Effect of preoperative immunonutrition on postoperative short-term clinical outcomes in patients with gastric cancer cachexia: a prospective randomized controlled trial.

BACKGROUND: Although current guidelines(ESPEN guideline: Clinical nutrition in surgery and other guidelines) recommend preoperative immunonutrition for cachectic gastric cancer patients, the strength of the recommendation is weak, and the level of evidence is low. The benefits of preoperative immunonutrition still remain controversial. PATIENTS AND METHODS: 112 patients with gastric cancer cachexia were enrolled in the study and randomly assigned in a 1:1 ratio to receive either preoperative enteral immunonutrition support (IN, n = 56) or standard enteral nutrition support (SEN, n = 56). The primary endpoint was the incidence of infectious complications, and the secondary endpoints included the nutritional indicators, inflammatory markers, immune parameters, postoperative recovery and complications and gastrointestinal intolerance reactions. RESULTS: The incidence of postoperative infectious complications(P = 0.040) and overall complications (P = 0.049)was significantly lower in the IN group compared to the SEN group. In terms of laboratory inflammatory indexes, patients in the IN group demonstrated significantly lower levels of white blood cells (WBC), C-reactive protein (CRP), and interleukin-6 (IL-6), as well as higher levels of lymphocytes (LYMPH) and immunoglobulin A (IgA), compared to patients in the SEN group, with statistically significant differences. In terms of clinical outcomes, the IN group had a shorter duration of antibiotic use (P = 0.048), shorter hospital stay (P = 0.018), and lower total hospital costs (P = 0.034) compared to the SEN group. The IN group also experienced significantly less weight loss after surgery (P = 0.043). CONCLUSION: Preoperative administration of immunonutrition formula has a positive impact on the incidence of infectious complications in patients with gastric cancer cachexia after surgery. It improves patients' inflammatory and immune status, shortens hospital stays, and reduces healthcare costs. Preoperative use of immunonutrition may contribute to the improvement of prognosis in this high-risk population.

Long term survival outcomes of surgery combined with hyperthermic intraperitoneal chemotherapy for perforated low-grade appendiceal mucinous neoplasms: A multicenter retrospective study.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.

Short- and long-term comparison of robotic versus laparoscopic gastrectomy for gastric cancer patients with BMI≥30 kg/m2: A propensity score matched analysis.

BACKGROUND: Although minimally invasive surgery (MIS) for gastric patients has gained popularity in recent decades, reports on the comparison of short and long clinical outcomes between robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer patients with BMI≥30 kg/m2 are still limited. METHODS: A total of 226 obese gastric cancer patients who underwent either RG (n = 81) or LG (n = 145) were enrolled in this study between October 2014 and September 2022. Propensity score matching (PSM) (1:1) was performed to reduce confounding bias. Short-term and long-term outcomes were compared between the RG and LG groups. RESULTS: The clinicopathological characteristics of 156 patients in the RG group (n = 79) and LG group (n = 79) were well balanced after PSM. Compared with the LG group, the RG group had a significantly shorter operation time, less estimated blood loss, more harvested lymph nodes, a faster postoperative recovery course, reduced surgical morbidity, and a shorter postoperative hospital stay. The long-term outcomes were comparable between the two groups. CONCLUSIONS: RG is a safe and feasible approach for gastric cancer with a BMI≥30 kg/m2 and has better short-term clinical outcomes than LG. However, RG is similar to LG in terms of long-term prognosis.

Deep Learning Radiomics Nomogram Based on Enhanced CT to Predict the Response of Metastatic Lymph Nodes to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

BACKGROUND: We aimed to construct and validate a deep learning (DL) radiomics nomogram using baseline and restage enhanced computed tomography (CT) images and clinical characteristics to predict the response of metastatic lymph nodes to neoadjuvant chemotherapy (NACT) in locally advanced gastric cancer (LAGC). METHODS: We prospectively enrolled 112 patients with LAGC who received NACT from January 2021 to August 2022. After applying the inclusion and exclusion criteria, 98 patients were randomized 7:3 to the training cohort (n = 68) and validation cohort (n = 30). We established and compared three radiomics signatures based on three phases of CT images before and after NACT, namely radiomics-baseline, radiomics-delta, and radiomics-restage. Then, we developed a clinical model, DL model, and a nomogram to predict the response of LAGC after NACT. We evaluated the predictive accuracy and clinical validity of each model using the receiver operating characteristic curve and decision curve analysis, respectively. RESULTS: The radiomics-delta signature was the best predictor among the three radiomics signatures. So, we developed and validated a DL delta radiomics nomogram (DLDRN). In the validation cohort, the DLDRN produced an area under the receiver operating curve of 0.94 (95% confidence interval, 0.82-0.96) and demonstrated adequate differentiation of good response to NACT. Furthermore, the DLDRN significantly outperformed the clinical model and DL model (p < 0.001). The clinical utility of the DLDRN was confirmed through decision curve analysis. CONCLUSIONS: In patients with LAGC, the DLDRN effectively predicted a therapeutic response in metastatic lymph nodes, which could provide valuable information for individualized treatment.

Multimodal prehabilitation to improve the clinical outcomes of frail elderly patients with gastric cancer: a study protocol for a multicentre randomised controlled trial (GISSG+2201).

INTRODUCTION: Gastric cancer (GC) diagnosed in the elderly population has become a serious public health problem worldwide. Given the combined effects of frailty and the consequences of cancer treatment, older individuals with GC are more likely than young patients to suffer from postoperative complications and poor clinical outcomes. Nutrition, functional capacity and psychological state-based multimodal prehabilitation, which is dominated by Enhanced Recovery After Surgery (ERAS) pathway management, has been shown to reduce postoperative complications, promote functional recovery and decrease hospitalisation time in certain malignancies. However, no previous studies have investigated the clinical application of multimodal prehabilitation in frail older patients with GC. METHODS AND ANALYSIS: The study is a prospective, multicentre randomised controlled trial in which a total of 368 participants who meet the inclusion criteria will be randomised into either a prehabilitation group or an ERAS group. The prehabilitation group will receive multimodal prehabilitation combined with ERAS at least 2 weeks before the gastrectomy is performed, including physical and respiratory training, nutritional support, and therapy and psychosocial treatment. The ERAS group patients will be treated according to the ERAS pathway. All interventions will be supervised by family members. The primary outcome measures are the incidence and severity of postoperative complications. Secondary outcomes include survival, functional capacity and other short-term postoperative outcomes. Overall, the multimodal prehabilitation protocol may improve functional capacity, reduce the surgical stress response and concomitant systemic inflammation, and potentially modulate the tumour microenvironment to improve short-term and long-term clinical outcomes and patients' quality of life. ETHICS AND DISSEMINATION: All procedures and participating centres of this study were approved by their respective ethics committees (QYFYKYLL 916111920). The final study results will be published separately in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05352802.

A retrospective study comprising 228 cases of pediatric scalp and skull lesions.

BACKGROUND: Most neurosurgery presentations in children present with a mass that may be scalp and skull lesions, including neoplastic and congenital malformed structural lesions, respectively. Clinicians should make early diagnoses and identify cases requiring surgical intervention promptly to help achieve a better prognosis. METHOD: This study retrospectively reviewed studies on children's scalp and skull lesions within a pediatric medical center's department of neurosurgery. The detailed clinical information and pathological types of these cases were scrutinized. RESULT: A total of 228 children's scalp and skull lesions with clinical information and identified histopathology types were summarized. The most common scalp and skull lesions were benign dermoid cysts; malignant types were rare but can occur in children. CONCLUSION: Based on the combined clinical symptoms and image information, children's scalp and skull lesions should be diagnosed early. Malignant scalp and skull lesions/other special cases should be treated seriously.

Short- and long-term outcomes of laparoscopic or robotic radical gastrectomy based on preoperative perigastric artery CTA surgical decision-making: a high-volume center retrospective study with propensity score matching.

BACKGROUND: Some studies have demonstrated the short-term recovery course for patients who underwent laparoscopic gastrectomy according to preoperative computed tomography angiography (CTA) assessment. However, reports of the long-term oncological outcomes are still limited. METHODS: The data of 988 consecutive patients who underwent laparoscopic or robotic radical gastrectomy between January 2014 and September 2018 were analyzed retrospectively at our center, and propensity score matching was used to eliminate bias. Study cohorts were divided into the CTA group (n = 498) and the non-CTA group (n = 490) depending on whether preoperative CTA was available. The primary and secondary endpoints were the 3-year overall survival (OS) and disease-free survival (DFS) rates and the intraoperative course and short-term outcomes, respectively. RESULTS: 431 patients were included in each group after PSM. Compared with the non-CTA group, the CTA group had more harvested lymph nodes and less operative time, blood loss, intraoperative vascular injury and total cost, especially in the subgroup analysis with BMI ≥ 25 kg/m2 patients. There was no difference in the 3 year OS and DFS between the CTA group and the non-CTA group. When further stratified by BMI < 25 or ≥ 25 kg/m2, the 3-year OS and DFS were significantly higher in the CTA group than in the non-CTA group in terms of BMI ≥ 25 kg/m2. CONCLUSIONS: Laparoscopic or robotic radical gastrectomy based on preoperative perigastric artery CTA surgical decision-making has the possibility of improving short-term outcomes. However, there is no difference in the long-term prognosis, except for a subgroup of patients with BMI ≥ 25 kg/m2.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator.

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

The Consistence of Dynamic Contrast-Enhanced MRI and Filter-Exchange Imaging in Measuring Water Exchange Across the Blood-Brain Barrier in High-Grade Glioma.

BACKGROUND: Water exchange across blood-brain barrier (BBB) (WEXBBB ) is an emerging biomarker of BBB dysfunction with potential applications in many brain diseases. Several MRI methods have been proposed to measure WEXBBB , but evidence remains scarce whether different methods can produce comparable WEXBBB . PURPOSE: To explore whether dynamic contrast-enhanced (DCE)-MRI and vascular water exchange imaging (VEXI) could produce comparable WEXBBB in high-grade glioma (HGG) patients. STUDY TYPE: Prospective cross-sectional. SUBJECTS: 13 HGG patients (58.4 ± 9.4 years, 9 females, 4 WHO III and 9 WHO IV). FIELD STRENGTH/SEQUENCE: A 3 T, spoiled gradient-recalled-echo DCE-MRI and VEXI containing two pulsed-gradient spin-echo blocks separated by a mixing block. ASSESSMENTS: The enhanced tumor and contralateral normal-appearing white matter (cNAWM) volume-of-interests (VOIs) were drew by two neuroradiologists. And whole-brain NAWM and normal-appearing gray matter (NAGM) without tumor-affected regions were segmented by automated segmentation algorithm in FSL. STATISTICAL TESTS: Student's t-test was used to evaluate parameters difference between cNAWM and tumor, NAGM and NAWM, respectively. The correlation between vascular water efflux rate constant (kbo ) from DCE-MRI and apparent exchange rate across BBB (AXRBBB ) from VEXI was evaluated by Pearson correlation. P < 0.05 was considered statistically significant. RESULTS: Compared with cNAWM, both kbo and AXRBBB were significantly reduced in tumor (kbo = 3.50 ± 1.18 sec-1 vs. 1.03 ± 0.75 sec-1 ; AXRBBB = 3.54 ± 1.11 sec-1 vs. 1.94 ± 1.04 sec-1 ). Both kbo and AXRBBB showed significantly higher values in NAWM than NAGM (kbo = 3.50 ± 0.59 sec-1 vs. 2.10 ± 0.56 sec-1 ; AXRBBB = 3.35 ± 0.77 sec-1 vs. 2.07 ± 0.52 sec-1 ). The VOI-averaged kbo and AXRBBB were also linearly correlated in tumor, NAWM, and NAGM (r = 0.59). DATA CONCLUSION: DCE-MRI and VEXI showed comparable and correlated WEXBBB in HGG patients, suggesting that the consistence and reliability of these two MRI methods in measuring WEXBBB . EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 1.

Comparison of short- and long-term outcomes between laparoscopic and open gastrectomy for locally advanced gastric cancer following neoadjuvant chemotherapy: a propensity score matching analysis.

BACKGROUND: This study was performed to evaluate the safety and efficacy of laparoscopic gastrectomy (LG) in patients with locally advanced gastric cancer (LAGC) who received neoadjuvant chemotherapy (NACT). METHODS: We retrospectively analyzed patients who underwent gastrectomy for LAGC (cT2-4aN+M0) after NACT from January 2015 to December 2019. The patients were divided into a LG group and an open gastrectomy (OG) group. The short- and long-term outcomes in both groups were examined following propensity score matching. RESULTS: We retrospectively reviewed 288 patients with LAGC who underwent gastrectomy following NACT. Of these 288 patients, 218 were enrolled; after 1:1 propensity score matching, each group comprised 81 patients. The LG group had significantly lower estimated blood loss than the OG group [80 (50-110) vs. 280 (210-320) mL, P < 0.001) but a longer operation time [205 (186.5-222.5) vs. 182 (170-190) min, P < 0.001], a lower postoperative complication rate (24.7% vs. 42.0%, P = 0.002), and a shorter postoperative hospitalization period [8 (7-10) vs. 10 (8-11.5) days, P = 0.001]. Subgroup analysis revealed that patients who underwent laparoscopic distal gastrectomy had a lower rate of postoperative complications than patients in the OG group (18.8% vs. 38.6%, P = 0.034); however, such a pattern was not seen in patients who underwent total gastrectomy (32.3% vs. 45.9%, P = 0.251). The 3-year matched cohort analysis showed no significant difference in overall survival or recurrence-free survival (log-rank P = 0.816 and P = 0.726, respectively) (71.3% and 65.0% in OG vs. 69.1% and 61.7% in LG, respectively). CONCLUSION: In the short term, LG following NACT is safer and more effective than OG. However, the long-term results are comparable.

Development and validation of nomograms for predicting overall survival and cancer-specific survival in elderly patients with locally advanced gastric cancer: a population-based study.

OBJECTIVE: To evaluate the multiple factors influencing the survival of elderly patients with locally advanced gastric cancer (LAGC) and develop and validate the novel nomograms for predicting the survival. METHODS: The clinical features of patients treated between 2000 and 2018 were collected and collated from the Surveillance, Epidemiology, and End Results (SEER) database and three medical centres in China, and the patients were randomly divided into a training cohort (3494), internal validation cohort (1497) and external validation cohort (841). Univariate and multivariate analyses of the prognostic values were performed to identify independent prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS), and two nomogram models were developed. Harrell's concordance index (C-index) and calibration curves were employed to assess discrimination and calibration. Decision curve analysis (DCA) and receiver-operating characteristic (ROC) curves were utilized to investigate the clinical usefulness. RESULTS: In the SEER database, the 5-year OS of the patients was 31.08%, while the 5-year CSS of the patients was 44.09%. Furthermore, in the external validation set, the 5-year OS of the patients was 49.58%, and the 5-year CSS of these patients was 53.51%. After statistical analysis, nine independent prognostic factors of OS and CSS were identified, including age, race, tumour size, differentiation, TNM stage, gastrectomy type, lymph node metastasis (LNM), lymph node ratio (LNR) and chemotherapy. The C-index (approximately 0.7) and calibration curve (close to the optimal calibration line) indicated satisfactory discrimination and calibration of the nomogram. DCA and ROC curves showed that the developed nomogram was superior to TNM stage. CONCLUSION: The novel validated nomogram could accurately predict the prognosis of individual elderly patients with LAGC and guide the selection of clinical treatment measures.

Crystal structures of dimeric and heptameric mtHsp60 reveal the mechanism of chaperonin inactivation.

Mitochondrial Hsp60 (mtHsp60) plays a crucial role in maintaining the proper folding of proteins in the mitochondria. mtHsp60 self-assembles into a ring-shaped heptamer, which can further form a double-ring tetradecamer in the presence of ATP and mtHsp10. However, mtHsp60 tends to dissociate in vitro, unlike its prokaryotic homologue, GroEL. The molecular structure of dissociated mtHsp60 and the mechanism behind its dissociation remain unclear. In this study, we demonstrated that Epinephelus coioides mtHsp60 (EcHsp60) can form a dimeric structure with inactive ATPase activity. The crystal structure of this dimer reveals symmetrical subunit interactions and a rearranged equatorial domain. The α4 helix of each subunit extends and interacts with its adjacent subunit, leading to the disruption of the ATP-binding pocket. Furthermore, an RLK motif in the apical domain contributes to stabilizing the dimeric complex. These structural and biochemical findings provide new insights into the conformational transitions and functional regulation of this ancient chaperonin.

Intraoperative performance and outcomes of robotic and laparoscopic total gastrectomy for gastric cancer: A high-volume center retrospective propensity score matching study.

BACKGROUND: Studies on robotic total gastrectomy (RTG) are currently limited. This study aimed to compare the intraoperative performance as well as short- and long-term outcomes of RTG and laparoscopic total gastrectomy (LTG). METHODS: A total of 969 patients underwent robotic (n = 161) or laparoscopic (n = 636) total gastrectomy between October 2014 and October 2021. The two groups of patients were matched 1:3 using the propensity score matching (PSM) method. The intraoperative performance as well as short- and long-term outcomes of the robotic (n = 147) and the laparoscopic (n = 371) groups were compared. RESULTS: After matching, the estimated intraoperative blood loss was lower (80.51 ± 68.77 vs. 89.89 ± 66.12, p = 0.008), and the total number of lymph node dissections was higher (34.74 ± 12.44 vs. 29.83 ± 12.22, p < 0.001) in the RTG group compared with the LTG group. More lymph node dissections at the upper edge of the pancreas were performed in the RTG group than in the LTG (12.59 ± 4.18 vs. 10.33 ± 4.58, p = 0.001). Additionally, postoperative recovery indicators and laboratory data were greater in the RTG group than those in the LTG group, while postoperative complications were comparable between the two groups (19.0% vs. 18.9%, p = 0.962). For overweight or obese patients with body mass indexes (BMIs) ≥25, certain clinical outcomes of the RTG remained advantageous, and no significant differences in three-year overall survival (OS) or relapse-free survival (RFS) were observed. CONCLUSIONS: Robotic total gastrectomy demonstrated better intraoperative performance, could improve the short-term clinical outcomes of patients, and was more conducive to patient recovery. However, the long-term efficacies of the two approaches were similar. Robotic surgical systems may reduce surgical stress responses in patients, allowing them to receive postoperative chemotherapy sooner.

Characterization in Potent Modulation on Voltage-Gated Na+ Current Exerted by Deltamethrin, a Pyrethroid Insecticide.

Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na+ (NaV) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na+ current (INa) in pituitary tumor (GH3) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient, INa(T)) or sustained (late, INa(L)) INa; consequently, the EC50 value required for DLT-stimulated INa(T) or INa(L) was determined to be 11.2 or 2.5 µM, respectively. However, neither the fast nor slow component in the inactivation time constant of INa(T) activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate INa with a slowing in inactivation time course of the current. The INa(L) augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of INa(T) became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of INa(L) and tail INa (INa(Tail)) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys(V)) of persistent INa was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys(V) behavior of INa exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.

Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway.

Aim: Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. Methods: Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). Results: The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (ß2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, ß2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, ß2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. Conclusions: Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.

Water exchange detected by shutter speed dynamic contrast enhanced-MRI help distinguish solitary brain metastasis from glioblastoma.

PURPOSE: This study aimed to explore the feasibility of transmembrane water exchange parameters detected by brain shutter speed (BSS) dynamic contrast enhanced (DCE)MRI, which is validated to be associated with aquaporin-4 expression, in distinguishing glioblastoma (GBM) from solitary brain metastasis (SBM). METHODS: 40 patients (mean age: 58.6 ± 11.7 years old, male/female: 23/17) with GBM and 48 patients (mean age: 61.7 ± 10.5 years old, male/female: 28/20) with SBM were enrolled in this observational study. BSS DCE-MRI was performed before operation. Intravascular water efflux rate constant (kbo) and intracellular water efflux rate constant (kio) within the peritumoral region and enhancing tumor were calculated from SS-DCE, respectively. The difference of these two parameters between GBM and SBM was explored. Immunohistochemical staining aquaporin-4 of was performed to validate its underlying biological mechanism. RESULTS: The kbo was found to be statistically different within both peritumoral region {SBM vs. GBM (s-1): 1.0[0.4,1.7] vs. 1.5[0.9,2.1], p = 0.009} and enhanced tumor {SBM vs. GBM (s-1): 0.2[0.1,0.5] vs. 0.4[0.1,1.3], p = 0.034}. Immunohistochemical analysis reveals the high perivascular aquaporin-4 expression in GBM may contribute the higher kbo value than that of SBM. CONCLUSIONS: kbo derived from BSS DCE-MRI was an independent pathophysiological parameter for separating GBM from SBM, in which kbo might be associated with the perivascular aquaporin-4 expression.

Characterization in Effective Stimulation on the Magnitude, Gating, Frequency Dependence, and Hysteresis of INa Exerted by Picaridin (or Icaridin), a Known Insect Repellent.

Picaridin (icaridin), a member of the piperidine chemical family, is a broad-spectrum arthropod repellent. Its actions have been largely thought to be due to its interaction with odorant receptor proteins. However, to our knowledge, to what extent the presence of picaridin can modify the magnitude, gating, and/or the strength of voltage-dependent hysteresis (Hys(V)) of plasmalemmal ionic currents, such as, voltage-gated Na+ current [INa], has not been entirely explored. In GH3 pituitary tumor cells, we demonstrated that with exposure to picaridin the transient (INa(T)) and late (INa(L)) components of voltage-gated Na+ current (INa) were differentially stimulated with effective EC50's of 32.7 and 2.8 µM, respectively. Upon cell exposure to it, the steady-state current versus voltage relationship INa(T) was shifted to more hyperpolarized potentials. Moreover, its presence caused a rightward shift in the midpoint for the steady-state inactivate curve of the current. The cumulative inhibition of INa(T) induced during repetitive stimuli became retarded during its exposure. The recovery time course from the INa block elicited, following the conditioning pulse stimulation, was satisfactorily fitted by two exponential processes. Moreover, the fast and slow time constants of recovery from the INa block by the same conditioning protocol were noticeably increased in the presence of picaridin. However, the fraction in fast or slow component of recovery time course was, respectively, increased or decreased with an increase in picaridin concentrations. The Hys(V)'s strength of persistent INa (INa(P)), responding to triangular ramp voltage, was also enhanced during cell exposure to picaridin. The magnitude of resurgent INa (INa(R)) was raised in its presence. Picaritin-induced increases of INa(P) or INa(R) intrinsically in GH3 cells could be attenuated by further addition of ranolazine. The predictions of molecular docking also disclosed that there are possible interactions of the picaridin molecule with the hNaV1.7 channel. Taken literally, the stimulation of INa exerted by the exposure to picaridin is expected to exert impacts on the functional activities residing in electrically excitable cells.

Predictive value of serum adiponectin and hemoglobin levels for vascular cognitive impairment in ischemic stroke patients.

Objectives: To investigate the potential predictive value of serum adiponectin (APN) and hemoglobin (Hb) levels for the occurrence of vascular cognitive impairment in ischemic stroke patients. Methods: Eighty ischemic stroke patients, admitted to our hospital between June 2019 and November 2020, were retrospectively divided into no cognitive impairment (NCI) group (n=43) and cognitive impairment (CI) group (n=37) based on Montreal Cognitive Assessment (MoCA) scale scoring at three months follow-up. ELISA was used to assess serum Hb and APN levels and receiver operating characteristic (ROC) curves were created to evaluate correlation. Results: Serum APN and Hb levels were lower in the vascular cognitive impairment group compared to non-impaired counterparts. Pearson correlation analysis showed that both APN and Hb levels were positively correlated with MoCA scores. Area under curve analysis indicated predictive value for serum APN and Hb for predicting cognitive impairment in ischemic stroke patients. Conclusion: Serum APN and Hb levels in ischemic stroke patients have value for predicting vascular cognitive impairment and may be suitable for helping dictate treatment planning.

Clinical use of HD-MTX monotherapy in a rare case of refractory primary bone diffuse large B-cell lymphoma with long-term survival after local radiotherapy: A case report.

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) has been rarely reported because of its low incidence. The optimal treatment plan for patients with relapsed/refractory PB-DLBCL remains controversial. In this study, we present a case of a 57-year-old patient with refractory PB-DLBCL to better understand this disease. The patient developed lumbosacral/low extremity pain. A lumbar magnetic resonance imaging (MRI) revealed skeletal lesions with osteolysis in L4-L5 and S1. With the failure of multi-line chemotherapy, the patient developed paralysis of both lower limbs. 18-Fluorinefluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and MRI showed new lesions in the femoral head, cervical and thoracic vertebrae. We tried to treat the patient with adjuvant radiotherapy and 10 courses of high-dose methotrexate (HD-MTX)-based monotherapy, after which the patient was able to walk and achieved complete remission (CR). To the best of our knowledge, this is the first attempt to use local radiotherapy combined with an HD-MTX regimen successfully for the treatment of refractory PB-DLBCL.