Functional constipation （FC） is a clinically common functional bowel disorder characterized by a protracted course and associations with various chronic disorders and psychological abnormalities. Although not life-threatening， FC significantly impairs patients' quality of life. FC subtypes include slow-transit constipation （STC）， defecatory disorder （DD）， and normal-transit constipation （NTC）. The pathological mechanisms underlying FC have not been fully elucidated， and overall clinical efficacy remains unsatisfactory. Animal models of FC serve as essential tools for the study of disease mechanisms and the development of novel therapeutics. This article systematically reviews the current state of research on the animal models of FC and identifies that rodents， particularly rats and mice， are the most commonly used species. Dogs and pigs are also employed in complex intervention studies due to their physiological similarities to humans， though their use is limited by housing challenges and ethical considerations. Induction methods vary across different FC subtypes. STC models are primarily established with chemical agents such as loperamide or compound diphenoxylate. DD modeling often involves low-fiber diets combined with methylene blue injection or rectal narrowing. NTC modeling mainly relies on low-fiber dietary interventions. In addition， disease-syndrome combination models based on traditional Chinese medicine （TCM） theory have been developed， encompassing excess patterns such as heat accumulation， cold accumulation， and Qi stagnation， as well as deficiency patterns including Qi deficiency， blood deficiency， Yin deficiency， and Yang deficiency. These are achieved through an approach of disease model + syndrome induction， enabling the integration of mechanisms from both Western and TCM perspectives. Models are evaluated from two aspects： disease and syndrome manifestations （e.g.， colonic transit， secretory function， and TCM syndrome indicators such as mental state and body weight） and disease mechanisms （e.g.， enteric nervous system， interstitial cells of Cajal， smooth muscle cells， gut microbiota， and metabolites）. However， current research still faces challenges such as poor consistency in some models， non-specific interference in mechanism interpretation， insufficient studies on NTC， and lack of TCM tongue and pulse diagnosis in evaluation. Future efforts should focus on optimizing model stability and specificity to provide a more reliable experimental basis for investigating the pathological mechanisms of FC and developing therapeutic agents.

Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Objective:Postoperative neurosurgical bacterial meningitis (PNBM) has been frequently reported, but fewer studies have focused on the contemporaneous comparison of clinical features of PNBM caused by different pathogenic bacteria. This study aimed to simultaneously investigate the clinical characteristics and outcomes of PNBM by Gram-positive bacterial(GPB) or Gram-negative bacterial (GNB) infection.Methods:Inpatients with PNBM at our institution were recruited between February 2013 and October 2023. These PNBM patients were categorized into two groups: GPB infection and GNB infection. Data from electronic medical records were collected and analyzed.Results:A total of 401 patients with PNBM were finally included, with 78 (19.5%) having GPB infections and 323 (80.5%)having GNB infection. The average age of the patients was 56 years, and 55.1% were male. Compared to the GPB group, PNBM patients with GNB infection had significantly higher SOFA and APACHE Ⅱ scores, higher proportions of hyperthermia (body temperature>39°C) and altered consciousness, increased ratios of postoperative cerebral hemorrhage or intracranial aneurysm, as well as greater needs for ICU treatment and mechanical ventilation (all P <0.05). The proportions of inflammatory indicators such as blood CRP and PCT≥2 ng/mL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were significantly higher in the GNB group (all P<0.05). In contrast, The concentrations of hemoglobin and albumin were substantially lower in this group(both P <0.05). Additionally, the cerebrospinal fluid in the GNB group showed significantly higher nucleated cell counts, protein concentration, and adenosine deaminase concentration, and but lower glucose level (all P <0.001). A total of 426 bacterial strains were isolated, with 343 strains (80.5%) being GNB and 83 strains (19.5%) being GPB. Among these, 25 (6.2%) patients had 2 or more gram-positive or gram-negative bacterial infections. The proportions of multidrug-resistant (MDR) bacteria and intrathecal treatment were higher in the GNB group (80.5% vs. 68.7%, 36.5% vs. 2.6%, respectively), while the ratio of correct empirical antibiotic treatment was significantly lower (30.3% vs. 80.0%) (all P <0.05). In terms of outcomes, the length of stay in the ICU was significantly longer in the GNB group [(median (interquartile range, IQR): 11.5 (5.25,22.75) vs. 17.0 (9.0,30.0), P <0.01)], and the rate of septic shock (9.3% vs. 2.6%), poor prognosis (GCS≤8 at discharge) (65.9% vs. 32.1%), and 28-day hospital mortality rate (34.4% vs. 10.3%) were significantly higher compared to the GPB group (all P <0.05). However, there were no differences in 7-day hospital mortality and total hospitalization time. Conclusions:Gram-negative bacterial infections are more prevalent than Gram-positive bacterial infections in PNBM, and they are also associated with more severe symptoms, abnormal cerebrospinal fluid findings, higher severity, and more treatment difficulty. Despite comparable short-term (7-day) mortality rates between Gram-positive and Gram-negative bacterial infections, Gram-negative bacterial infections result in higher medium- to long-term (14-day and 28-day) case-fatality rates among patients with post-neurosurgical bacterial meningitis and are associated with overall poorer prognosis, warranting greater attention from clinicians.

The fundamental pathogenic mechanisms of inflammatory bowel disease(IBD),a chronic inflammatory illness affecting the gastrointestinal tract,are still not fully understood.Dipeptidyl peptidase Ⅳ(DPP-4)is a glycoprotein found on the cell surface that has signaling and enzymatic properties.In addition,there is growing evidence from animal models and clinical trials that DPP-4 inhibitors have potential impacts beyond only lowering blood sugar levels,such as immunomodulatory and anti-inflammatory capabilities.This article reviews the biological properties of DPP-4 and its research progress in the diagnosis and treatment of IBD.It also discusses the mechanism of DPP-4 in IBD,aiming to provide a more in-depth understanding of the role of DPP-4 in IBD.

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Objective:To explore the effect of the treatment of tendinous mallet finger deformity by the minimally invasive percutaneous quantitative suture technique eight times.Methods:A retrospective analysis was performed on patients with fresh tendinous mallet fingers who underwent surgery in the Department of Hand and Foot Microsurgery of Nanjing Jiangbei Hospital from April 2021 to April 2022. During the procedure, the extensor digitalis tendon in the zone Ⅰ was sutured percutaneous with 3-0 thread monofilament sutures in the "quantitative 8-stitch method" according to the pre-marked number sequence of 1 to 8, and fixed at the base of the distal phalanx via a constructed bone tunnel. Removal of the Kirschner wire 8 weeks, the brace was used to fix the affected finger in the dorsal extension. The flexion and extension of the affected finger were gradually strengthened. The function of the affected finger was evaluated according to the Crawford standard after operation and follow-up: the active flexion and extension range of motion of each joint of the affected finger and the contralateral healthy finger was measured, and the total active ranges of motion of the finger were recorded. Finger function was evaluated according to the total active range of motion (TAM) system of the American Association of Hand Surgeons.Results:A total of 10 patients (10 digits) were enrolled, including 7 males and 3 females, and the age ranged from 20 to 52 years old, with an average age of 36.5 years old. The distance of tendon break was ≤10 mm. The operation time of the patients was 20-30 min, with an average of 24.5 min. The intraoperative blood loss was minimal. All 10 cases were followed up and the follow-up period was 6 to 12 months, with an average of 7 months. Mallet finger deformities were all corrected postoperatively, dorsal skin of fingers without a scar, there were no knot exposure, skin necrosis and other complications. At the last follow-up, the mean active range of motion of the distal interphalangeal joint was 84.4° and the mean TAM of the injured finger was 265.6°. According to TAM system assessment criteria: 8 cases were excellent, and 2 cases were good.Conclusions:Satisfactory therapeutic outcome for the treatment of tendinous mallet finger deformity can be achieved by the minimally invasive percutaneous quantitative suture technique eight times. It is a simple, safe, and effective method with minimal invasion.

Objective:To explore the effect of the treatment of tendinous mallet finger deformity by the minimally invasive percutaneous quantitative suture technique eight times.Methods:A retrospective analysis was performed on patients with fresh tendinous mallet fingers who underwent surgery in the Department of Hand and Foot Microsurgery of Nanjing Jiangbei Hospital from April 2021 to April 2022. During the procedure, the extensor digitalis tendon in the zone Ⅰ was sutured percutaneous with 3-0 thread monofilament sutures in the "quantitative 8-stitch method" according to the pre-marked number sequence of 1 to 8, and fixed at the base of the distal phalanx via a constructed bone tunnel. Removal of the Kirschner wire 8 weeks, the brace was used to fix the affected finger in the dorsal extension. The flexion and extension of the affected finger were gradually strengthened. The function of the affected finger was evaluated according to the Crawford standard after operation and follow-up: the active flexion and extension range of motion of each joint of the affected finger and the contralateral healthy finger was measured, and the total active ranges of motion of the finger were recorded. Finger function was evaluated according to the total active range of motion (TAM) system of the American Association of Hand Surgeons.Results:A total of 10 patients (10 digits) were enrolled, including 7 males and 3 females, and the age ranged from 20 to 52 years old, with an average age of 36.5 years old. The distance of tendon break was ≤10 mm. The operation time of the patients was 20-30 min, with an average of 24.5 min. The intraoperative blood loss was minimal. All 10 cases were followed up and the follow-up period was 6 to 12 months, with an average of 7 months. Mallet finger deformities were all corrected postoperatively, dorsal skin of fingers without a scar, there were no knot exposure, skin necrosis and other complications. At the last follow-up, the mean active range of motion of the distal interphalangeal joint was 84.4° and the mean TAM of the injured finger was 265.6°. According to TAM system assessment criteria: 8 cases were excellent, and 2 cases were good.Conclusions:Satisfactory therapeutic outcome for the treatment of tendinous mallet finger deformity can be achieved by the minimally invasive percutaneous quantitative suture technique eight times. It is a simple, safe, and effective method with minimal invasion.

OBJECTIVE: To investigate the association of fetal cardiac structural abnormalities with chromosomal aneuploidies and copy number variations (CNVs) in amniocytes. METHODS: 328 pregnant women were subjected to fetal ultrasonography and chromosomal microarray analysis (CMA). Based on the fetal heart structure, the subjects were divided into normal (n=273) and abnormal groups (n=55). The detection rates of chromosomal aneuploidies and CNVs were compared between the two groups. Spearman method was used to assess the association between the results and fetal cardiac structural abnormalities. RESULTS: The detection rates for chromosomal aneuploidies and CNVs in the abnormal group were significantly higher than that in the normal group (P< 0.05), and the incidence of fetal cardiac structural abnormalities was strongly associated with chromosomal aneuploidies and CNVs (P< 0.05). CONCLUSION Fetal chromosomal aneuploidies and CNVs are strongly associated with cardiac structural abnormalities.
Aneuploidy ; Chromosome Aberrations ; DNA Copy Number Variations ; Female ; Fetus ; Humans ; Microarray Analysis ; Pregnancy ; Prenatal Diagnosis ; Ultrasonography, Prenatal

Objective:To investigate the efficacy and safety of different dosage regimens of levosimendan in elderly patients with severe heart failure.Methods:Thirty-two patients 75 years or older were randomly divided into a loading dose group (16 cases) in which levosimendan was maintained at 0.1 μg·kg -1·min -1 for 24 h after loaded with 6 μg/kg, and a maintenance dose group (16 cases) with same schedule without loading dose. The amino-terminal brain natriuretic peptide (NT-proBNP) before and after treatment was detected. Left ventricular ejection fraction (LVEF), stroke volume (SV), stroke volume index (SVI) by echocardiograph were monitored. Adverse events, the length of stay in ICU and 28-day mortality were recorded. Results:The NT-proBNP level in loading group after treatment was 1 950 (922,6 481)ng/L, which was improved than that before treatment [4 018(2 716,9 637)ng/L, P<0.05]. The result was similar in maintenance group [1 390 (599,3 297)ng/L vs. 4 576 (2 681,10 682)ng/L, P<0.05]. LVEF in loading group before and after treatment was (39.4±8.8) % vs. (48.9±9.2) % respectively, while in maintenance group it was (40.4±8.8) % vs. (48.7±12.0) % (both P<0.05). SV were also improved after treatment in both groups compared with baseline levels ( P<0.05). NT-proBNP started to decline on day 3 in the loading group, while on day 7 in the maintenance group. SVI recovered on day 14 in the loading group [ (29.4±6.5) ml/m 2 vs. (27.3±6.7) ml/m 2, P<0.05], while it did not change much in the maintenance group. There was no significant differences as to the length of stay in ICU [ (11.1±4.4) d in loading group vs. (9.6±3.5) d in maintenance group] and 28-day mortality rates were comparable (2/16 in loading group vs. 1/16 in maintenance group) . The adverse events were 7 vs. 2 cases in loading group and maintenance group respectively, which were mild and all alleviated. Conclusion:The application of levosimendan only with maintenance dose improves cardiac function in very elderly patients with severe heart failure. Adverse events are mild and manageable.

To analyze the correlation between transcutaneous oxygen pressure (PtcO2) and blood lactate in patients with septic shock. Fifty-sixpatients with septic shock were prospectively investigated. PtcO2 was monitored continuously for 6 hours, and arterial blood gas was measured at baseline (T0) and 6 hours (T6). Records of PtcO2, were analyzed for the correlation with lactate level and lactate clearance rate. PtcO2 valuesin the high lactate clearance group and the low one were compared.The lowest value of PtcO2 at T6 and duration of PtcO2<40 mmHg (1 mmHg=0.133 kPa) were both correlated with lactate level and lactate clearance rateat T6. The low predictive value of PtcO2 was 29 mmHg of lactate clearance under 20％with a sensitivity 85.2％and a specificity 65.5％. The low predictive value of PtcO2 in high lactate clearance group was significantly higher than that in low lactate clearance group, while the duration of PtcO2<40 mmHg was shorter than the latter. During 6 h continuous monitoring, patients with a significant low PtcO2 or prolonged duration of low PtcO2 have relatively high lactate or low lactate clearance after resuscitation.