study was to describe the neural basis of labor pain and to provide a brief summary of how epidural anesthesia may affect pain-related neuronal activity during labor. Possible future directions are also highlighted. By taking advantage of functional magnetic resonance imaging, brain activation maps and functional neural networks of women during labor that have been recently characterized were compared between pregnant women who received epidural anesthesia and those who did not. In the subgroup of women who did not receive epidural anesthesia, labor-related pain elicited activations in a distributed brain network that included regions within the primary somatosensory cortex (postcentral gyrus and left parietal operculum cortex) and within the traditional pain network (lentiform nucleus, insula, and anterior cingulate gyrus). The activation maps of women who had been administered epidural anesthesia were found to be different-especially with respect to the postcentral gyrus, the insula, and the anterior cingulate gyrus. Parturients who received epidural anesthesia were also compared with those who did not in terms of functional connectivity from selected sensory and affective regions. When analyzing women who did not receive epidural anesthesia, marked bilateral connections from the postcentral gyrus to the superior parietal lobule, supplementary motor area, precentral gyrus, and the right anterior supramarginal gyrus were observed. In contrast, women who received epidural anesthesia showed fewer connections from the postcentral gyrus-being limited to the superior parietal lobule and supplementary motor area. Importantly, one of the most noticeable effects of epidural anesthesia was observed in the anterior cingulate cortex-a primary region that modulates pain perception. The increased outgoing connectivity from the anterior cingulate cortex in women who received epidural anesthesia indicates that the cognitive control exerted by this area might play a major role in the relief from labor pain. These findings not only affirmed the existence of a brain signature for pain experienced during labor, but they also showed that this signature can be altered by the administration of epidural anesthesia. This finding raises a question about the extent to which the cingulo-frontal cortex may exert top-down influences to gate women's experiences of labor-related pain. Because the anterior cingulate cortex is also involved in the processing and modulation of emotional content, such as fear and anxiety, a related question is about the extent to which the use of epidural anesthesia can affect different components of pain perception. Finally, inhibition of anterior cingulate cortex neurons may represent a potential new therapeutic target for alleviating labor-associated pain.

Metformin attenuates sevoflurane-induced neurogenesis damage and cognitive impairment: involvement of the Nrf2/G6PD pathway.

Anesthetics such as sevoflurane are commonly administered to infants and children. However, the possible neurotoxicity caused by prolonged or repetitive exposure to it should be a concern. The neuroprotective effects of metformin are observed in many models of neurological disorders. In this study, we investigated whether metformin could reduce the developmental neurotoxicity induced by sevoflurane exposure in neonatal rats and the potential mechanism. Postnatal day 7 (PND 7) Sprague-Dawley rats and neural stem cells (NSCs) were treated with normal saline or metformin before sevoflurane exposure. The Morris water maze (MWM) was used to observe spatial memory and learning at PND 35-42. Immunofluorescence staining was used to detect neurogenesis in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus at PND 14. MTT assays, immunofluorescence staining, and TUNEL staining were used to assess the viability, proliferation, differentiation, and apoptosis of NSCs. Western blotting and ELISA were used to assess the protein expression of cleaved caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), and glucose-6-phosphate dehydrogenase (G6PD) pathway-related molecules. Exposure to sevoflurane resulted in late cognitive defects, impaired neurogenesis in both the SVZ and SGZ, reduced NSC viability and proliferation, increased NSC apoptosis, and decreased protein expression of G6PD in vitro. Metformin pretreatment attenuated sevoflurane-induced cognitive functional decline and neurogenesis inhibition. Metformin pretreatment also increased the protein expression of Nrf2 and G6PD. However, treatment with the Nrf2 inhibitor, ML385 or the G6PD inhibitor, dehydroepiandrosterone (DHEA) reversed the protective effect of metformin on sevoflurane-induced NSC damage in vitro. Our findings suggested that metformin could reduce sevoflurane-induced neurogenesis damage and neurocognitive defects in the developing rat brain by influencing the Nrf2/G6PD signaling pathways.

Loganin alleviates myocardial ischemia-reperfusion injury through GLP-1R/NLRP3-mediated pyroptosis pathway.

Myocardial ischemia-reperfusion (I/R) injury is one of main pathological manifestations of cardiovascular outcomes related to NLRP3 inflammasome-mediated pyroptosis pathway. Loganin is an iridoid glycoside extracted from traditional Chinese medicines, which has multiple activities. However, the roles and mechanism of loganin in myocardial I/R injury remain largely unknown. The models of myocardial I/R injury were established using I/R-treated rats or OGD/R-treated H9C2 cardiomyocytes. Myocardial damage was assessed by TTC and hematoxylin-eosin staining. Pyroptosis-related marker levels were detected by immunohistochemistry, immunofluorescence and western blotting assays. Cell proliferation was examined via EdU assay. Cell apoptosis was investigated by LDH release and flow cytometry. The integrity of cell membrane was analyzed via Dil staining. GLP-1R and NLRP3 levels were detected by immunofluorescence and western blotting assays. Our results showed that loganin suppressed I/R-induced myocardial damage in rats by reducing myocardial infarct, injury and pyroptosis. In addition, loganin attenuated OGD/R-induced cardiomyocyte apoptosis through increasing cell proliferation and reducing LDH release and apoptotic rate. Loganin also mitigated OGD/R-induced cardiomyocyte pyroptosis by reducing cell membrane damage and levels of cleaved caspase-1, IL-1ß and IL-18. Furthermore, loganin repressed GLP-1R/NLRP3 pathway activation in OGD/R-treated H9C2 cardiomyocytes by enhancing GLP-1R expression and decreasing NLRP3 level. GLP-1R/NLRP3 activation by GLP-1R inhibition or NLRP3 overexpression reversed the suppressive effects of loganin on OGD/R-induced cardiomyocyte pyroptosis. These data indicated that loganin prevented OGD/R-induced proliferation inhibition, apoptosis and pyroptosis in OGD/R-treated cardiomyocytes by inhibiting GLP-1R/NLRP3 activity, indicating the therapeutic potential of loganin in myocardial I/R injury.

Risk estimation of degenerative joint disease in temporomandibular disorder patients with different types of sagittal and coronal disc displacements: MRI and CBCT analysis.

BACKGROUND: Degenerative joint disease (DJD) can be associated with disc displacement (DD) in temporomandibular disorder (TMD) patients. However, the relationship between different types of DDs and DJD remains unclear. OBJECTIVES: To investigate the odds ratios of different types of sagittal and coronal DDs confirmed by magnetic resonance imaging (MRI) and DJD confirmed by cone-beam computed tomography (CBCT) in TMD patients. METHODS: Radiographic data from 69 males and 232 females were collected for analysis. CBCT was used to diagnose DJD, with criteria including erosion, osteophytes, generalised sclerosis and cysts in the joint. Eight types of DDs were evaluated by sagittal and coronal MRIs: NA, no abnormality; SW, sideways; ADDR, anterior with reduction; ADDR+SW; ADDNR, anterior without reduction; ADDNR + SW; single SW; PDD, posterior; PDD + SW. The odds ratios of DJD in joints with different types of DDs were determined after joint correlation, age and gender adjustment. RESULTS: Compared with NA, the odds ratio of DJD in ADDR was 2.397 (95% CI [confidence interval]: 1.070-5.368), ADDR + SW was 4.808 (95% CI: 1.709-3.528), ADDNR was 29.982 (95% CI: 15.512-57.950) and ADDNR + SW was 25.974 (95% CI: 12.743-52.945). Erosion was significantly increased in ADDR, ADDR + SW, ADDNR and ADDNR + SW; osteophytes were significantly increased in ADDR + SW, ADDNR and ADDNR + SW; and generalised sclerosis and cysts were significantly increased in ADDNR and ADDNR + SW. There were no significant associations between single SW, PDD, PDD + SW and the DJD. CONCLUSIONS: ADDR, ADDR+SW, ADDNR and ADDNR+SW were associated with DJD. ADDNR had a significantly higher prevalence of DJD than ADDR. There were no significant relationships between single SW, PDD, PDD + SW and the DJD.

Exosomal microRNA-140-3p from human umbilical cord mesenchymal stem cells attenuates joint injury of rats with rheumatoid arthritis by silencing SGK1.

OBJECTIVE: Over the years, microRNAs (miRNAs) have been involved in the pathogenesis of rheumatoid arthritis (RA). We aim to investigate the role of human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomal miR-140-3p in RA development. METHODS: Exosomes(exo) were isolated from human umbilical cord-derived mesenchymal stem cells (HUCMSCs), and this isolation was followed by the transfer of miR-140-3p. RA rat models were constructed by collagen II adjuvant and respectively treated with HUCMSCs-exo or HUCMSCs-exo carrying miR-140-3p mimic/inhibitor, and expression of miR-140-3p and serum- and glucocorticoid-inducible kinase 1 (SGK1) was assessed. Then, RA score and inflammation scoring, fibrosis degree and apoptosis, serum inflammatory response and oxidative stress in joint tissues were determined. The RA synovial fibroblasts (RASFs) were extracted from rats and identified. Conducted with relative treatment, the migration, proliferation and apoptosis in RASFs were determined. RESULTS: MiR-140-3p was decreased while SGK1 was increased in RA rats. HUCMSCs-exo or upregulated exosomal miR-140-3p improved pathological changes and suppressed inflammation, oxidative stress and fibrosis in RA rats, and also constrained and RASF growth. Overexpression of SGK1 reversed the inhibition of RASF growth caused by overexpression of miR-140-3p. CONCLUSION: Upregulated exosomal miR-140-3p attenuated joint injury of RA rats by silencing SGK1. This research provided further understanding of the role of exosomal miR-140-3p in RA development.

Pharmacological and non-pharmacological treatments for restless legs syndrome in end-stage kidney disease: a systematic review and component network meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is common among patients with end-stage kidney disease (ESKD) and is associated with poor outcomes. Several recently published studies had focused on pharmacological and non-pharmacological treatments of RLS, but an updated meta-analysis has not been conducted. METHODS: The study population was adult ESKD patients on dialysis with RLS. Randomized controlled trials (RCTs) were selected. The primary outcome was reduction in RLS severity. The secondary outcomes were improvement in sleep quality and treatment-related adverse events. Frequentist standard network meta-analysis (NMA) and additive component NMA were performed. The evidence certainty was assessed using the Confidence in NMA (CINeMA) framework. RESULTS: A total of 24 RCTs with 1252 participants were enrolled and 14 interventions were compared. Cool dialysate produced the largest RLS severity score reduction {mean difference [MD] 16.82 [95% confidence interval (CI) 10.635-23.02]} and a high level of confidence. Other potential non-pharmacological interventions include intradialytic stretching exercise [MD 12.00 (95% CI 7.04-16.97)] and aromatherapy massage [MD 10.91 (95% CI 6.96-14.85)], but all with limited confidence of evidence. Among the pharmacological interventions, gabapentin was the most effective [MD 8.95 (95% CI 1.95-15.85)], which also improved sleep quality [standardized MD 2.00 (95% CI 0.47-3.53)]. No statically significant adverse events were detected. CONCLUSIONS: The NMA supports that cool dialysate is appropriate to treat patients with ESKD and RLS. Gabapentin is the most effective pharmacological intervention and also might improve sleep quality. Further parallel RCTs with sufficient sample sizes are required to evaluate these potential interventions and long-term effects.

Comparison between peritoneal dialysis and hemodialysis on kidney function recovery in incident kidney failure: A nationwide cohort study.

BACKGROUND: Patients with kidney failure who start dialysis have a chance of kidney function recovery. Whether the initial dialysis modality affects the possibility of recovery is not fully understood. METHODS: We included patients diagnosed with kidney failure requiring dialysis during 2001-2013 from the Taiwan National Health Insurance Research Database. We excluded diabetic and elderly patients. Kidney function recovery was defined as not receiving dialysis therapy for longer than 3 months. The primary outcome was kidney function recovery, and the secondary outcome was all-cause mortality during a 3-year follow up. RESULTS: A total of 12,619 patients was eligible for analysis, with 981 received PD and 11,638 received HD. Total 620 patients had kidney function recovery during a 3-year follow up, which represented 4.9% of the entire cohort. After propensity score matching, the PD groups were more likely to experience kidney function recovery (subdistribution hazard ratio [SHR]: 1.64, 95% confidence interval [CI]: 1.19-2.25). The risk of all-cause mortality between groups did not significantly differ (hazard ratio [HR]: 1.23, 95% CI: 0.89-1.70). CONCLUSION: The study found that in nonelderly, nondiabetic patients who received inadequate predialysis nephrology care before kidney failure, PD is associated with a higher chance of kidney function recovery.

Growth and physiological responses in a submerged clonal aquatic plant and multiple-endpoint assessment under prolonged exposure to ciprofloxacin.

Ciprofloxacin is ubiquitous and poses a potential threat to aquatic ecosystems. However, the comprehensive effect of prolonged ciprofloxacin exposure on the submerged clonal plant Vallisneria natans (Lour.) Hara remains unknown. Growth and physiological responses in V. natans exposed to ciprofloxacin at concentrations of 0, 0.05, 0.25, 1.25, 2.5, 5 and 10 mg/L were repeatedly evaluated on Days 7, 14, 28, 42 and 56. V. natans maintained good growth properties under 0.05-0.25 mg/L ciprofloxacin treatments, while the inhibition effect on plant growth induced by higher-concentration treatments increased over time. The IC50 values of ciprofloxacin for growth endpoints ranged from 1.6 mg/L to 5.3 mg/L and displayed time-dependent decreases. Pigment contents were significantly stimulated by ciprofloxacin on Day 7 but decreased to varying degrees as the exposure time was extended. Soluble protein and hydrogen peroxide content rose significantly over the first 14 days of treatment with 0.25-10 mg/L ciprofloxacin but decreased under 1.25-10 mg/L ciprofloxacin treatments since Day 28. Antioxidants including superoxide dismutase, catalase, guaiacol peroxidase, ascorbate peroxidase and proline functioned well in mitigating oxidative stress under different ciprofloxacin concentrations, lowering the comprehensive toxic effects of ciprofloxacin on V. natans during the period from Day 14 to Day 42, as evidenced by decreased IBR (integrated biomarker response) values. However, the toxic pressure of ciprofloxacin on V. natans peaked on Day 56. These findings suggest that exposure time can influence the responses of V. natans exposed to ciprofloxacin and that IBR can be employed to evaluate the integrated impacts of prolonged ciprofloxacin contamination in aquatic settings.

The clinical value of dual-energy computed tomography and diffusion-weighted imaging in the context of liver cancer: A narrative review.

The dual-energy computed tomography (DECT) and diffusion-weighted magnetic resonance imaging (DWI-MRI) are used to diagnose liver cancer. The clinical value of these two examination methods needs to be further summarized. We collected and summarized relevant literature published from 2011 to 2021. The diagnostic performance of DECT was assessed between conventional computed tomography and DWI-MRI. DWI-MRI had a 69% sensitivity for detecting small hepatocellular carcinoma (HCC) lesions and a 60% diagnostic specificity for differentiating between types of HCC lesions. DECT had a sensitivity to small liver lesions (<1 cm) of 69%, and the diagnostic specificity for HCC and metastasis was about 60%. DWI was more sensitive (90.3% vs. 74.9%) and accurate (91.9% vs. 76.9%) in diagnosing HCC compared with conventional MRI sequencing. With the aid of contrast media, DWI-MRI had 90.0% specificity for detecting small HCCs (smaller than 1 cm). Furthermore, DWI-MRI not only provided physicians with valuable diagnostic information but also delivered histological grading information, with 78% accuracy for all benign lesions and 71% for solid lesions. DECT had relatively high sensitivity and required a lower contrast medium dose. With standardized quantitative parameters, it can be an extremely useful tool for HCC surveillance. DWI-MRI is the preferred imaging process as it produces high-contrast images for supporting an early diagnosis (high sensitivity and specificity) and provides histological information using non-ionizing radiation.

Contribution of WNT2B Genetic Variants to Ischemic Stroke Occurrence in a Chinese Han Population.

ABSTRACT: Wnt signaling pathway-related WNT2B gene was upregulated in ischemic brain damage. We aimed to assess the contribution of WNT2B genetic variant to ischemic stroke (IS) susceptibility in the Chinese Han population. Five polymorphisms including rs3790606, rs351364, rs3790608, rs12037987, and rs10776752 in WNT2B were genotyped using Agena MassARRAY platform in 476 healthy controls and 501 patients with IS. Odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender were estimated by logistic regression analysis. Analysis of variance was used to evaluate the association between genotypes of WNT2B variants and blood lipid parameters. Rs12037987 (OR = 1.82, 95% CI: 1.18-2.82, P = 0.007) and rs10776752 (OR = 1.74, 95% CI: 1.13-2.68, P = 0.012) were related to the increased IS susceptibility. Interestingly, rs12037987 (OR = 2.01, P = 0.028) and rs10776752 (OR = 2.02, P = 0.028) had the higher IS risk in the subjects younger than or equal to 65 years. Rs12037987 (OR = 2.70, P = 0.013), rs10776752 (OR = 2.71, P = 0.012), and rs3790606 (OR = 1.89, P = 0.036) manifested an increasing-risk association with IS occurrence in women. Moreover, rs3790606 genotype was related to serum levels of triglyceride (P = 0.008) and total cholesterol (P = 0.001). Our study reported that rs12037987 and rs10776752 were associated with the increased risk for IS in the Chinese Han population. Our findings may be useful for insight into the contribution of WNT2B variants to the complex pathogenesis of IS.

Superatomic and adsorption properties of Ni atom doped Au clusters.

Due to their strong relativistic effects, Au clusters exhibit many unusual geometric structures. Among them, Au7-, Au8 and Au9+ have 18 valence electrons satisfying the magic numbers in the jellium model, respectively, but these three non-spherical clusters are not superatoms. In general, a single dopant atom can drastically change the structural and electronic properties of Au clusters. Here, we searched structures of NiAu7-, NiAu8 and NiAu9+ clusters using the genetic algorithm program (GA) combined with density functional theory (DFT). It was found that the alloy clusters are all 3D spherical structures. The molecular orbitals and density of states analysis indicate that they have completely filled superatomic shells (1S21P6), in which the electronic structure of the Ni atom is d10. Then, the electrostatic potential surfaces of the alloy clusters are analyzed, and the calculated results show that the NiAu8 superatom has remarkable σ-holes with positive potential regions. Moreover, these electron-deficient regions can be considered as interaction sites with some electron donors. After a Lewis base CO gas molecule is adsorbed on the Au-based superatom, we found that the C-O bond distance becomes slightly elongated and its stretching frequency presents a significant red-shift. This is due to the fact that 5d electrons of the Au atom of the NiAu8 transfer towards the anti-bond π orbitals of the CO molecule. Hence, this is an effective strategy for finding new types of superatoms and potential catalysts for covalent bond activation.

TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities.

TAFRO syndrome is an extremely rare form of idiopathic MCD, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis on bone marrow biopsy, and organomegaly. Like idiopathic MCD, renal involvement is also a common presentation in patients with TAFRO syndrome. Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy. Several molecular mechanisms have been previously postulated in order to explain the TAFRO syndrome symptoms, including abnormal production of interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), etc. The role of these cytokines in renal injury, however, is not well understood. The aim of this review article is to summarize the latest knowledge of molecular mechanisms behind the TAFRO syndrome and their potential role in renal damage.