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.

Neutralizing antibodies have been designed to specifically target and bind to the receptor binding domain (RBD) of spike (S) protein to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus from attaching to angiotensin converting enzyme 2 (ACE2). This study reports a distinctive nanobody, designated as VHH21, that directly catalyzes the S-trimer into an irreversible transition state through postfusion conformational changes. Derived from camels immunized with multiple antigens, a set of nanobodies with high affinity for the S1 protein displays abilities to neutralize pseudovirion infections with a broad resistance to variants of concern of SARS-CoV-2, including SARS-CoV and BatRaTG13. Importantly, a super-resolution screening and analysis platform based on visual fluorescence probes was designed and applied to monitor single proteins and protein subunits. A spontaneously occurring dimeric form of VHH21 was obtained to rapidly destroy the S-trimer. Structural analysis via cryogenic electron microscopy revealed that VHH21 targets specific conserved epitopes on the S protein, distinct from the ACE2 binding site on the RBD, which destabilizes the fusion process. This research highlights the potential of VHH21 as an abzyme-like nanobody (nanoabzyme) possessing broad-spectrum binding capabilities and highly effective anti-viral properties and offers a promising strategy for combating coronavirus outbreaks.
Single-Domain Antibodies/immunology* ; Spike Glycoprotein, Coronavirus/metabolism* ; SARS-CoV-2/immunology* ; Animals ; Humans ; Antibodies, Neutralizing/immunology* ; Camelus ; COVID-19/immunology* ; Antibodies, Viral/immunology* ; Angiotensin-Converting Enzyme 2

Objective To analyze the distribution characteristics of the single nucleotide polymorphism (SNP) site rs76206423 in the promoter region of the interleukin-2 receptor (IL-2R) β gene among Han males in a high radiation background area (HBRA) in Yangjiang City. Methods A total of 48 male participants from Tangkou Town, Yangxi County, Yangjiang City (HBRA group), and 51 male participants from Hengpo Town, Enping City (control group) were selected as the research subjects using the random number table method. Peripheral venous blood samples of participants from both groups were collected, and genomic DNA was extracted. The genotyping and allele frequency distribution of the rs76206423 (A/G) site in the IL-2R β promoter region was detected among the participants in both groups using the SNP detection method. The difference of allele frequencies between population in HBRA group and five area of East Asia, South Asia, Africa, Europe, and the Americas published in the Human Genome Project database from National Center for Biotechnology Information were analyzed. Results The allele frequencies of rs76206423 of population in both groups conformed to Hardy-Weinberg equilibrium (P>0.05). In the HBRA group, the AA genotype was predominant (64.6%), while the AG genotype was the most common in the control group (51.0%), with a significant difference (P<0.05). Population in both groups showed a predominance of the variant allele A (78.1% and 72.5%, respectively), with no significant difference (P>0.05). The frequency of the G allele of rs76206423 in the population in HBRA group was higher than those in South Asian, African, European, and American populations (all P<0.01), but showed no significant difference compared with East Asian populations (P>0.05). Conclusion In the Han male population from the HBRA in Yangjiang City, the rs76206423 site in the IL-2R β gene promoter region is predominantly composed of the wild-type A allele and AA genotype, indicating genetic stability and a relatively high degree of variation at this locus.

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Objective To analyze the distribution and drug resistance patterns of pathogenic bacteria in bile and blood cultures obtained from patients with biliary stones accompanied by acute biliary tract infection,to evaluate the clinical appropriate-ness of antibiotic use based on drug sensitivity results,and to provide evidence for empirical antibiotic treatment in such patients.Methods The clinical data of 161 patients with biliary calculi complicated by acute biliary tract infection who were admitted to the First People's Hospital of Neijiang from 2017 to 2023 were retrospectively analyzed.The results of microbial culture,drug sensitivity analysis,and patient characteristics were assessed to evaluate the appropriateness of clinical antimicrobial therapy.Results Among the 161 patients with positive cultures,212 strains of pathogenic bacteria were detected.The predominant patho-gens were Escherichia coli,Klebsiella pneumoniae subspecies,and Enterococcus faecium.Age and underlying diseases significantly affected the distribution of Escherichia coli and Klebsiella pneumoniae subspecies.Within the gram-negative bacterial group,Esche-richia coli and Klebsiella pneumoniae subspecies exhibited higher drug resistance to commonly used broad-spectrum penicillin,third-generation cephalosporin and quinolones but lower resistance rates to piperacillin and tazobactam;furthermore,elderly indi-viduals aged ≥65 years showed higher resistance rates to ceftriaxone than those under age 65 while people with drug exposure history had higher ceftazidime resistance rates that were statistically significant.In contrast to Enterococcus faecalis which displayed low antimicrobial resistance rates for most drugs tested in this study,Enterococcus faecium demonstrated high levels of antibiotic resistance;however,both Enterococcus faecalis and Enterococcus faecium exhibited zero-resistance rates against vancomycin and tigecycline although this may be attributed to their small sample size in our study cohort.Finally,we found that empirical anti-in-fective drugs,as well as target anti-infective drugs,were not prescribed rationally among these patients due mainly to inappropriate combinations of antibiotics or incorrect dosages.Conclusions The predominant pathogens in patients with acute biliary tract infection are gram-negative bacteria,Gram-positive bacteria,and fungi;however,the potential involvement of anaerobic bacteria should not be overlooked.Vancomycin exhibits sensitivity against gram-positive bacteria,yet the overall rationality of antibiotic usage remains suboptimal.Enhanced clinical testing for pathogenic microorganisms is imperative in the management of biliary stones accompanied by acute biliary tract infection.In contrast,clinical pharmacists should provide comprehensive training on anti-infective drugs to clinicians to facilitate their judicious selection of antibiotics based on drug sensitivity results and prevent the e-mergence of multidrug-resistant bacteria.

Objective To study the relationship of serum 25-hydroxyvitamin D3[25-(OH)D3],myostatin(MSTN),limb skeletal muscle index(ASMI)with osteopenia(OP)in patients with rheumatoid arthritis(RA)complicated with sarcopenia(SA).Methods A total of 244 RA patients selected as case group,and 123 healthy people who underwent physical examination in our hospital during the same period were selected as control group.The general data,serum levels of 25-(OH)D3,MSTN,ASMI and peripheral blood immune cells were compared among the two groups.The diagnostic value of serum 25-(OH)D3,MSTN and ASMI in RA patients with SA complicated with OP and the correlation between serum 25-(OH)D3,MSTN,ASMI and peripheral blood immune cells were analyzed.Results The levels of serum 25-(OH)D3,peripheral blood regulatory T lymphocyte(Treg)cells and ASMI in the case group were lower than those in the control group,while the levels of serum MSTN,peripheral blood helper T lymphocyte 17(Th17)cells and Th17/Treg were higher than those in the control group(P＜0.05).Among the 244 RA patients,171 had no SA,73 had SA,and the incidence of SA was 29.92％.The levels of serum 25-(OH)D3,peripheral blood Treg cells and ASMI in the SA group were lower than those in the non-SA group,and the levels of serum MSTN,peripheral blood Th17 cells and Th17/Treg were higher than those in the non-SA group(P＜0.05).The levels of serum 25-(OH)D3,peripheral blood Treg cells and ASMI in the OP group were lower than those in the non-OP group,while the levels of serum MSTN,peripheral blood Th17 cells and Th17/Treg were higher than those in the non-OP group(P＜0.05).The area under the curve(AUC)of combined detection of serum 25-(OH)D3,MSTN and ASMI for the diagnosis of OP in RA patients with SA was higher than that of the three alone(P＜0.05).Serum 25-(OH)D3 and ASMI in RA patients with SA complicated with or without OP were negatively correlated with peripheral blood Th17 cell level and Th17/Treg(P＜0.05),and positively correlated with peripheral blood Treg cell level(P＜0.05).The level of serum MSTN was positively correlated with the level of Th17 cells and Th17/Treg in peripheral blood(P＜0.05),and negatively correlated with the level of Treg cells in peripheral blood(P＜0.05).Conclusion The incidence of OP in RA patients with SA is high.At the same time,the occurrence of SA and OP can lead to the decrease of serum 25-(OH)D3,peripheral blood Th17 cell,Th17/Treg and ASMI,and the increase of serum MSTN and peripheral blood Treg cell.The combination detection of 25-(OH)D3,MSTN and ASMI can effectively improve the diagnosis of OP in RA patients with SA,and the levels of the three are significantly correlated with peripheral blood Th17 cells,Treg cells and Th17/Treg.

Objective:To evaluate the safety of neoadjuvant therapy with pembrolizumab combined with 5-fluorouracil (5-FU) and cisplatin in patients with advanced temporal bone squamous cell carcinoma (TBSCC), and its impact on tumor response rate and disease-free survival (DFS).Methods:This prospective, single-arm, open-label clinical study enrolled patients with advanced (Stage Ⅲ/Ⅳ) TBSCC from Sun Yat-sen Memorial Hospital. Patients received 2-3 cycles of neoadjuvant therapy with pembrolizumab, 5-FU, and cisplatin, followed by definitive surgery. Postoperatively, patients received 6 cycles of pembrolizumab combined with radiotherapy. The primary endpoint was the 2-year disease-free survival (DFS) rate. Secondary endpoints included objective response rate (ORR) and safety indicators. Survival analysis was performed using the Kaplan-Meier method. Adverse events (AE) were assessed using the National Cancer Institute′s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Statistical analyses were conducted using SPSS software, version 22.0.Results:From August 2021 to April 2024, 16 patients with advanced TBSCC were enrolled (13 males and 3 females), with a median age of 54 years and a median follow-up time of 2.32 years. Following neoadjuvant therapy, the objective response rate (ORR) was 64.3% (9/14), and the disease control rate (DCR) was 92.9% (13/14). The 2-year DFS rate was 86.6%. Common treatment-related adverse events (TRAE) included leukopenia (56.3%, 9/16), nausea and vomiting (50.0%, 8/16), diarrhea, oral mucositis, and elevated liver function tests (25.0%, 4/16). One patient (6.25%) experienced a grade 3 adverse event.Conclusion:Neoadjuvant pembrolizumab-chemotherapy significantly enhances objective response rate and disease-free survival in advanced TBSCC.

OBJECTIVE: To observe the clinical efficacy of thread-embedding at the combined lower he-sea and front-mu points for functional constipation with intestinal excess heat. METHODS: A total of 80 patients with functional constipation of intestinal excess heat were randomly divided into a thread-embedding group (40 cases, 2 cases dropped out) and a Chinese patent medication group (40 cases, 1 case dropped out). Based on the theory of combined lower he-sea and front-mu points for diseases of fu organs, Zhongwan (CV12), Guanyuan (CV4) and bilateral Zusanli (ST36), Shangjuxu (ST37), Tianshu (ST25), Xiajuxu (ST39) were selected and thread-embedding therapy was delivered in the thread-embedding group, once a week. Maren Runchang pill was given orally in the Chinese patent medication group, 6-12 g each time, twice a day. Both groups were treated for 4 weeks. Before and after treatment, the scores of constipation assessment scale (CAS), Bristol stool form scale (BSFS), patient-assessment of constipation quality of life (PAC-QOL) and TCM syndrome were observed, and the clinical efficacy was evaluated after treatment in the two groups. RESULTS: After treatment, the CAS scores and the TCM syndrome scores were decreased compared with those before treatment (P<0.05), while the BSFS scores were increased compared with those before treatment (P<0.05) in the two groups; the total scores, as well as the physical discomfort and psychosocial discomfort scores of PAC-QOL were decreased compared with those before treatment (P<0.05) in the two groups, the worry and anxiety, and the satisfaction scores of PAC-QOL were decreased compared with those before treatment (P<0.05) in the thread-embedding group. After treatment, the CAS score, the total score and item-scores of PAC-QOL, as well as the TCM syndrome score in the thread-embedding group were lower than those in the Chinese patent medication group (P<0.05). The total effective rate was 78.9% (30/38) in the thread-embedding group, which was higher than 56.4% (22/39) in the Chinese patent medication group (P<0.05). CONCLUSION Thread-embedding at the combined lower he-sea and front-mu points can effectively treat functional constipation with intestinal excess heat and improve quality of life.
Humans ; Constipation/physiopathology* ; Male ; Female ; Middle Aged ; Acupuncture Points ; Adult ; Acupuncture Therapy ; Aged ; Treatment Outcome ; Young Adult ; Intestines/physiopathology* ; Quality of Life

Objective To investigate whether evodiamine(EVO)can alleviate liver injury in septic rats by influencing the nucleo-tide-binding and oligomerization domain(NOD)-like receptor protein 3(NLRP3)/interleukin-1 β(IL-1β)/caspase-1 signaling pathway.Methods A rat model of sepsis-induced liver damage was constructed,and the successfully modeled rats were assigned to the model,L-EVO,M-EVO,H-EVO(administered orally at 4,8,and 16 mg/kg of EVO),and H-EVO+NLRP3(administered orally at 16 mg/kg of EVO+intraperitoneal injection of 1 mg/kg of NLRP3 signaling pathway activator sodium salt)groups,each with ten rats.In addition,ten normal rats were selected as the control group(that is,the sham surgery group,without ligation or puncture,using the same steps as for the model group).The control and model groups were administered with equal amounts of physiological saline once daily for 28 d,consecutively.A reagent kit was used to assess rat liver function.Hematoxylin and eosin(HE)staining was used to analyze pathological changes in the liver tissue.Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)staining was used to assess apoptosis in liver tissue cells.ELISA was used to analyze IL-6,tumor necrosis factor α(TNF-α),and IL-1β levels in serum.Western blotting was used to detect changes in protein expression of the NLRP3/IL-1β/caspase-1 signaling pathway components in liver tissues.Results For the control group,the liver tissues of rats in the model group lost their normal structure,with an uneven distribution of liver cells accompanied by edema and vacuoles.For the model group,the L-EVO,M-EVO,and H-EVO groups exhibited a relatively neat arrangement of liver tissue cells,reduced edema,and vacuoles.As the dose increased,the morphology of liver tissue cells recovered significantly.For the H-EVO group,the H-EVO+NLRP3 group exhibited a disordered arrangement of liver tissue cells with edema and vacuoles.For the control group,the model group showed increased alanine aminotransferase(ALT),aspartate aminotransferase(AST),liver tissue cell apoptosis rate,serum IL-6,TNF-α,and IL-1β levels,and expression of NLRP,IL-1β,and caspase-1 protein in the liver tissue(P＜0.05).For the model group,the L-EVO,M-EVO,and H-EVO groups showed lower ALT,AST,liver tissue cell apoptosis rate,serum IL-6,TNF-α,and IL-1β levels,and expression of NLRP,IL-1β,and caspase-1 protein in the liver tissue(P＜0.05).For the H-EVO group,the H-EVO+NLRP3 group had higher ALT,AST,liver tissue cell apoptosis rate,serum IL-6,TNF-α,and IL-1β levels,and expression of NLRP,IL-1β,and caspase-1 pro-tein in the liver tissue(P＜0.05).Conclusion EVO can alleviate liver injury in septic rats by influencing the NLRP3/IL-1β/caspase-1 signaling pathway.

Objective:To systematically evaluate the unmet needs and challenges of caregivers of cancer patients at home and clarify their unmet needs.Methods:A computerized search was conducted in PubMed, Web of Science, Embase, Cochrane Library, ProQuest, Scopus, CINAHL, China National Knowledge Infrastructure, Wanfang Data, VIP, and China Biology Medicine disc for qualitative studies on the unmet needs and challenges of caregivers of cancer patients in the home environment. The search time limit was from the establishment of the databases to April 30, 2024. The Joanna Briggs Institute Centre for Evidence-Based Healthcare's quality assessment criteria for qualitative research were used to evaluate the quality of the literatures, and the aggregative integration method was used to summarize and integrate the research results.Results:A total of 17 articles were finally included, which were summarized into eight new categories. Further synthesis yielded three integrated results: caregivers in the home environment face multi-dimensional unmet needs and challenges related to patients; caregivers in the home environment face challenges and unmet needs in self-care; caregivers in the home environment are hesitant to obtain external support, and continuity and sustainability are hindered.Conclusions:Medical staff should accurately assess the unmet needs of caregivers of cancer patients at home, pay attention to their negative experiences, promote positive coping, optimize the patient-and family-centered cancer care model, and strengthen social support.