Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis.

Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. Although glucose is known to stimulate insulin secretion by ß cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers KATP channel-dependent calcium signaling, which promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic sulfonylurea drugs to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.

Triglyceride-glucose index is strongly associated with all-cause mortality in elderly females with diabetic foot ulcers: A 9-year follow-up study.

This study aims to explore the association between the triglyceride-glucose (TyG) index and all-cause mortality in patients with diabetic foot ulcers (DFUs) through an ambispective cohort study. A total of 555 inpatients with DFUs were qualified to participate in the trial study from 2013 to 2022. Throughout a median 63-month period, all subjects were followed up every 6 months. According to the three quantiles of the TyG index, participants were divided into three groups: low-level (≤8.75, n = 185), moderate-level (8.76-9.33, n = 185) and high-level (≥9.34, n = 185). The association between the TyG index and all-cause mortality in patients with DFUs was then assessed. During the follow-up period, out of 555 patients with DFUs, 116 died (20.9%). After adjusting for confounding factors, the TyG index was positively associated with all-cause mortality in patients with DFUs (HR = 1.733; 95% CI = 1.341-2.241; p < 0.001). Compared with the low-level TyG index, the moderate-level TyG index (HR = 1.685; 95% CI = 1.011-2.810; p = 0.045) and the high-level TyG index (HR = 2.769; 95% CI = 1.678-4.568; p < 0.001) were positively correlated with all-cause mortality in patients with DFUs. Additionally, in subgroup analysis, both females (HR = 1.905; 95% CI = 1.250-2.904; p = 0.003), males (HR = 1.729; 95% CI = 1.240-2.409; p = 0.001), younger (<65 years old) (HR = 1.467; 95% CI = 1.008-2.135; p = 0.046) and elderly (≥ 65) (HR = 1.933; 95% CI = 1.339-2.791; p < 0.001) showed a positive correlation between TyG index and all-cause mortality rate in patients with DFUs. Furthermore, in the high-level TyG index group compared, males (HR = 2.699; 95% CI = 1.457-4.998) and participants aged <65 years (HR = 2.031; 95% CI = 0.972-4.242), with the TyG index level increase by 1.0, the risk for all-cause mortality increased 3.277-fold in females (HR = 4.277; 95% CI = 1.645-11.124) and 1.909-fold in elderly aged ≥65 years (HR = 2.909; 95% CI = 1.486-5.695), respectively. Kaplan-Meier survival curve analysis showed that the higher the TyG index level, the higher risk of all-cause mortality in patients with DFUs (log-rank, all p < 0.001). Briefly, this study implies a strong positive correlation between the TyG index and all-cause mortality in patients with DFUs, especially in older women. Therefore, special attention should be paid to elderly females with DFUs because they have a higher TyG index level and risk of all-cause mortality than other populations in daily clinical practice.

The triglyceride glucose index as a sensitive predictor for the risk of MACCEs in patients with diabetic foot ulcers: An ambispective longitudinal cohort study.

The triglyceride glucose (TyG) index has been confirmed a predictive value for type 2 diabetes mellitus (T2DM). However, no research has yet confirmed whether there is a linear correlation between the TyG index and MACCEs in DFUs. The present study aimed to delve into the association between the TyG index and the risk of MACCEs in patients with DFUs. A total of 960 inpatients with DFUs were recruited. All participants were followed up every 6 months for 11 years with a median of 83 months. According to the cut-off value of the TyG index acquired from receiver operating characteristic (ROC) analysis, the subjects were divided into two groups: low-level (<9.12, n = 480) and high-level (≥9.12, n = 480). The relationship between the TyG index and MACCEs was evaluated by the multivariable Cox regression model, restricted cubic spline (RCS) model, stratified analysis and the Kaplan-Meier survival analysis. Out of 960 participants, 271 experienced MACCEs (28.22%), of whom 79 (29.15%) died. ROC analysis got the optimal TyG index cut-off value of 9.12. Multivariable Cox regression analysis combined with the RCS model showed that the TyG index was positively associated with MACCEs in an S-shaped non-linear dose-dependent manner within the range of TyG index 7.5-9.5 (p < 0.001). The Kaplan-Meier survival analysis indicated the higher the TyG index, the greater the cumulative incidence of MACCEs (log-rank, p < 0.001). The study first confirmed an S-shaped non-linear dose-dependent positive relationship between the TyG index and the risk of MACCEs in DFUs. Consequently, lowering the TyG index level aids in improving the prognosis of patients with DFUs.

Autologous wound margin point columnar full-thickness skin grafting combined with negative pressure wound therapy improves wound healing in refractory diabetic foot ulcers.

Diabetic lower extremity ulcers (DLEUs) are a severe complication of diabetes mellitus (DM) and are difficult to heal. This study aimed to explore the efficacy of autologous point columnar full-thickness skin graft taken from the ulcer wound margin combined with negative pressure wound therapy (NPWT) in refractory DLEUs. This is a prospective cohort study. A total of 40 inpatients with refractory DLEUs were recruited in the Diabetes Foot Center of Guangxi Zhuang Autonomous Region People's Hospital from October 2019 to November 2021. According to the doctors' professional suggestions and the patients' personal wishes, these enrolled patients were divided into two groups based on different topical wound management: the graft group (n = 18) and the conventional wound therapeutic (CWT) group (n = 22). The efficacy evaluations included the time to complete re-epithelialization of the wound and healing speed within 14 days of graft treatment or after 14 days of graft treatment in the two groups. Before the treatment, the graft group had a significantly larger ulcer area than the CWT group [27.22 (15.28, 46.59) versus 10.92 (7.00, 24.93) cm2 , P < .01]. However, the time to complete wound re-epithelialization in the graft group was shorter than in the CWT group [58.22 ± 30.60 versus 86.09 ± 49.54 d, P < .05]. Meanwhile, the healing speed in graft group was markedly faster than in CWT group, whether within 14 days [0.60 (0.40, 0.92) versus 0.16 (0.07, 0.34) cm2 /d, P < .01] or after 14 days of graft treatment [0.57 (0.45, 0.91) versus 0.13 (0.08, 0.27) cm2 /d, P < .01]. However, the total treatment cost in the graft group was lower than in the CWT group [419.59 ± 137.20 versus 663.97 ± 497.02 $, P < .05]. The novel treatment modality of autologous full-thickness skin graft taken from the ulcer wound margin combined with NPWT has hereby proposed for the first time, and is a safe, effective, and reliable method with a good performance-to-cost ratio to promote wound healing and shorten the healing time for DLEUs.

[Chuanzhi Tongluo Capsules antagonizes cerebral ischemia-reperfusion injury in mice by inhibiting neuroinflammation and oxidative stress].

Chuanzhi Tongluo Capsules(CZTL) is effective in activating blood, resolving stasis, replenishing Qi, and dredging collaterals, which has been widely used in clinical treatment of stroke(cerebral infarction) differentiated into the syndrome of wind striking meridian and collateral in the recovery stage characterized by blood stasis and Qi deficiency. However, its modern pharmacological mechanisms of action remain unclear. This study duplicated the middle cerebral artery occlusion and reperfusion(MCAO/R) model in mice using the suture-occluded method to explore the protective effect and mechanism of CZTL on ischemic stroke. The mice were divided into the sham-operation group, model group, and CZTL group. The ones in the CZTL group were gavaged with 0.3 g·kg~(-1)·d~(-1) CZTL for three successive days. One hour after the last intragastric administration, those in the model and CZTL groups were subjected to MCAO/R. After 24 h reperfusion, the effects of CZTL on neurological deficit score, cerebral infarction area, brain edema, and brain histopathology were evaluated. The levels of reactive oxygen species(ROS), malondialdehyde(MDA), interleukin-6(IL-6), interleukin-1ß(IL-1ß), and tumor necrosis factor-α(TNF-α) and the activity of superoxide dismutase(SOD) in brain tissue homogenate were detected using corresponding assay kits. The expression of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), Toll like receptor 4(TLR4), and phosphorylated nuclear factor-κB P65 subunit(p-NF-κB P65) were assayed by Western blot. The results indicated that CZTL significantly reduced the neurological deficit score, brain edema, and infarct volume, improved the brain histopathology, inhibited the expression of ROS, MDA, IL-6, IL-1ß, and TNF-α in the brain tissue, and up-regulated the activity of SOD, down-regulated the expression of pro-apoptotic protein Bax, promoted the expression of anti-apoptotic protein Bcl-2, and suppressed the expression of TLR4 and p-NF-κB P65 phosphorylation of MCAO/R mice. All these have demonstrated that CZTL has a significant protective effect against MCAO/R injury in mice, which may be related to its resistance to neuroinflammation and oxidative stress.

Obstetric outcomes for twins from different conception methods - A multicenter cross-sectional study from China.

INTRODUCTION: The effects of assisted reproductive technology on the outcomes of twin pregnancies are controversial. Therefore, the purpose of this study was to compare the maternal and perinatal outcomes of twin pregnancies conceived spontaneously and those conceived by assisted reproductive technology. MATERIAL AND METHODS: This was a cross-sectional study performed at Peking Union Medical College Hospital (PUMCH). Data on twin pregnancies (conceived spontaneously and by in vitro fertilization [IVF]/intracytoplasmic sperm injection [ICSI]) were obtained from the National Birth Registry of China for the period between 1 October 2016, and 30 September 2017. The primary obstetric outcomes were compared between twin pregnancies conceived by different methods. Logistic regression analysis with 95% confidence intervals (95% CI) was used for the multivariate analysis. RESULTS: A total of 3270 twin pregnancies (2003 and 1209 conceived spontaneously and by IVF/ICSI, respectively) were identified. The proportion of twin pregnancies among all pregnancies was 3.4% (3332/97 278). Multiple regression analysis indicated that the incidences of gestational diabetes mellitus (adjusted odds ratio [AOR] = 1.42, 95% CI 1.10-1.83, p = 0.007), preterm premature rupture of membranes (AOR = 1.65, 95% CI 1.21-2.25, p = 0.002), placenta accreta spectrum (AOR = 2.12, 95% CI 1.42-3.17, p < 0.001) and postpartum hemorrhage (AOR = 1.38, 95% CI 1.02-1.86, p = 0.037) were significantly higher in the IVF/ICSI group than in the natural pregnancy group. Multivariate analysis also revealed that conception mode was not an independent risk factor for neonate outcomes. CONCLUSIONS: In twin pregnancies, IVF/ICSI is independently associated with multiple maternal complications, including gestational diabetes mellitus, preterm premature rupture of membranes and placenta accreta spectrum compared with spontaneous conception, although potential residual confounders due to indications for assisted reproductive technology exist.

Integrative proteomics and immunochemistry analysis of the factors in the necrosis and repair in acetaminophen-induced acute liver injury in mice.

Acetaminophen (APAP) overdose-induced acute liver injury (AILI) is a significant clinical problem worldwide, the hepatotoxicity mechanisms are well elucidated, but the factors involved in the necrosis and repair still remain to be investigated. APAP was injected intraperitoneally in male Institute of Cancer Research (ICR) mice. Quantitative proteome analysis of liver tissues was performed by 2-nitrobenzenesulfenyl tagging, two-dimensional-nano high-performance liquid chromatography separation, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis. Diffrenetial proteins were verified by the immunochemistry method. 36 and 44 differentially expressed proteins were identified, respectively, at 24 hr after APAP (200 or 300 mg·kg -1 ) administration. The decrease in the mitochondrial protective proteins Prdx6, Prdx3, and Aldh2 accounted for the accumulation of excessive reactive oxygen species (ROS) and aldehydes, impairing mitochondria structure and function. The Gzmf combined with Bax and Apaf-1 jointly contributed to the necrosis. The blockage of Stat3 activation led to the overexpression of unphosphorylated Stat3 and the overproduction of Bax. The overexpression of unphosphorylated Stat3 represented necrosis; the alternation from Stat3 to p-Stat3 in necrotic regions represented hepatocytes from death to renewal. The high expressions of P4hα1, Ncam, α-SMA, and Cygb were involved in the liver repair, they were not only the markers of activated HSC but also represented an intermediate stage of hepatocytes from damage or necrosis to renewal. Our data provided a comprehensive report on the profile and dynamic changes of the liver proteins in AILI; the involvement of Gzmf and the role of Stat3 in necrosis were revealed; and the role of hepatocyte in liver self-repair was well clarified.

Cardiotoxicity and Mechanism of Particulate Matter 2.5 (PM2.5) Exposure in Offspring Rats During Pregnancy.

BACKGROUND The aim of this study was to investigate the cardiotoxicity and mechanism of particulate matter 2.5 (PM2.5) exposure on offspring rats during pregnancy. MATERIAL AND METHODS Wistar rats were used to establish a PM2.5 exposure animal model during pregnancy, and they were divided into a control group, a low-dose group, a middle-dose group, and a high-dose group according to PM2.5 exposure dose. The pathological changes of heart tissue, the rate of myocardial cell apoptosis, the levels of LDH, AST, and CM-KB in serum, and the difference in mitochondrial fusion genes (OPA1 and Mfn1) and mitochondrial genes (Drp1 and Fis1) were compared among groups. RESULTS The arrangement of myocardial fibers in offspring mice of PM2.5 exposure groups became disordered, the shape of some cardiomyocytes became irregular, and some staining darker nuclei appeared. The apoptotic rates of myocardium in offspring rats exposed to PM2.5 were (12.61±0.93)% in the low-dose group, (25.14±1.53)% in the middle-dose group, and (30.13±1.50)% in the high-dose group, which were all significantly higher than in the control group (9.12±0.80)% (P<0.05). The levels of LDH, AST, and CM-KB and the expression of OPA1, Mfn1, Drp1, and Fis1 in offspring mice of PM2.5 exposure groups increased with the increase of PM2.5 exposure dose, and were significantly higher than that of the control group (P<0.05). CONCLUSIONS The mitochondria of the offspring mice were damaged due to the abnormal expression of mitochondrial fusion/splicing gene by PM2.5 exposure during pregnancy, and the hearts of offspring mice were damaged due to damaged mitochondria.

Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development.

Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-ß/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.

Tanshinone II-A is protective against human umbilical vein endothelial cell injury after exposure to serum from preeclampsia patients.

BACKGROUND/AIMS: Preeclampsia (PE) is one of the most common and dangerous complications during pregnancy and is characterized by high blood pressure and significant amounts of protein in the urine. Vascular endothelial cell dysfunction is the major pathology in PE. This study was designed to assay the effects of tanshinone II-A (TII-A) on human umbilical vein endothelial cell (HUVEC) injury after incubation with serum from PE patients and to determine the underlying mechanism. METHODS: After treating HUVECs with different TII-A concentrations, cell viability, apoptosis and CD40/CD40 ligand (CD40L) mRNA and protein expression levels were measured. RESULTS: Incubation of HUVECs with serum from PE patients induced morphological alterations, caused decreased cell viability and increased the rate of apoptosis. However, TII-A (5-40 µg/ml) significantly reversed these injuries. Importantly, preapplication of TII-A attenuated PE sera-induced expression of CD40 and CD40L mRNA and protein. CONCLUSION: TII-A has a protective effect against PE sera, likely through regulation of the CD40/CD40L signal transduction pathway.

Geriatric nutritional risk index as a predictor for fragility fracture risk in elderly with type 2 diabetes mellitus: A 9-year ambispective longitudinal cohort study.

BACKGROUND & AIMS: The elderly are prone to fragility fractures, especially those suffering from type 2 diabetes mellitus (T2DM) combined with osteoporosis. Although studies have confirmed the association between GNRI and the prevalence of osteoporosis, the relationship between GNRI and fragility fracture risk and the individualized 10-year probability of osteoporotic fragility fractures estimated by FRAX remains unclear. This study aims to delve into the association between the GNRI and a fragility fracture and the 10-year probability of hip fracture (HF) and major osteoporotic fracture (MOF) evaluated by FRAX in elderly with T2DM. METHODS: A total of 580 patients with T2DM aged ≥60 were recruited in the study from 2014 to 2023. This research is an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 3.8 years through outpatient services, medical records, and home fixed-line telephone interviews. According to the tertiles of GNRI, all subjects were divided into three groups: low-level (59.72-94.56, n = 194), moderate-level (94.56-100.22, n = 193), and high-level (100.22-116.45, n = 193). The relationship between GNRI and a fragility fracture and the 10-year probability of HF and MOF calculated by FRAX was assessed by receiver operating characteristic (ROC) analysis, Spearman correlation analyses, restricted cubic spline (RCS) analyses, multivariable Cox regression analyses, stratified analyses, and Kaplan-Meier survival analysis. RESULTS: Of 580 participants, 102 experienced fragile fracture events (17.59%). ROC analysis demonstrated that the optimal GNRI cut-off value was 98.58 with a sensitivity of 75.49% and a specificity of 47.49%, respectively. Spearman partial correlation analyses revealed that GNRI was positively related to 25-hydroxy vitamin D [25-(OH) D] (r = 0.165, P < 0.001) and bone mineral density (BMD) [lumbar spine (LS), r = 0.088, P = 0.034; femoral neck (FN), r = 0.167, P < 0.001; total hip (TH), r = 0.171, P < 0.001]; negatively correlated with MOF (r = -0.105, P = 0.012) and HF (r = -0.154, P < 0.001). RCS analyses showed that GNRI was inversely S-shaped dose-dependent with a fragility fracture event (P < 0.001) and was Z-shaped with the 10-year MOF (P = 0.03) and HF (P = 0.01) risk assessed by FRAX, respectively. Multivariate Cox regression analysis demonstrated that compared with high-level GNRI, moderate-level [hazard ratio (HR) = 1.950; 95% confidence interval (CI) = 1.076-3.535; P = 0.028] and low-level (HR = 2.538; 95% CI = 1.378-4.672; P = 0.003) had an increased risk of fragility fracture. Stratified analysis exhibited that GNRI was negatively correlated with the risk of fragility fracture, which the stratification factors presented in the forest plot were not confounding factors and did not affect the prediction effect of GNRI on the fragility fracture events in this overall cohort population (P for interaction > 0.05), despite elderly females aged ≥70, with body mass index (BMI) ≥24, hypertension, and with or without anemia (all P < 0.05). Kaplan-Meier survival analysis identified that the lower-level GNRI group had a higher cumulative incidence of fragility fractures (log-rank, all P < 0.001). CONCLUSION: This study confirms for the first time that GNRI is negatively related to a fragility fracture and the 10-year probability of osteoporotic fragility fractures assessed by FRAX in an inverse S-shaped and Z-shaped dose-dependent pattern in elderly with T2DM, respectively. GNRI may serve as a valuable predictor for fragility fracture risk in elderly with T2DM. Therefore, in routine clinical practice, paying attention to the nutritional status of the elderly with T2DM and giving appropriate dietary guidance may help prevent a fragility fracture event.

Differential miRNA expression profiles between the first and third trimester human placentas.

To determine placental microRNA (miRNA) expression at different gestational age, total RNA from six first and six third trimester placentas was isolated. miRNA expression was analyzed by Affymetrix miRNA microarray, and miRNA clusters were identified by web-based programs MirClust and miRGen Cluster. qRT-PCR was carried out to validate miRNA expression, and in situ hybridization (ISH) was performed to determine compartmental localization of miRNAs within villous tissue. A total of 208 miRNA transcripts, which represent 191 mature miRNAs, were found differently expressed between first and third trimester placentas. miRNAs within the miR-17-92 cluster, C14MC, miR-371 cluster, and C19MC were significantly upregulated in the first trimester placentas. In contrast, miRNAs of the let-7 family, miR-34 family, miR-29a cluster, miR-195 cluster, and miR-181c cluster were significantly upregulated in the third trimester placentas. Increased miR-371-5p, miR-17-3p, and miR-708-5p expression and decreased miR-125b-5p and miR-139-5p expression in the first trimester placentas were confirmed by qRT-PCR. Different expression pattern for miR-371-5p and miR-125b-5p within villous tissue was demonstrated by ISH. Distinct miRNA cluster expression profiles between the first and third trimester placentas were identified. miRNAs that regulate innate/adaptive immune responses are strongly expressed in both first and third trimester placentas. miRNAs that exert oncogenic, angiogenic, and antiapoptotic properties are dominantly expressed in the first trimester placentas, whereas miRNAs that promote cell differentiation and function as tumor suppressors are strongly expressed in the third trimester placentas. These results indicate that miRNAs play critical roles in placental development.

Triglyceride Glucose Index is Strongly Associated with a Fragility Fracture in Postmenopausal Elderly Females with Type 2 Diabetes Mellitus Combined with Osteoporosis: A 6-Year Follow-Up Study.

Purpose: The triglyceride glucose (TyG) index serves as an indicator of insulin resistance (IR), which is also associated with bone metabolism. However, research on the relationship between the TyG index and a fragility fracture in individuals with type 2 diabetes mellitus (T2DM) or osteoporosis (OP) remains sparse. This study aims to explore the association between the TyG index and fragility fracture risk in postmenopausal elderly females with T2DM combined with OP based on an ambispective cohort study. Patients and Methods: A total of 220 postmenopausal women hospitalized with T2DM combined with OP between January 2015 and December 2020 were eligible for inclusion in this study. All participants were followed up every 6 months for 6 years with a median of 42 months. According to the tertiles of the TyG index, participants were divided into three groups: low-level (≤ 8.79, n =73), moderate-level (8.80-9.32, n=73), and high-level (≥ 9.33, n=74). The association between the TyG index and fragility fracture risk was then assessed. Results: Out of 220 patients, 46 experienced fragility fracture events (20.9%). Multivariate Cox regression analysis showed that the TyG index was positively associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Furthermore, compared to the low-level group, with the TyG index level increase by 1.0, the risk for fragility fracture increased 1.293-fold in the high-level group (HR=2.293, 95% CI=1.007-5.221, P < 0.05). Kaplan-Meier survival analysis indicated that fragility fractures were more likely to occur in patients with high levels of TyG index (log-rank, all P < 0.05). Conclusion: Our study showed that the TyG index was strongly associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Therefore, special attention should be paid to postmenopausal elderly females with T2DM combined with OP in routine clinical practice.

A Novel Wound Therapy Modality: Autologous Wound Edge Dotted Full-Thickness Skin Grafting Improving Diabetic Foot Ulcer Healing.

Aim: To explore the therapeutic efficacy of autologous wound edge-dotted full-thickness skin grafting in improving diabetic foot ulcer healing. Methods: Sixty-three patients were divided into three groups: conventional wound therapy (CWT) (n = 23), platelet-rich plasma (PRP) (n = 20), and graft (n = 20). All participants were followed up for 12 weeks. The therapeutic efficacy of the three different wound treatment modalities was analyzed. Results: After follow-up, 37 (58.7%) patients showed complete wound re-epithelialization, of which 10 (43.5%) occurred in the CWT group, 14 (70.0%) in the PRP group, and 13 (65.0%) in the graft group. Multivariate Cox analysis showed that the independent predictive factors for ulcer healing were different treatment modalities (graft: HR = 3.214, 95% CI=1.300-7.945, P < 0.05; platelet-rich plasma: HR = 3.075, 95% CI=1.320-7.161, P < 0.01), ABI (HR = 9.917, 95% CI=2.675-36.760, P < 0.01), and TcPO2 (HR = 1.040; 95% CI=1.005-1.076; P < 0.05). Stratified analysis showed that higher ABI in graft group or PRP group had higher wound healing rate (graft group: HR = 3.748, 95% CI=1.210-11.607, P < 0.05; PRP group: HR = 5.029, 95% CI=1.743-14.509, P < 0.05); higher TcPO2 in the graft group had higher wound healing rate (HR = 15.805, 95% CI=4.414-56.594, P < 0.01). Additionally, the wound healing time (P < 0.0167) and cumulative healing rate (P < 0.05) in both the PRP group and graft group were more advantageous. The graft group promotes wound re-epithelialization earlier and faster than in the CWT group and PRP group (P < 0.05). Meanwhile, the graft group had lower medical costs (P < 0.0167). Conclusion: Autologous wound edge dotted full-thickness skin grafting has a higher cost-performance ratio than traditional diabetic foot ulcer wound care and is worthy of further clinical application.

The Ratio of Serum Uric Acid to Glycosylated Haemoglobin as a Predictor of All-Mortality in Elderly Patients with Diabetic Foot Ulcers: A Longitudinal Cohort Study.

Aim: To clarify the relationship between serum uric acid (UA) and glycosylated hemoglobin (UA/HbA1c) ratio and all-cause mortality in patients with diabetic foot ulcers (DFUs). Methods: A total of 172 inpatients with DFUs (PEDIS grades 2-4) were eligible for inclusion in this study from 2018 to 2023. This was a retrospective, longitudinal cohort study. All subjects were followed up every 6 months for a median of 60 months. According to the cutoff value of the UA/HbA1c ratio of 39.07 obtained from ROC analysis, the participants were divided into two groups: low-level (≤ 39.07, n = 107) and high-level (> 39.07, n = 65) groups. The correlation between UA/HbA1c ratio and all-cause mortality was also evaluated by Cox regression analysis TheKaplan-Meier survival curve analysis and Log rank tests were used to assess the incidence rates of all-cause mortality. The contribution rate of risk factors was estimated by the population-attributable risk percentage (PAR%) analysis. Results: ROC analysis showed that the optimal cutoff values for UA and the UA/HbA1c ratio were 372 µmol/L and 39.07, respectively. Multivariate Cox regression analysis indicated that a high UA/HbA1c ratio (HR =4.63; 95% CI = 2.004-10.7, P < 0.001) was independently associated with a high risk of all-cause mortality in patients with DFUs. Stratified analysis indicated that subjects aged ≥ 60 years had a greater risk of all-cause mortality associated with a high UA/HbA1c ratio (HR = 4.450; 95% CI = 1.711-11.574, P = 0.002). Kaplan-Meier survival analysis showed that all-cause mortality had a significant positive association with a high UA/HbA1c ratio (log-rank, P < 0.001) and a significant negative correlation with the lowered HbA1c level (< 6.5%) after a follow-up of 32 months (log-rank, P < 0.001). The population attributable risk percentage (PAR%) analysis suggested that the contribution rate of the high-level UA/HbA1c ratio to all-cause mortality was 33.7%, which was much greater than the 19.69% of UA. Conclusion: In brief, our study showed that for every 1.0% increase in the UA/HbA1c ratio, the all-cause mortality rate in elderly patients with DFUs aged ≥ 60 years increased by 3.45-fold. For elderly patients with DFUs, a safe and effective strategy to reduce all-cause mortality is to strictly control serum UA levels to < 372 µmol/L and appropriately loosen the control goal of HbA1c to ≥ 6.5%.

Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies.

Vitamin D insufficiency/deficiency during pregnancy has been linked to increased risk of preeclampsia. Placenta dysfunction plays an important role in the pathogenesis of this pregnancy disorder. In this study, we tested the hypothesis that disturbed vitamin D metabolism takes place in preeclamptic placentas. Protein expressions of vitamin D binding protein (VDBP), 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D receptor (VDR) were examined in placentas from normotensive and preeclamptic pregnancies. By immunostaining we found that in normal placenta VDBP, CYP24A1, and VDR expressions are localized mainly in trophoblasts, whereas CYP2R1 and CYP27B1 expressions are localized mainly in villous core fetal vessel endothelium. Protein expressions of CYP2R1 and VDR are reduced, but CYP27B1 and CYP24A1 expressions are elevated, in preeclamptic compared with normotensive placentas. Because increased oxidative stress is an underlying pathophysiology in placental trophoblasts in preeclampsia, we further determined whether oxidative stress contributes to altered vitamin D metabolic system in placental trophoblasts. Trophoblasts isolated from normal-term placentas were treated with hypoxic-inducing agent CoCl(2), and protein expressions of VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR were determined. We found that hypoxia-induced downregulation of VDBP, CYP2R1, and VDR and upregulation of CYP27B1 and CYP24A1 expressions were consistent with that seen in preeclamptic placentas. CuZnSOD expression was also downregulated in trophoblasts treated with CoCl(2). These results provide direct evidence of disrupted vitamin D metabolic homeostasis in the preeclamptic placenta and suggest that increased oxidative stress could be a causative factor of altered vitamin D metabolism in preeclamptic placentas.

Preeclampsia serum upregulates CD40/CD40L expression and induces apoptosis in human umbilical cord endothelial cells.

BACKGROUND: The endothelial cell dysfunction observed in preeclampsia (PE) may be induced by CD40/CD40L signaling. This study investigated the role of CD40/CD40L in the pathogenesis of PE by comparing the effect of maternal serum obtained from healthy pregnant women and PE patients on HUVEC cell growth, apoptosis and CD40/CD40L expression. METHODS: Maternal serum was obtained from 20 patients with PE (PE group) as well as 20 healthy pregnant women (control group). The human umbilical endothelial cell line, CRL1730, was cultured in the presence of maternal serum for 24, 48, and 72 h after which cell growth and apoptosis were assessed by MTT and flow cytometry analysis, respectively. CD40/CD40L expression was determined using flow cytometry and RT-PCR analyses. RESULTS: As compared to CRL1730 cells treated with control sera, those treated with PE sera had altered morphology, decreased cell growth, increased apoptosis and greater CD40/CD40L protein and mRNA expression. Stimulation of CD40/CD40L protein and mRNA expression by PE sera was greatest at 24 h. CONCLUSIONS: PE sera may induce endothelial cell damage possibly through increased CD40/CD40L expression in early-onset PE. Further studies are necessary to determine the factor(s) in PE sera responsible for the observed changes in endothelial cell viability.

Perinatal maternal characteristics predict a high risk of neonatal asphyxia: A multi-center retrospective cohort study in China.

Objective: This study aimed to identify various perinatal maternal characteristics that contributed to neonatal asphyxia (NA) in term and late-preterm newborns based on the data obtained from a Chinese birth registry cohort and to establish an effective model for predicting a high risk of asphyxia. Method: We retrospectively reviewed and analyzed the birth database from July 1, 2016, to June 30, 2017, in the main economically developed regions of China. Asphyxia was defined as an Apgar score <7 at 5 min post-delivery with umbilical cord arterial blood pH < 7.2 in the infant born after 34weeks. We compared the perinatal maternal characteristics of the newborns who developed asphyxia (NA group, n = 1,152) and those who did not (no NA group, n = 86,393). Candidate predictors of NA were analyzed using multivariable logistic regression. Subsequently, a prediction model was developed and validated by an independent test group. Result: Of the maternal characteristics, duration of PROM ≥ 48 h, a gestational week at birth <37, prolonged duration of labor, hypertensive disorder, nuchal cord, and birth weight <2,500 or ≥4,000 g, abnormal fetal heart rate, meconium-stained amniotic fluid, and placenta previa were included in the predicting model, which presented a good performance in external validation (c-statistic of 0.731). Conclusion: Our model relied heavily on clinical predictors that may be determined before or during birth, and pregnant women at high risk of NA might be recognized earlier in pregnancy and childbirth using this methodology, allowing them to avoid being neglected and delayed. Future studies should be conducted to assess its usefulness.

Risk Factors for Macrosomia in Multipara: A Multi-Center Retrospective Study.

The increased incidence of macrosomia has caused an enormous burden after the transition from the almost 40-year one-child policy to the universal two-child policy in 2015 and further to the three-child policy in 2021 in China. However, studies on risk factors of macrosomia in multipara under the new fertility policy in China are limited. We aim to explore the incidence and risk factors for macrosomia in multipara to provide the scientific basis for preventing macrosomia in multipara. A multi-center retrospective study was conducted among 6200 women who had two consecutive deliveries in the same hospital and their second newborn was delivered from January to October 2018 at one of 18 hospitals in 12 provinces in China. Macrosomia was defined as birth weight ≥ 4000 g. Logistic regression models were performed to analyze risk factors for macrosomia in multipara. The incidence of macrosomia in multipara was 7.6% (470/6200) and the recurrence rate of macrosomia in multipara was 27.2% (121/445). After adjusting for potential confounders, a higher prepregnancy BMI, higher gestational weight gain, history of macrosomia, a longer gestation in the subsequent pregnancy were independent risk factors of macrosomia in multipara (p < 0.05). Healthcare education and preconception consultation should be conducted for multipara patients with a history of macrosomia to promote maintaining optimal prepregnancy BMI and avoid excessive gestational weight gain to prevent macrosomia.

Three Novel Homozygous Mutations of the SLC12A3 Gene in a Gitelman Syndrome Patient.

AIM: Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis. In this study, we investigated the clinical presentation and sequenced 26 exons of SLC12A3 gene in a patient with a clinical suspicion of GS. METHODS: Clinical work-up including clinical examination, electrocardiography (ECG), chest X-ray, bone mineral density (BMD), and ultrasound examination was conducted and all exons of SLC12A3 gene were analyzed by whole-exome sequencing. RESULTS: The patient showed hypokalemia, hypomagnesemia, and metabolic alkalosis and was found to have four novel homozygous missense mutations including one known mutation (c.1456 G>A in exon 12) and three novel mutations (c.366A > G in exon 2, c.791C > G in exon 6 and c.1027C > T in exon 8). CONCLUSION: Four mutation sites of SLC12A3 gene were found in the patient, three of which have not been reported before. These results may be useful for better understanding the function of this gene and can assist clinicians with treatment decision-making.