The prescription Mahuang Shengmatang in the Treatise on Cold Damage （《伤寒论》） has sparked considerable debate among medical practitioners throughout history， with varying opinions on its indications， pathogenesis described in the text， principle of compatibility， and clinical applications. Both ancient and modern interpreters of Mahuang Shengmatang often focus on herbal compatibility as a primary approach to deduce the pathogenesis and treatment methods. Building upon this foundation， this paper utilizes herbal dosage as a clue to discern the primary and secondary herbs in the prescription. It further analyzes the principle of compatibility based on herbal indications， summarizing the indications and therapeutic principles of this prescription. Ultimately， it reveals the underlying pathogenesis reflected in the text. The internal closure of heat and toxin leads to the stagnation of Qi， preventing Yang Qi from reaching the extremities and causing cold hands and feet. When the pathogenic Qi finds no outlet， it floods both the upper and lower regions of the body， attacking the throat and causing cough with expectoration of pus and blood， and descending to the large intestine to consume Yin fluids， resulting in persistent diarrhea. Based on this pathogenesis， the paper expands the scope of symptoms and signs associated with the prescription， providing a more detailed portrayal of the applicable patient population and enhancing the basis for clinical prescription references. Additionally， the paper presents considerations on several controversial topics， suggesting that the "lower pulse" described in the text refers to the lower limb arterial pulsation， and the symptoms and signs resemble those of septic shock in modern medicine. Therefore， Mahuang Shengmatang should be categorized as a prescription for treating warm diseases and it is not developed by ZHANG Zhongjing. By employing a detailed discussion on the syndrome， pathogenesis， and clinical application in the texts of Mahuang Shengmatang from the dosage， principle of compatibility， and herbal indications， this paper not only enriches the theoretical foundation of Mahuang Shengmatang but also provides a comprehensive perspective and fresh ideas for understanding its clinical application.

ObjectiveTo explore the main mechanism of self-precipitation formed during the decoction of Sinitang（SNT）， and to provide a research basis for exploring the differences in the toxic and effective components of this compound. MethodsThe average precipitation yields of SNT， Glycyrrhizae Radix et Rhizoma（GRR）-Aconiti Lateralis Radix Praeparata（ALRP） decoction（GF）， ALRP-Zingiberis Rhizoma（ZR） decoction（FJ）， GRR-ZR decoction（GJD）， ALRP decoction（FZ）， ZR decoction（GJ） and GRR decoction（GC） were determined. The four main self-precipitation samples of SNT， GF， FZ and GC were physically characterized by particle size， scanning electron microscopy（SEM）， pH， total dissolved solids（TDS）， conductivity， and Fourier transform infrared spectroscopy（FT-IR） analysis. The chemical compositions of SNT decoction and its different phases was identified by ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry（UPLC-Q-Exactive Orbitrap-MS） for SNT， SNT self-precipitation and SNT supernatant， and the contents of its main toxic and effective components were determined by high performance liquid chromatography（HPLC）. ResultsPrecipitation yield results of the 7 samples of SNT decoction and single decoction showed that SNT had the highest self-precipitation yield. The formation of SNT self-precipitation was mainly related to the reaction between ALRP and GRR components to form complexes， and FT-IR showed that GRR had the greatest influence on the formation of self-precipitation. A total of 110 components were identified in the SNT decoction， including 100 components in the SNT self-precipitation and 106 components in the SNT supernatant. And quantitative results of the main toxic and effective components revealed that the reaction between ALRP and GRR components formed complexes， resulting in the following content hierarchy for free components：SNT decoctionsupernatantself-precipitation， these components included free liquiritin， benzoylmesaconine， benzoylaconitine， benzoylhypacoitine， liquiritigenin， aconitine， hypoaconitine， isoliquiritigenin and ammonium glycyrrhizinate. ConclusionSNT exhibits spontaneous precipitation during compound decoction， with GRR exerting the greatest influence on its formation. This suggests GRR plays a significant role in the detoxification of SNT. The differences in the self-precipitated toxic-effective components of SNT compound decoction primarily manifest as changes in component content， reflecting the characteristics of SNT "deposition in vitro and sustained release in vivo" and the importance of "administered at draught" in the clinical application of SNT.

Objective To explore the value of dynamic MRI imaging in investigate the morphologic and dynamic factors of low anterior resection syndrome(LARS)after anal preservation surgery in patients with low rectal cancer.Methods Thirty-five patients who developed LARS after anal preservation surgery for low rectal cancer were prospectively collected.Subjects were underwent routine MRI and dynamic MRI of pelvis 1 week before and 3 months after surgery respectively.Routine MRI was used as the resting phase,and dynamic MRI was used to obtain the rapture phase and forceful phase.Parameters such as anal rectus angle(ARA),the length of the line connecting lower edge of pubic symphysis to the posterior wall attachment point of puborectal muscle(H-line),the vertical length from posterior wall attachment point of puborectal muscle to pubococcygeal line(M-line),thickness of puborectal muscle,and thickness of internal and external anal sphincter were measured at the three time phases.The differences between preoperative and postoperative,and moderate and severe LARS patients were compared by measuring relevant indicators.Results The preoperative and postoperative ARA,H-line length and M-line length of LARS patients were the smallest in the rapture phase,the largest in the forceful phase,and the middle in the resting phase.The postoperative thickness of puborectalis muscle and internal and external anal sphincter were the largest in the rapture phase,the smallest in the forceful phase,and the middle in the resting phase.There were significant differences between the three phases(P＜0.05).There were no significant differences between the three phases of postoperative puborectalis muscle thickness and internal and external sphincter thickness(P＞0.05).The postoperative ARA was greater than preoperative ARA in LARS patients,and the thickness of puborectalis muscle,the internal anal sphincter(resting phase and rapture phase),and the external anal sphincter were smaller than preoperative ARA,and the differences were statistically significant(P＜0.05).The ARA in resting phase and rapture phase was greater in patients with severe LARS than that of patients with mild LARS,and the thickness of internal anal sphincter in resting phase was less in patients with severe LARS than that of patients with mild LARS(P＜0.05).However,the differences between the other indicators were not statistically significant(P＞0.05).Conclusion Dynamic MRI examination technology combines dynamic images with quantitative indicators can be used as an important evaluation basis for LARS patients.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:To investigate the efficacy of different types of neoadjuvant therapy for esophageal cancer.Methods:The clinical data of 542 patients with esophageal squamous cell carcinoma (ESCC) who received neoadjuvant therapy in Anyang Tumor Hospital of Science and Technology from January 2015 to May 2022 were retrospectively analyzed. These patients, consisting of 198 females and 344 males, with 289 cases aging ≤ 65 and 253 cases aging >65, were divided into a neoadjuvant chemoradiotherapy (NCRT) group (137 cases), a neoadjuvant chemotherapy (NCT) group (241 cases), and a neoadjuvant immunotherapy plus chemotherapy (NICT) group (164 cases). In this study, primary endpoints included major pathological response (MPR) and pathologic complete response (pCR) rates, and secondary endpoints comprised overall survival (OS), progression-free survival (PFS), and safety. Survival analysis was performed using the Kaplan-Meier method, and inter-group comparisons were made using the Log-rank test. Furthermore, prognostic factors were analyzed based on the Cox proportional hazards regression model.Results:The NCRT, NCT, and NICT groups exhibited MPR and pCR rates of 66.4% (91/137) and 35.3% (85/241), 63.4% (104/164) and 35.8% (49/137), and 6.6% (16/241) and 31.1% (51/164), respectively ( χ2=1.67, P < 0.001). These groups displayed 1-, 2-, and 3-year OS rates of 89.8%, 85.9%, and 91.9%; 82.3%, 71.4%, and 81.5%; and 72.3%, 61.4%, and 77.8%, respectively, with significant differences ( χ2=9.20, P < 0.01). Furthermore, they exhibited 1-, 2-, and 3-year PFS rates of 81.5%, 75.9%, and 80.1%; 67.9%, 61.0%, and 65.5%; and 66.6%, 53.5%, and 65.3%, respectively, with significant differences ( χ2=4.62, P < 0.05). Multivariate analysis showed that therapeutic modality, T stage, and N stage were independent prognostic factors for OS ( P < 0.05). Additionally, there was no difference in adverse reactions and postoperative complications among the three groups. Conclusions:Compared to NCT, NICT and NCRT feature higher pCR and MPR rates, along with more survival benefits. Therefore, neoadjuvant immunotherapy has the potential to serve as a preoperative therapeutic modality for esophageal cancer, yet large-scale randomized controlled trials are still required for confirmation.

Objective:To evaluate the efficacy and safety of immunotherapy with or without radiotherapy in the treatment of recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC).Methods:A retrospective analysis was conducted on the data of 75 patients with R/M ESCC treated with sintilimab at Anyang Tumor Hospital from January 2020 to October 2021. The patients were divided into the radiotherapy (RT) group ( n=37) and non-radiotherapy (NRT) group ( n=38) based on whether they received radiotherapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse effects were compared between two groups. Count data were expressed as composition ratios and analyzed using Chi-square test or Fisher's exact test. Survival analysis was performed using Kaplan-Meier method and log-rank test. Results:There was no statistically significant difference in ORR and DCR between the RT and NRT groups (70% vs. 61%, P=0.375; 95% vs. 89%, P=0.414). However, the complete response (CR) rate in the RT group was higher compared to that in the NRT group (19% vs. 3%, P=0.022). The median follow-up duration was 25.4 months. There was no statistically significant difference in the median PFS and OS between the RT and NRT groups (13.8 months vs. 9.9 months, P=0.221; 20.2 months vs. 18.9 months, P=0.214). Subgroup analysis demonstrated that among patients with recurrence or metastasis confined to local and / or ≤3 distant lymph nodes, there was no statistically significant difference in the median PFS between the RT and NRT groups (15.1 months vs. 8.4 months, P=0.115), but the median OS in the RT group was better than that in the NRT group (not reached vs. 12.3 months, P=0.036). Compared to the NRT group, besides an increase in grade 1-2 pneumonitis (41% vs. 18%, P=0.035), no significant increase in treatment-related toxicity was observed in the RT group. Conclusion:Immunotherapy combined with radiotherapy is safe in patients with R/M ESCC, and shows survival benefit in patients with recurrence or metastasis confined to local and / or ≤3 distant lymph nodes.

Background The benchmark dose (BMD) method calculates the dose associated with a specific change in response based on a specific dose-response relationship. Compared with the traditional no observed adverse effect level (NOAEL) method, the BMD method has many advantages, and the 95% lower confidence limit of benchmark dose lower limit (BMDL) is recommended to replace NOAEL in deriving biological exposure limits. No authority has yet published any health-based guideline for rare earth elements. Objective To evaluate genotoxicity threshold induced by acute exposure to neodymium nitrate in mice using BMD modeling through micronucleus test and comet assay. Methods SPF grade mice (n=90) were randomly divided into nine groups, including seven neodymium nitrate exposure groups, one control group (distilled water), and one positive control group (200 mg·kg⁻¹ ethyl methanesulfonate), 10 mice in each group, half male and half female. The seven dose groups were fed by gavage with different concentrations of neodymium nitrate solution (male: 14, 27, 39, 55, 77, 109, and 219 mg·kg⁻¹; female: 24, 49, 69, 97, 138, 195, and 389 mg·kg⁻¹) twice at an interval of 21 h. Three hours after the last exposure, the animals were neutralized by cervical dislocation. The bone marrow of mice femur was taken to calculate the micronucleus rate of bone marrow cells, and the liver and stomach were taken for comet test. Results The best fitting models for the increase of polychromatophil micronucleus rate in bone marrow of female and male mice induced by neodymium nitrate were the exponential 4 model and the hill model, respectively. The BMD and the BMDL of female mice were calculated to be 31.37 mg·kg⁻¹ and 21.90 mg·kg⁻¹, and those of male mice were calculated to be 58.62 mg·kg⁻¹ and 54.31 mg·kg⁻¹, respectively. The best fitting models for DNA damage induced by neodymium nitrate in female and male mouse hepatocytes were the exponential 5 model and the exponential 4 model, respectively, and the calculated BMD and BMDL were 27.15 mg·kg⁻¹ and 11.99 mg·kg⁻¹ for female mice, and 16.28 mg·kg⁻¹ and 10.47 mg·kg⁻¹ for male mice, respectively. The hill model was the best fitting model for DNA damage of gastric adenocytes in both female and male mice, and the calculated BMD and BMDL were 36.73 mg·kg⁻¹ and 19.92 mg·kg⁻¹ for female mice, and 24.74 mg·kg⁻¹ and 14.08 mg·kg⁻¹ for male mice, respectively. Conclusion Taken the micronucleus rate of bone marrow cells, DNA damage of liver cells and gastric gland cells as the end points of genotoxicity, the BMDL of neodymium nitrate is 10.47 mg·kg⁻¹, which can be used as the threshold of genotoxic effects induced by acute exposure to neodymium nitrate in mice.

Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
Humans ; Ischemic Stroke ; Brain/metabolism* ; Macrophages ; Brain Ischemia/metabolism* ; Microglia/metabolism* ; Gene Expression Profiling ; Anti-Inflammatory Agents ; Neuronal Plasticity/physiology* ; Infarction/metabolism*

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To construct a Chinese neonatal model of early-onset sepsis (EOS) using the Kaiser Permanente sepsis risk calculator and laboratory indicators and validate its clinical prediction potential.Methods:Newborns with a gestational age of ≥34 weeks, who were hospitalized in the Department of Neonatology, the First Affiliated Hospital of Zhengzhou University from January 2020 to June 2022 were retrospectively recruited.Their clinical data were collected.Predictors were screened via the multivariate regression analysis, and the Nomogram model was constructed using R software and RStudio software.Hosmer-Lemeshow test, receiver operating characteristic curve, the decision curve analysis (DCA) were used to evaluate the prediction potential of the Nomogram.Results:A total of 769 patients were enrolled, including 107 patients in the EOS group (5 culture-confirmed cases and 102 clinically diagnosed cases), and 662 cases in the non-EOS group.Ten variables were screened and introduced into the Nomogram, including the gestational age, birth weight, body temperature, white blood cell count, C-reactive protein, procalcitonin, premature rupture of membranes≥18 h, infection of Group B Streptococcus, ventilator application, and prenatal antibiotics.The predictive model showed good discrimination and consistency, with the area under the curve of 0.834 (95% CI: 0.771-0.896). The DCA of the prediction model showed that it was effective in clinical application within the effective threshold of 6%-95%, with a net benefit following the application of corresponding treatment measures. Conclusions:A Chinese neonatal model of EOS was created by using the Kaiser Permanente sepsis risk calculator and laboratory indicators, which has been validated effective.It provides references for clinical management and the guidance for the use of antibiotics.