BACKGROUND:The pathogenesis of diabetic peripheral neuropathy has not yet been clarified,and TAM(Tyro3,Axl,and MerTK)receptor tyrosine kinases can control apoptotic cells and suppress inflammatory responses in the central nervous system. OBJECTIVE:To investigate the difference of Mer receptor tyrosine kinase(MerTK)levels in plasma and sciatic nerve tissue of Sprague-Dawley rats with type 2 diabetes and diabetic peripheral neuropathy,and to study the correlation between MerTK and diabetic peripheral neuropathy. METHODS:Forty male Sprague-Dawley were randomly divided into control group with 15 rats,type 2 diabetes group with 10 rats,and diabetic peripheral neuropathy group with 15 rats.The control group was fed with ordinary diet,while the experimental groups were fed with high-fat and high-sugar diet.After 6 weeks,intraperitoneal injection of streptozotocin at the minimum dose of 35 mg/kg was administered in the two experimental groups.After 14 days,tail vein blood was collected to detect blood glucose.If blood glucose≥16.7 mmol/L,the model of type 2 diabetes was successfully established.Rats in the diabetic peripheral neuropathy group continued to be fed with a high-sugar and high-fat diet for 8 weeks.The sciatic nerve conduction velocity of rats was detected through live isolation under anesthesia.Blood samples were collected from the abdominal aorta,and the sciatic nerve tissue was collected.Histological changes of nerve fibers in each group were observed under a light microscope to confirm the success of diabetic peripheral neuropathy modeling.ELISA was used to detect peripheral blood glucose,blood lipids and serum MerTK levels in rats;hematoxylin-eosin staining was used to observe the histological changes in the sciatic nerve;immunofluorescence,immunohistochemistry and western blot were used to detect the expression of MerTK in the sciatic nerve tissue. RESULTS AND CONCLUSION:The Sprague-Dawley rat models of type 2 diabetes and type 2 diabetes peripheral neuropathy were successfully constructed,and the modeling rate of diabetic peripheral neuropathy was 80%.Compared with the control group,the blood glucose levels of rats in the type 2 diabetes and diabetic peripheral neuropathy groups were significantly higher(P<0.000 1),while the blood glucose level in the diabetic peripheral neuropathy group was higher than that in the type 2 diabetes group;and the sciatic nerve conduction velocity was significantly decreased(P<0.05),which was lower in the diabetic peripheral neuropathy group than the type 2 diabetes group.Histological examination:Compared with the control group,the sciatic nerve nuclei were reduced in the type 2 diabetes group,with some vacuolar degeneration and phagocytosis;in the diabetic peripheral neuropathy group,the cell body was swollen,the nuclear spacing was increased,vacuolar degeneration was observed,and the myelin sheath was partitioned and unsmooth,and lattice-like axons appeared.Serum MerTK levels were significantly higher in the diabetic peripheral neuropathy group than the control group.Expression of MerTK in the sciatic nerve tissue was significantly upregulated in the diabetic peripheral neuropathy group compared with the control group(P<0.05).To conclude,elevated levels of MerTK in plasma and sciatic nerve tissue of rats with diabetic peripheral neuropathy are presumably related to its anti-inflammatory and immunomodulatory effects.

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

OBJECTIVE: To investigate the feasibility and prognostic implications of assessing volume status during early fluid resuscitation in septic patients based on estimated plasma volume status (ePVS). METHODS: A prospective study was conducted. Patients with sepsis admitted to intensive care unit (ICU) of the First Affiliated Hospital of Kunming Medical University from March to December in 2023 were enrolled. The general information and laboratory indicators at ICU admission were recorded, and ePVS, sequential organ failure assessment (SOFA) score, acute physiology and chronic health status evaluation II (APACHE II) score were calculated. The vital signs, arterial blood gas analysis and volume status related indicators before liquid resuscitation (T0h) and 3 hours (T3h) and 6 hours (T6h) of fluid resuscitation were recorded. The diameter and variability of the inferior vena cava (IVC) were measured by ultrasound, and ePVS, percentage change value of estimated plasma volume status (ΔePVS%), difference in central venous-to-arterial partial pressure of carbon dioxide (Pcv-aCO₂), and lactate clearance rate (LCR) were calculated. Patients were divided into sepsis group and septic shock group based on the diagnosis at ICU admission, and septic patients were subdivided into survival group and death group based on their 28-day survival status. The differences in clinical data between the groups were compared. The correlation between ePVS or ΔePVS% and volume status related indicators during early liquid resuscitation was analyzed by Spearman rank sum correlation test. The predictive value of each variable for 28-day survival in patients with sepsis was analyzed by receiver operator characteristic curve (ROC curve), and 28-day death risk factors were analyzed by Logistic regression method. RESULTS: Fifty-four septic patients were enrolled in the final analysis, including 17 with sepsis and 37 with septic shock; 34 survived at 28 days and 20 died, with a 28-day survival rate of 63.0%. Compared with the sepsis group, the septic shock group had a lower venous ePVS at ICU admission [dL/g: 4.96 (3.67, 7.15) vs. 7.55 (4.36, 10.07), P < 0.05]. Compared with the death group, the survival group had higher T6h arterial and venous ΔePVS%, and albumin [Alb; T6h arterial ΔePVS% (%): 11.57% (-1.82%, 31.35%) vs. 0.48% (-5.67%, 6.02%), T6h venous ΔePVS%: 9.62% (3.59%, 25.75%) vs. 1.52% (-9.65%, 7.72%), Alb (g/L): 27.57±4.15 vs. 23.77±6.97, all P < 0.05], lower SOFA score, APACHE II score, AST, T0h Lac, and T3h and T6h norepinephrine dosage [SOFA score: 9.00 (8.00, 10.00) vs. 11.50 (9.25, 14.50), APACHE II score: 18.00 (14.75, 21.25) vs. 25.50 (21.00, 30.00), AST (U/L): 34.09 (23.20, 56.64) vs. 79.24 (25.34, 196.59), T0h Lac (mmol/L): 1.75 (1.40, 2.93) vs. 3.25 (2.33, 5.30), norepinephrine dosage (mg): 0.98 (< 0.01, 3.10) vs. 4.60 (1.05, 8.55) at T3h, 1.82 (0.38, 5.30) vs. 8.20 (2.80, 17.73) at T6h, all P < 0.05]. While there were no significantly differences in other basic data and ePVS at all of the time points before and after resuscitation between the two groups. Correlation analysis showed that T6h venous ePVS was significantly positively correlated with T6h IVC variability in septic patients (r = 0.360, P < 0.05), T0h arterial ePVS was significantly negatively correlated with T3h and T6h liquid intake volume (r₁ = -0.367, r₂ = -0.280, both P < 0.05), and venous ePVS at ICU admission was significantly positively correlated with NT-proBNP at ICU admission (r = 0.409, P < 0.05). T6h venous ΔePVS% was significantly positively correlated with T3h liquid intake volume and T6h LCR (r₁ = 0.286, r₂ = 0.286, both P < 0.05), and significantly negatively correlated with T6h urine volume and T6h change value of Pcv-aCO₂ (ΔPcv-aCO₂; r₁ = -0.321, r₂ = -0.371, both P < 0.05). ROC curve analysis showed that the area under the ROC curve (AUC) of T6h venous ΔePVS% for predicting 28-day survival in septic patients was 0.726 [95% confidence interval (95%CI) was 0.578-0.875, P = 0.006], with a sensitivity of 82.4%, a specificity of 60.0%, and an optimal cut-off value of 3.09%. Binary multifactorial Logistic regression analysis showed that an increase in T6h venous ΔePVS% was a protective factor for 28-day death in patients with sepsis on early fluid resuscitation [odds ratio (OR) = 0.900, 95%CI was 0.834-0.972, P = 0.007]. CONCLUSIONS ePVS may have potential for assessing the volume status of septic patients during early fluid resuscitation. The ΔePVS% during early fluid resuscitation may help to identify septic patients with a poor prognosis.
Humans ; Prognosis ; Fluid Therapy ; Sepsis/physiopathology* ; Prospective Studies ; Plasma Volume ; Intensive Care Units ; Resuscitation ; Male ; Female ; Middle Aged ; Shock, Septic/therapy*

Objective:To develop a genotyping method for the Junior blood type and report on a rare blood type with Jr(a-).Methods:Healthy O-type RhD+ volunteer donors of the Shenzhen Blood Center from January to May 2021 ( n=1 568) and a pedigree with difficult cross-matching ( n=3) were selected as the study subjects. Serological methods were used for proband′s blood type identification, unexpected antibody identification, and antibody titer determination. Polymerase chain reaction-sequence specific primer (PCR-SSP) method was used for typing the proband′s RHD gene. ABCG2 gene coding region sequencing and a PCR-SSP genotyping method were established for determining the genotypes of the proband and his family members and screening of Jra antigen-negative rare blood type among the 1 568 blood donors. Results:The proband′s ABO and RhD blood types were respectively determined as B and partial D (RHDDVI.3/RHD01N.01), Junior blood type Jra antigen was negative, and plasma had contained anti-D and anti-Jra. Sequencing of the ABCG2 gene revealed that the proband′s genotype was ABGG201N.01/ABGG201N.01 [homozygous c. 376C>T (p.Gln126X) variants], which is the most common Jr(a-) blood type allele in the Asian population. Screening of the voluntary blood donors has detected no Jr(a-) rare blood type. Statistical analysis of the heterozygotes suggested that the allelic frequency for ABCG2*01N.01 (c.376T) was 0.45%, and the frequency of Jr(a-) rare blood type with this molecular background was about 0.2‰. Conclusion:A very rare case of partial DVI.3 type and Jr(a-) rare blood type has been identified. And a method for identifying the Junior blood type through sequencing the coding regions of the ABCG2 gene and PCR-SSP has been established.

Objective To investigate the effect of whey protein supplementation on rehabilitation of stroke-related sarcopenia patients with diabetes mellitus.Methods Forty-seven stroke-related sarcopenia patients with diabetes mellitus admitted to the First Affiliated Hospital of Wenzhou Medical University from January 2021 to September 2023 were selected and divided into observation group(24 cases)and control group(23 cases)according to random number table method.Patients in both groups were given normal diabetic diet,conventional drug therapy and rehabilitation training,and patients in observation group were given whey protein powder orally every day for 4 weeks.The non-hemiplegic hand grip strength,appendicular skeletal muscle mass index(ASMI),modified Barthel index(MBI),Fugl-Meyer assessment(FMA),mini-nutritional assessment short-form(MNA-SF),serum albumin(Alb),C-reactive protein(CRP)were compared between two groups before and after intervention.Results After intervention,the grip strength,ASMI,FMA,MBI of two groups were significantly higher than before ntervention,and CRP level was significantly lower than before intervention(P<0.05).The grip strength,ASMI,FMA,MBI,MNA-SF score and Alb of observation group were significantly higher than those of control group,while CRP was significantly lower than that of control group(P<0.05).ASMI was positively correlated with Alb,MNA-SF score and grip strength(P<0.05),while CRP was negatively correlated with Alb,MNA-SF score and ASMI(P<0.05).Conclusion Supplementation of whey protein can improve the nutritional status,muscle strength and muscle mass of patients with stroke-related sarcopenia complicated with diabetes mellitus,and improve the physical motor function and the ability of daily living.

Objective To explore the regulatory effect of Mertk expression level on NF-κb pathway in rat Schwann cells and its possible mechanism.Methods Rat Schwann cells were cultured in vitro,and the expression of Mertk in Schwann cells exposed to high glucose was detected by Western blot.Co-immunoprecipitation was used to detect the interaction between endogenous Mertk and Ikbkb.Western blot was used to detect the expression levels of Ikbkb,P65 and tumor necrosis factor-α in Schwann cells after Mertk silencing.The protein expressions of Mertk,Ikbkb and P65 after silencing Mertk were detected by immunofluorescence.Results Mertk was expressed in Schwann cells,and the expression level increased with the increase of glucose concentration.Co-immunoprecipitation assay showed that Mertk interacted with Ikbkb in rat Schwann cells.Compared with the control group,the expression level of Mertk was significantly decreased(P<0.05),while Ikbkb,P65 and TNF-α were significantly increased(P<0.05)after knock down expression of Mertk in Schwann cells.Immunofluorescence experiments showed that the fluorescence of Mertk was decreased,and the fluorescence of Ikbkb and P65 was increased in the silenced Schwann cells.Conclusion After the expression of Mertk is decreased,it can mediate the regulation of NF-κb pathway in Schwann cells through interaction with Ikbkb,and up-regulate the expression of P65 and inflammatory factor TNF-α.

This study aimed to explore key quality control factors that affected the prognosis of intensive care unit (ICU) patients in Chinese mainland over six years (2015-2020). The data for this study were from 31 provincial and municipal hospitals (3425 hospital ICUs) and included 2 110 685 ICU patients, for a total of 27 607 376 ICU hospitalization days. We found that 15 initially established quality control indicators were good predictors of patient prognosis, including percentage of ICU patients out of all inpatients (%), percentage of ICU bed occupancy of total inpatient bed occupancy (%), percentage of all ICU inpatients with an APACHE II score ⩾15 (%), three-hour (surviving sepsis campaign) SSC bundle compliance (%), six-hour SSC bundle compliance (%), rate of microbe detection before antibiotics (%), percentage of drug deep venous thrombosis (DVT) prophylaxis (%), percentage of unplanned endotracheal extubations (%), percentage of patients reintubated within 48 hours (%), unplanned transfers to the ICU (%), 48-h ICU readmission rate (%), ventilator associated pneumonia (VAP) (per 1000 ventilator days), catheter related blood stream infection (CRBSI) (per 1000 catheter days), catheter-associated urinary tract infections (CAUTI) (per 1000 catheter days), in-hospital mortality (%). When exploratory factor analysis was applied, the 15 indicators were divided into 6 core elements that varied in weight regarding quality evaluation: nosocomial infection management (21.35%), compliance with the Surviving Sepsis Campaign guidelines (17.97%), ICU resources (17.46%), airway management (15.53%), prevention of deep-vein thrombosis (14.07%), and severity of patient condition (13.61%). Based on the different weights of the core elements associated with the 15 indicators, we developed an integrated quality scoring system defined as F score=21.35%xnosocomial infection management + 17.97%xcompliance with SSC guidelines + 17.46%×ICU resources + 15.53%×airway management + 14.07%×DVT prevention + 13.61%×severity of patient condition. This evidence-based quality scoring system will help in assessing the key elements of quality management and establish a foundation for further optimization of the quality control indicator system.
Humans ; China/epidemiology* ; Cross Infection/epidemiology* ; Intensive Care Units/statistics & numerical data* ; Quality Control ; Quality Indicators, Health Care/statistics & numerical data* ; Sepsis/therapy* ; East Asian People/statistics & numerical data*

Clinical post competence and medical ethics literacy are the key qualities that applied medical talents should have. The synergy of medical education is an effective way to deepen the reform of competence-oriented medical education. Under the background of synergy of medical education and considering the orientation of training applied medical talents in our college, we explore a progressive path of "three early education", which means early exposure to specialties, early exposure to practice, and early exposure to clinical practice. Meanwhile, we strengthen the cultivation of medical students' medical ethics literacy throughout the whole process of "three early education", laying a solid foundation for medical students before they enter the stage of clinical practice training. Practice shows that the progressive "three early education" mode and the cultivation of medical ethics literacy throughout the whole process can effectively improve medical students' clinical post competence.

Objective:To evaluate the role of small ubiquitin-associated modifier (SUMO) E3 ligase (PIAS)-regulated SUMOylation of peroxisome proliferator-activated receptor γ (PPARγ) in the endogenous protective mechanism against endotoxin-induced acute lung injury (ALI) in mice.Methods:Experiment Ⅰ Twenty-four clean-grade wild type male C57BL/6 mice, aged 6-8 weeks, weighing 18-22 g, were divided into 4 groups ( n=6 each) using a random number table method: control group (C group), ALI group, ALI+ PPARγ inducer TZD group (ALI+ T group) and ALI+ TZD+ SUMOylation inhibitor anacardic acid group (ALI+ T+ A group). Lipopolysaccharide (LPS) 15 mg/kg was injected into the tail vein to develop the ALI model. In ALI+ T+ A group, anacardic acid 5 mg/kg was intraperitoneally injected at 1 h before LPS administration. In ALI+ T group and ALI+ T+ A group, TZD 50 mg/kg was intraperitoneally injected at 30 min before LPS administration. The mice were sacrificed at 12 h after LPS administration, and the lung tissues were obtained to examine the pathological changes which were scored and to determine the wet/dry (W/D) weight ratio, and expression of PIAS1, PIAS2, PIAS3 and PIASy protein and mRNA (by Western blot or polymerase chain reaction). Experiment Ⅱ Mouse alveolar macrophages (MH-S cells) were cultured in vitro and divided into 4 groups ( n=5 each) using a random number table method: control group (C group), LPS group, LPS+ PIAS2 siRNA group (L+ P group) and LPS+ Con siRNA group (L+ C group). Cells were routinely cultured in group C. Cells were stimulated with 10 μg/ml LPS to develop the model of endotoxin challenge. PIAS2 siRNA 50 nmol/L and Con siRNA 50 nmol/L were transfected at 48 h before LPS was added in L+ P group and L+ C group, respectively. The cells were collected at 24 h of incubation with LPS to determine the cell viability, levels of M1 and M2 alveolar macrophages (by flow cytometry), expression of PIAS2 and PPARγ (by Western blot), co-expression of PPARγ-SUMO1 (by immunoprecipitation) and expression of tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) mRNA (by polymerase chain reaction). The ratio of M1/M2 was calculated. Results:Experiment Ⅰ Compared with C group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was up-regulated in the other three groups ( P<0.05). Compared with ALI group, the lung injury scores and W/D ratio were significantly decreased, and the expression of PIAS2 protein and mRNA was up-regulated in ALI+ T group and ALI+ T+ A group ( P<0.05). Compared with ALI+ T group, the lung injury scores and W/D ratio were significantly increased, and the expression of PIAS2 protein and mRNA was down-regulated in ALI+ T+ A group ( P<0.05). There was no significant difference in the expression of PIAS1, PIAS3 and PIASy protein and mRNA in lung tissues among the four groups ( P>0.05). Experiment Ⅱ Compared with C group, the cell viability was significantly decreased, the expression of PPARγ and co-expression of PPARγ-SUMO1 was up-regulated, the levels of M1 and M2 macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was up-regulated, and the expression of IL-10 mRNA was down-regulated in the other three groups, and PIAS2 expression was significantly up-regulated in L group and L+ C group ( P<0.05). Compared with L group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and PPARγ-SUMO1 co-expression were down-regulated, the M1 macrophage level and M1/M2 ratio were increased, TNF-α mRNA expression was up-regulated, and the expression of IL-10 mRNA was down-regulated in L+ P group ( P<0.05), and no significant change was found in the parameters mentioned above in L+ C group ( P>0.05). Compared with L+ C group, the cell viability was significantly decreased, the expression of PIAS2 and PPARγ and co-expression of PPARγ-SUMO1 were down-regulated, the level of M1 alveolar macrophages and M1/M2 ratio were increased, the expression of TNF-α mRNA was down-regulated, and the expression of IL-10 mRNA was up-regulated in L+ P group ( P<0.05). Conclusions:PIAS2-regulated SUMOylation of PPARγ is the endogenous protective mechanism against endotoxin-induced ALI in mice, which may be related to inhibition of macrophage polarization into M1 type and alleviation of inflammatory responses.

ObjectiveTo investigate the effects of upper limb robot-assisted training on cognitive function, upper limb motor function and activity of daily living for subacute stroke patients. MethodsFrom September, 2019 to September, 2020, 65 subacute stroke hemiplegic patients with cognitive impairment were randomly divided into control group (n = 32, two cases dropped) and experimental group (n = 33, three cases dropped). Both groups accepted conventional occupational therapy; and then, the control group accepted conventional cognitive training, while the experimental group accepted upper limb robot-assisted training, for four weeks. They were assessed with Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Fugl-Meyer Assessment-Upper Extremities (FMA-UE) and modified Barthel Index (MBI) before and after treatment. ResultsThe scores of MoCA, MMSE, FMA-UE and MBI improved after treatment in both groups (t > 22.11, Z > 4.79, P < 0.001), the MoCA total score and some item-scores, MMSE total score and some item-scores, FMA-UE total score and the score of arm, and score of MBI improved more in the experimental group than in the control group (t > 2.06, Z > 3.19, P < 0.05). ConclusionUpper limb robot-assisted training could facilitate to improve the cognitive function, upper limb motor function and activities of daily living in subacute stroke patients.