The Median Effective Dose of Intrathecal Hyperbaric Bupivacaine for Cesarean Section at Moderately High-Altitude.

Objective: Alterations in altitude can lead to an augmented requirement for local anesthesia among patients. Nevertheless, the necessity for an elevated dosage of local anesthetic for parturients at moderately high altitudes during spinal anesthesia for cesarean section remains uninvestigated. This up-down sequential study endeavors to determine the ED50 dose of bupivacaine required for spinal anesthesia during cesarean sections at moderately high-altitude. Methods: Thirty singleton parturients at moderately high altitude underwent elective cesarean section under combined spinal-epidural anesthesia. The up-and-down sequential method was employed, starting with an initial dose of 12mg (1.6mL) of 0.75% hyperbaric bupivacaine for the first participant. The dose for the next case was adjusted up or down by 0.75mg based on the effectiveness of the previous participant. Effectiveness was defined as the bilateral sensory block reaching T6 within 15 minutes after spinal anesthesia injection, without the need for additional epidural anesthesia before fetal delivery. The ED50 dose and 95% confidence interval were calculated using the Dixon sequential method and isotonic regression, respectively. The incidence of maternal hypotension, nausea, and vomiting during the study period was also recorded. Results: The ED50 of hyperbaric bupivacaine for spinal anesthesia in cesarean section was calculated as 8.23 mg (95% CI, 6.52-9.32 mg) using the Dixon up-and-down method. Further validation using isotonic regression yielded a value of 8.39 mg (95% CI, 7.48-9.30 mg), confirming the accuracy and sensitivity of the conclusion. During the operation, only 6 parturients experienced hypotension, and no adverse reactions such as nausea, vomiting, and shivering were observed. Conclusion: The ED50 dose of 0.75% hyperbaric bupivacaine for spinal anesthesia during cesarean section at moderately high altitude is 8.23 mg, which exceeds the ED50 dose typically required by parturients at low altitude. Comprehensive investigations are warranted to ascertain the ED90 or ED95 dose of local anesthetics for cesarean section at moderately high altitudes, thereby offering enhanced guidance for clinical practice.

The effects of psychiatric disorders on the risk of chronic heart failure: a univariable and multivariable Mendelian randomization study.

Background: Substantial evidence suggests an association between psychiatric disorders and chronic heart failure. However, further investigation is needed to confirm the causal relationship between these psychiatric disorders and chronic heart failure. To address this, we evaluated the potential effects of five psychiatric disorders on chronic heart failure using two-sample Mendelian Randomization (MR). Methods: We selected single nucleotide polymorphisms (SNPs) associated with chronic heart failure and five psychiatric disorders (Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Major Depression, Bipolar Disorder and Schizophrenia (SCZ)). Univariable (UVMR) and multivariable two-sample Mendelian Randomization (MVMR) were employed to assess causality between these conditions. Ever smoked and alcohol consumption were controlled for mediating effects in the multivariable MR. The inverse variance weighting (IVW) and Wald ratio estimator methods served as the primary analytical methods for estimating potential causal effects. MR-Egger and weighted median analyses were also conducted to validate the results. Sensitivity analyses included the funnel plot, leave-one-out, and MR-Egger intercept tests. Additionally, potential mediators were investigated through risk factor analyses. Results: Genetically predicted heart failure was significantly associated with ADHD (odds ratio (OR), 1.12; 95% CI, 1.04-1.20; p = 0.001), ASD (OR, 1.29; 95% CI, 1.07-1.56; p = 0.008), bipolar disorder (OR, 0.89; 95% CI, 0.83-0.96; p = 0.001), major depression (OR, 1.15; 95% CI, 1.03-1.29; p = 0.015), SCZ (OR, 1.04; 95% CI, 1.00-1.07; p = 0.024). Several risk factors for heart failure are implicated in the above cause-and-effect relationship, including ever smoked and alcohol consumption. Conclusion: Our study demonstrated ADHD, ASD, SCZ and major depression may have a causal relationship with an increased risk of heart failure. In contrast, bipolar disorder was associated with a reduced risk of heart failure, which could potentially be mediated by ever smoked and alcohol consumption. Therefore, prevention strategies for heart failure should also incorporate mental health considerations, and vice versa.

Serum soluble TREM2 is an independent biomarker associated with coronary heart disease.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.

Lipoaspirate fluid derived factors and extracellular vesicles accelerate wound healing in a rat burn model.

Background: The regenerative capabilities of derivatives derived from the fat layer of lipoaspirate have been demonstrated. However, the large volume of lipoaspirate fluid has not attracted extensive attention in clinical applications. In this study, we aimed to isolate the factors and extracellular vesicles from human lipoaspirate fluid and evaluate their potential therapeutic efficacy. Methods: Lipoaspirate fluid derived factors and extracellular vesicles (LF-FVs) were prepared from human lipoaspirate and characterized by nanoparticle tracking analysis, size-exclusion chromatography and adipokine antibody arrays. The therapeutic potential of LF-FVs was evaluated on fibroblasts in vitro and rat burn model in vivo. Wound healing process was recorded on days 2, 4, 8, 10, 12 and 16 post-treatment. The scar formation was analyzed by histology, immunofluorescent staining and scar-related gene expression at day 35 post-treatment. Results: The results of nanoparticle tracking analysis and size-exclusion chromatography indicated that LF-FVs were enriched with proteins and extracellular vesicles. Specific adipokines (adiponectin and IGF-1) were detected in LF-FVs. In vitro, LF-FVs augmented the proliferation and migration of fibroblasts in a dose-dependent manner. In vivo, the results showed that LF-FVs significantly accelerated burn wound healing. Moreover, LF-FVs improved the quality of wound healing, including regenerating cutaneous appendages (hair follicles and sebaceous glands) and decreasing scar formation in the healed skin. Conclusion: LF-FVs were successfully prepared from lipoaspirate liquid, which were cell-free and enriched with extracellular vesicles. Additionally, they were found to improve wound healing in a rat burn model, suggesting that LF-FVs could be potentially used for wound regeneration in clinical settings.

Independent association of PCSK9 with platelet reactivity in subjects without statin or antiplatelet agents.

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could predict cardiovascular event in patients with well-controlled LDL-C levels, suggesting an LDL-independent mechanism of PCSK9 on the cardiovascular system. Accumulating evidence suggests PCSK9 might be associated with increased platelet reactivity. This study aimed to assess the relationship between PCSK9 levels and platelet reactivity in subjects not taking statins or antiplatelet agents. Methods: A cross-sectional study was conducted to investigate the independent contribution of PCSK9 to platelet activity by controlling for the potential confounding factors. The study population included 89 subjects from a health examination centre who underwent routine annual health check-ups or had an examination before a selective operation. Subjects taking statins or antiplatelet agents were excluded. Adenosine diphosphate (ADP)-induced platelet aggregation was determined by PL-11 platelet analyzer using impedance aggregometry and plasma PCSK9 levels were determined using an ELISA. Serum Lipid profile was assessed by measuring the concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), with low-density lipoprotein cholesterol (LDL-C) being directly measured using enzymatic techniques. The association between PCSK9 and platelet reactivity was investigated. Results: The study subjects were composed of 53 males and 36 females with an average age of 55 (±11) years old. The univariate correlation analysis showed significant correlation between ADP-induced maximal aggregation rate (MAR) and PCSK9 (r = 0.55, p < 0.001) as well as TC (r = 0.23, p = 0.028), LDL-C (r = 0.27, p < 0.001), and PLT (r = 0.31, p = 0.005). Being male (41.2% vs. 46.6, p = 0.04) and smoking (37.4 vs. 46.2%, p = 0.016) were associated with lower ADP-induced MAR than being female and non-smoking. However, there is no correlation between PCSK9 and AA-induced platelet maximal aggregation rate (r = 0.17, p = 0.12). Multiple regression analysis suggested that PCSK9 contributed independently to ADP-induced maximal aggregation rate (ß = 0.08, p = 0.004) after controlling for the effect of TC, LDL-C, PLT, being male, and smoking. Conclusions: PCSK9 is positively associated with platelet reactivity, which may partly account for the beneficial effect of PCSK9 inhibition in reducing the risk of major adverse cardiovascular events after acute coronary syndrome (ACS).

Independent association of Lp(a) with platelet reactivity in subjects without statins or antiplatelet agents.

The physiological effect of Lp(a) on platelet activity is unclear. Previous studies explored the relationship between Lp(a) and platelet aggregation in patients taking statins and antiplatelet agents, but few was conducted in individuals without the bias of those drugs that either influence Lp(a) or platelet activity. The aim of this study was to assess the relationship between Lp(a) levels and platelet aggregation in subjects not taking statins or antiplatelet drugs. A hospital-based cross-sectional study was conducted to investigate the independent contribution of Lp(a) to platelet activity by controlling the effects of potential confounding factors including lipoprotein-associated phospholipase A2 [Lp-PLA2]. Blood samples were collected from 92 subjects without statins or antiplatelet agents from the Second Xiangya Hospital. The univariate correlation analysis showed a significant correlation between AA-induced average aggregation rate [AAR] and ApoB (r = 0.324, P = 0.002), ApoA1 (r = 0.252, P = 0.015), Lp(a) (r = 0.370, P < 0.001), Lp-PLA2 (r = 0.233, P = 0.025) and platelet counts [PLT] (r = 0.389, P < 0.001). Multivariate regression analysis suggested that Lp(a) contributed independently to AA-induced average aggregation rate (ß = 0.023, P = 0.027) after controlling for the effects of ApoB, Lp-PLA2 and platelet counts. Lp(a) is positively associated with platelet aggregation independent of Lp-PLA2, which may partly account for the atherothrombotic effect of Lp(a).

Case report: A homozygous ADAMTSL2 missense variant causes geleophysic dysplasia with high similarity to Weill-Marchesani syndrome.

Background: Geleophysic dysplasia and Weill-Marchesani syndrome from the acromelic dysplasias group of genetic skeletal disorders share remarkable clinical and genetic overlap. Methods: Ophthalmological, physical, radiological examinations were conducted with a female patient in her early 30 s. Whole exome sequencing followed by Sanger sequencing validation was performed to identify the genetic cause. Results: The patient, born to consanguineous Chinese parents, presented with microspherophakia, lens subluxation, high myopia, short statue, small hands and feet, stiff joints, and thickened skin. A diagnosis of Weill-Marchesani syndrome was initially made for her. However, genetic testing reveals that the patient is homozygous for the c.1966G>A (p.Gly656Ser) variant in ADAMTSL2, and that the patient's healthy mother and daughter are heterozygous for the variant. As mutations in ADAMTSL2 are known to cause autosomal recessive geleophysic dysplasia, the patient is re-diagnosed with geleophysic dysplasia in terms of her genotype and phenotype. Conclusion: The present study describes the clinical phenotype of the homozygous ADAMTSL2 p. Gly656Ser variant, which increases our understanding of the genotype-phenotype correlation in acromelic dysplasias.

Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism.

Hypothyroidism is often associated with elevated serum levels of total cholesterol, LDL-C and triglycerides. Thyroid hormone (TH) affects the production, clearance and transformation of cholesterol, but current research shows that thyroid-stimulating hormone (TSH) also participates in lipid metabolism independently of TH. Therefore, the mechanism of hypothyroidism-related dyslipidemia is associated with the decrease of TH and the increase of TSH levels. Some newly identified regulatory factors, such as proprotein convertase subtilisin/kexin type 9, angiogenin-like proteins and fibroblast growth factors are the underlying causes of dyslipidemia in hypothyroidism. HDL serum concentration changes were not consistent, and its function was reportedly impaired. The current review focuses on the updated understanding of the mechanism of hypothyroidism-related dyslipidemia.

Influence of sugammadex versus neostigmine for neuromuscular block reversal on the incidence of postoperative pulmonary complications: a meta-analysis of randomized controlled trials.

BACKGROUND: The influence of sugammadex for reversal of neuromuscular block (NMB) on postoperative pulmonary complications (PPCs), compared with neostigmine, remains to be determined. We performed a meta-analysis of randomized controlled trials (RCTs) to compare the incidence of PPCs between patients who received sugammadex versus neostigmine. METHODS: Relevant studies were obtained by searching the PubMed, Embase, and Cochrane Library databases. A random effects model incorporating the potential heterogeneity was used to pool the results. RESULTS: Fourteen RCTs including 1478 adult patients who underwent surgeries with general anesthesia were included, and of these, 753 received sugammadex and 725 received neostigmine for reversal of NMB. The pooled results showed that sugammadex was associated with a lower risk of overall PPCs compared to neostigmine (odds ratio [OR]: 0.62, 95% confidence interval [CI]: 0.43-0.89, p = 0.01; I2 = 0%). This finding remained consistent after exclusion of two studies with potential overlapping events (OR: 0.58, 95% CI: 0.36-0.96, p = 0.03; I2=9%). Stratified analyses according to the categories of PPCs showed that sugammadex was associated with a significantly lower risk of postoperative respiratory failure (OR: 0.60, 95% CI: 0.38-0.97, p = 0.04; I2 = 0%) but not of postoperative pulmonary infection (OR: 0.79, p = 0.71), atelectasis (OR: 0.78, p = 0.33), or pneumothorax (OR: 0.87, p = 0.79). CONCLUSIONS: Compared with neostigmine, the use of sugammadex for reversal of NMB was associated with a lower risk of PPCs, mainly due to a lower incidence of postoperative respiratory failure with the use of sugammadex.

Associations of Serum Pepsinogens and Helicobacter Pylori Infection with High-Sensitivity C-Reactive Protein in Medical Examination Population.

OBJECTIVE: This study aimed to clarify the distribution characteristics of serum pepsinogen (PG) and Helicobacter pylori in the medical examination population and to explore the relationships of PG level and H. pylori infection status with the high-sensitivity C-reactive protein (hsCRP) level and their significance in health examination. METHODS: We detected H. pylori infection by C13 urea breath test, the serum pepsinogen I (PGI) and pepsinogen II (PGII) contents were measured by chemiluminescence microparticle immunoassay, and the PGI/PGII ratio was calculated. In addition, the serum hsCRP level was determined by the Abbott C16000 automatic biochemical analyzer. RESULTS: The PGI and hsCRP levels were significantly higher in men than in women, and the PGII level was slightly higher in men than in women (both P <.05). The PGI, PGII, and hsCRP levels were positively correlated with age (r = 0.210, 0.287, and 0.133, respectively; P <.05), whereas the PGI/PGII ratio was negatively correlated with age (r = -0.190; P <.05). The positive H. pylori infection rate was 30.2% among the patients in this study; H. pylori infection was not related to sex (P >.05), and the difference in age stratification was not statistically significant (P >.05). The abnormal PGI/PGII ratio in the medical examination population was not correlated with sex (P >.05). In the H. pylori positive infection group, the proportion of PGI/PGII ratio <3, the PGI and PGII levels were significantly higher than those in the H. pylori negative infection group, and the PGI/PGII ratio was significantly lower than that in the negative group (both P <.05). The hsCRP level was not associated with H. pylori infection (P >.05), and it was significantly higher in the PGI/PGII ratio <3 group than in the PGI/PGII ratio ≥3 group (P <.05). CONCLUSION: The PGI and PGII levels and the PGI/PGII ratio are correlated with H. pylori infection. The abnormal PGI/PGII ratio is closely related to H. pylori infection and hsCRP level. Therefore, H. pylori infection status and hsCRP level should be considered when determining atrophic gastritis by the PGI/PGII ratio.

Exosomes in Pathogen Infections: A Bridge to Deliver Molecules and Link Functions.

Exosomes are extracellular vesicles derived from cell endocytosis which act as transmitters between cells. They are composed of proteins, lipids, and RNAs through which they participate in cellular crosstalk. Consequently, they play an important role in health and disease. Our view is that exosomes exert a bidirectional regulatory effect on pathogen infections by delivering their content. First, exosomes containing proteins and RNAs derived from pathogens can promote infections in three ways: (1) mediating further infection by transmitting pathogen-related molecules; (2) participating in the immune escape of pathogens; and (3) inhibiting immune responses by favoring immune cell apoptosis. Second, exosomes play anti-infection roles through: (1) inhibiting pathogen proliferation and infection directly; (2) inducing immune responses such as those related to the function of monocyte-macrophages, NK cells, T cells, and B cells. We believe that exosomes act as "bridges" during pathogen infections through the mechanisms mentioned above. The purpose of this review is to describe present findings regarding exosomes and pathogen infections, and highlight their enormous potential in clinical diagnosis and treatment. We discuss two opposite aspects: infection and anti-infection, and we hypothesize a balance between them. At the same time, we elaborate on the role of exosomes in immune regulation.

Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway.

Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide to 1-methylnicotinamide (1-MNA), is overexpressed in a variety of human cancers and serves as a potential anti-cancer target. In this study, we investigated the effect of NNMT on 5-fluorouracil (5-FU) sensitivity of colorectal cancer (CRC) cells, and the underlying mechanisms. Our results show that down-regulation of NNMT in CRC HT-29 cells diminishes 5-FU resistance, while over expression of NNMT in SW480 cells enhances it. NNMT reduces reactive oxygen species (ROS) production induced by 5-FU by increasing 1-MNA in CRC cells. The reduction in ROS leads to inactivation of the ASK1-p38 mitogen-activated protein kinase (MAPK) pathway, which reduces 5-FU-induced apoptosis. In vivo, NNMT attenuates 5-FU-induced inhibition of CRC tumor growth in nude mice. These observations suggest that NNMT and the 1-MNA it produces inhibit the ASK1-p38 MAPK pathway, resulting in increased CRC cell resistance to 5-FU.

Diagnostic significance of circulating multiple miRNAs in breast cancer: a systematic review and meta-analysis.

AIMS: To determine whether circulating multiple miRNAs can be used as novel biomarkers for the diagnosis in breast cancer, we performed a systematic review and meta-analysis. MATERIALS & METHODS: After searching the databases of PubMed, EMBASE and Web of Science, we used the bivariate meta-analysis model to summarize the diagnostic indices and plot the summary receiver operator characteristic curve. RESULTS: The summary estimates revealed that the pooled sensitivity was 88% (95% CI: 82-93%); specificity was 84% (95% CI: 74-91%); positive likelihood ratio was 4.69 (95% CI: 2.93-7.51); negative likelihood ratio was 0.15 (95% CI: 0.09-0.25); diagnostic odds ratio was 38.21 (95% CI: 13.41-108.85); and the area under the curve was 0.93 (95% CI: 0.90-0.95). CONCLUSION: These results suggested that circulating multiple miRNAs might serve as novel biomarkers for breast cancer, with a relatively high level of accuracy.

Nicotinamide N-methyltransferase enhances the capacity of tumorigenesis associated with the promotion of cell cycle progression in human colorectal cancer cells.

Nicotinamide N-methyltransferase (NNMT), an enzyme involved in the biotransformation and detoxification of many drugs and xenobiotic compounds, has been found to be overexpressed in several malignancies, including colorectal cancer. However, the biological function of NNMT and the related mechanisms in colorectal cancer have not been elucidated. In the present study, we investigated the effects of NNMT on tumorigenesis by overexpressing NNMT in the human colorectal cancer cells line SW480 which lacks constitutive NNMT expression, and downregulating NNMT expression in HT-29 cells, which exhibit high endogenous expression of NNMT. We found that NNMT significantly accelerates cell proliferation, enhances colony formation in vitro and tumorigenicity in mice; it also inhibits apoptosis, promotes cell cycle progression, increases ATP and 1-methylnicotinamide level and decreases ROS level. We also showed that 1-methylnicotinamide accelerates cell growth, inhibits apoptosis, promotes cell cycle progression, attenuates ROS production and increases ATP level. Our results indicate that NNMT enhances the capacity of tumorigenesis associated with the inhibition of cell apoptosis and the promotion of cell cycle progression in human colorectal cancer cells and the 1-methylnicotinamide increased by NNMT mediates the cellular effects of NNMT in cells. NNMT may play a vital role in energy balance and ROS induction.