Chronic heart failure （CHF） is a complex clinical syndrome caused by ventricular dysfunction， with mitochondrial energy metabolism disorder being a critical factor in disease progression. Heart-Yang deficiency syndrome， as the core pathogenesis of CHF， persists throughout the disease course. Insufficiency of heart-Yang leads to weakened warming and propelling functions， resulting in the accumulation of phlegm-fluid， blood stasis， and dampness. This eventually causes Qi stagnation with phlegm obstruction and blood stasis with water retention， forming a vicious cycle that exacerbates disease progression. According to the theory of reinforcing Yang， the clinical experience of the traditional Chinese medicine （TCM） master Tang Zuxuan in treating CHF with heart-Yang deficiency syndrome， and achievements from molecular biological studies， this study innovatively proposes an integrated research framework of "TCM syndrome differentiation and staging-mitochondrial metabolism mechanisms-intervention with Yang-reinforcing prescriptions" which is characterized by the integration of traditional Chinese and Western medicine. Heart-Yang deficiency syndrome is classified into mild （Stage Ⅰ-Ⅱ）， severe （Stage Ⅲ）， and critical （Stage Ⅳ） stages. The study elucidates the precise correlations between the pathogenesis of each stage and mitochondrial metabolism disorders from theoretical， pathophysiological， and therapeutic perspectives. The mild stage is characterized by impaired biogenesis and substrate-utilization imbalance， corresponding to heart-Yang deficiency and phlegm-fluid aggregation. Linggui Zhugantang and similar prescriptions can significantly improve the expression of peroxisome proliferator-activated receptor gamma co-activator-1α（PGC-1α）/silent information regulator 2 homolog 1 （SIRT1） and ATPase activity. The severe stage centers on oxidative stress and structural damage， reflecting Yang deficiency with water overflow and phlegm-blood stasis intermingling. At this stage， Zhenwu Tang and Qiangxin Tang can effectively mitigate oxidative stress damage， increase adenosine triphosphate （ATP） content， and repair mitochondrial structure. The critical stage arises from calcium overload and mitochondrial disintegration， leading to the collapse of Yin-Yang equilibrium. At this stage， Yang-restoring and crisis-resolving prescriptions such as Fuling Sini Tang and Qili Qiangxin capsules can inhibit abnormal opening of the mitochondrial permeability transition pore （MPTP）， reduce cardiomyocyte apoptosis rate， and protect mitochondrial function. By summarizing the characteristics of mitochondrial energy metabolism disorders at different stages of CHF， this study explores the application of the theory of reinforcing Yang in treating heart-Yang deficiency syndrome and provides new insights for the clinical diagnosis and treatment of CHF.

ObjectiveTo explore the mechanism of ventricular remodeling mediated by the p38 mitogen-activated protein kinase （MAPK）/nuclear factor kappa B （NF-κB） signaling pathway in the rat model of chronic heart failure （CHF） with heart-blood stasis syndrome， as well as the intervention effect of Danhong injection. MethodsIn vivo experiment： SPF-grade male SD rats were assigned via the random number table method into 4 groups： Sham operation， model， captopril （8.8 mg·kg^-1）， and Danhong injection （6.0 mL·kg^-1）. The model of CHF with heart-blood stasis syndrome was established by abdominal aortic constriction， and the sham operation group only underwent laparotomy without constriction. All the groups were treated continuously for 15 days. The tongue color of rats was observed. Echocardiography， hemorheology， heart mass index （HMI）， and left ventricular mass index （LVMI） were measured. Hematoxylin-eosin （HE） staining and Masson staining were performed to observe the pathological and fibrotic changes of the myocardial tissue. Enzyme-linked immunosorbent assay （ELISA） was employed to quantify the levels of N-terminal pro-B-type natriuretic peptide （NT-proBNP）， interleukin-6 （IL-6）， angiotensin Ⅱ （AngⅡ）， tumor necrosis factor-α （TNF-α）， and Creactive protein （CRP） in the serum， as well as the levels of matrix metalloproteinase-2 （MMP-2） and matrix metalloproteinase-9 （MMP-9） in the myocardial tissue. Western blot was used to quantify the protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65 in the myocardial tissue. In vitro experiment： H9C2 cardiomyocytes were treated with 1×10^-6 mol·L^-1 AngⅡ to establish a model of myocardial hypertrophy. H9C2 cardiomyocytes were allocated into normal， model， inhibitor + Danhong injection， Danhong injection （20 mL·L^-1）， and inhibitor （SB203580， 5 μmol·L^-1） groups. CCK-8 assay was used to detect the viability of H9C2 cardiomyocytes. Rhodamine-labeled phalloidin staining was used to reveal the area of cardiomyocytes. Real-time PCR was performed to determine the mRNA levels of atrial natriuretic peptide （ANP） and brain natriuretic peptide （BNP）. Western blot was used to assess the protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65. ResultsIn vivo experiment： Compared with the sham operation group， the model group showed purplish-dark tongue with decreased R， G， B values of the tongue surface （P<0.01）， increased whole blood viscosity （at low， medium， and high shear rates） （P<0.01）， decreased left ventricular ejection fraction （LVEF） and left ventricular fractional shortening （LVFS） （P<0.01）， increased left ventricular end-diastolic diameter （LVIDd）， left ventricular end-systolic diameter （LVIDs）， and left ventricular posterior wall thickness at end-diastole （LVPWd） （P<0.01）， raised LVMI and HMI （P<0.01）， and elevated levels of NT-proBNP， TNF-α， IL-6， and CRP in the serum and MMP-2 and MMP-9 in the myocardial tissue （P<0.01）. The HE and Masson staining of the myocardial tissue showed compensatory myocardial hypertrophy， fibrosis， and massive inflammatory cell infiltration in the model group. Additionally， the model group presented up-regulated protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65 in the myocardial tissue （P<0.01）. Compared with the model group， each administration group showed increased R， G， B values of the tongue surface （P<0.05， P<0.01）， decreased whole blood viscosity （at low， medium， and high shear rates） （P<0.05， P<0.01）， increased LVEF and LVFS （P<0.01）， decreased LVIDd， LVIDs， and LVPWd （P<0.05， P<0.01）， declined LVMI and HMI （P<0.05， P<0.01）， and lowered levels of NT-proBNP， TNF-α， IL-6， and CRP in the serum and MMP-2 and MMP-9 in the myocardial tissue （P<0.01）. HE and Masson staining showed alleviated compensatory myocardial hypertrophy， reduced fibrosis， and decreased expression of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65 in the myocardial tissue （P<0.01）. In vitro experiment： When the concentration of Danhong injection reached 20 mL·L^-1， the survival rate of H9C2 cardiomyocytes was the highest （P<0.01）. Compared with the normal group， the model group showed up-regulated mRNA levels of ANP and BNP （P<0.01）， increased relative cell surface area （P<0.01）， and raised protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65 （P<0.01）. Compared with the model group， each administration group showed down-regulated mRNA levels of ANP and BNP （P<0.01）， reduced relative cell surface area （P<0.05， P<0.01）， and down-regulated protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB p65/NF-κB p65 （P<0.05， P<0.01）. ConclusionDanhong injection can regulate ventricular remodeling through the p38 MAPK/NF-κB pathway， thereby exerting a protective effect on the rat model of CHF with heart-blood stasis syndrome.

ObjectiveTo investigate the effects of Danhong injection on mitochondrial dynamics， morphology， and function in the rat model of chronic heart failure by mediating the adenosine 5'-monophosphate （AMP）-activated protein kinase （AMPK）/dynamin-related protein 1 （Drp1） pathway. MethodsFrom 75 SD rats， 15 rats were randomly selected as the sham group， and the remaining 60 rats were used to prepare a rat model of chronic heart failure by abdominal aortic constriction （AAC）. The modeled rats were randomly allocated into model， Danhong Injection （6 mL·kg^-1）， and captopril （8.8 mg·kg^-1） groups and administrated with corresponding agents for 15 consecutive days. The levels of N-terminal pro-brain natriuretic peptide （NT-pro BNP）， adenosine diphosphate （ADP）， adenosine triphosphate （ATP）， interleukin （IL）-6， IL-1β， and tumor necrosis factor （TNF）-α and the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ were determined by enzyme-linked immunosorbent assay. The changes in cardiac function were detected by echocardiography. The ultrastructural changes of myocardial mitochondria were observed by transmission electron microscopy. Western blot was employed to assess the protein levels of AMPK， p-AMPK， Drp1， p-Drp1， optic atrophy 1 （Opa1）， mitofusin （Mfn2）， and fission l （Fis1） in the myocardial tissue. Real-time PCR was performed to determine the mRNA levels of Opa1， Mfn2， and Fis1， and immunohistochemistry to detect the expression of p-AMPK. ResultsCompared with the sham group， the model group showed elevated levels of NT-pro BNP， ADP， TNF-α， IL-6， and IL-1β （P<0.01）， declined ATP level （P<0.01）， weakened activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ （P<0.01）， decreased left ventricular ejection fraction （LVEF） and left ventricular fraction shortening （LVFS） （P<0.01）， and increased left ventricular internal diameter at end-diastole （LVDd） and leaf ventricular internal diameter at end-systole （LVIDs） （P<0.01）. Electron microscopy results showed that the model group presented heavily abnormal myocardial structure， with large areas of myofilament structure destroyed and dissolved， significantly enlarged residual structural gaps， and fragmented mitochondria. Western blot results showed that the model group demonstrated down-regulated protein levels of p-AMPK， Mfn2， and Opa1 （P<0.01） and up-regulated protein levels of p-Drp1 and Fis1 （P<0.01） in the myocardial tissue. Real-time PCR results showed that the model group presented up-regulated mRNA level of Fis1 （P<0.01） and down-regulated mRNA levels of Mfn2 and Opa1 （P<0.01）. Immunohistochemistry results showed reduced expression of p-AMPK in the model group compared with sham group （P<0.01）. Compared with the model group， Danhong injection lowered the levels of NT-pro BNP， ADP， TNF-α， IL-6， and IL-1β （P<0.01）， raised the level of ATP （P<0.01）， increased the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ （P<0.05， P<0.01）， increased the LVEF and LVFS （P<0.01）， decreased the LVDd and LVIDs （P<0.05， P<0.01）， alleviated mitochondrial damage， up-regulated the protein levels of p-AMPK， Mfn2， and Opa1 （P<0.05， P<0.01）， down-regulated the protein levels of p-Drp1 and Fis1 （P<0.01）， reduced the mRNA level of Fis1 （P<0.01）， elevated the mRNA levels of Mfn2 and Opa1 （P<0.05， P<0.01）， and promoted the expression of p-AMPK （P<0.05）. ConclusionDanhong injection repairs the imbalance of mitochondrial dynamics， restores the mitochondrial function， improves the myocardial energy metabolism， and reduces the inflammatory response by regulating the AMPK/Drp1 pathway， thus improving the cardiac function.

Deficiency, stasis, water and toxin are of great significance in the pathogenesis and pathologic evolution of chronic heart failure (CHF). Based on "deficiency, blood stasis, water and toxin", the pathogenesis and treatment of CHF were discussed in this article. It was found that in the pathogenesis, deficiency--deficiency of heart qi and deficiency of heart yang were the origin of the disease, and blood stasis, water and toxin were the markers of the disease. Among them, blood stasis was the central pathological link, and also an important mechanism that could aggravate the disease and cause a vicious cycle; water-phlegm and water dampness were the basic pathological products; toxin-heat toxin, water toxin, and stasis toxin were the final results of disease progress and product accumulation. In terms of treatment, CHF can be divided into four stages: early, middle, late and end. In the early stage, tonifying qi and regulating heart can be used for the treatment of root cause, and promoting blood circulation and water can be used for the treatment of symptoms; tonifying qi and yin and reinforcing the healthy qi, reducing blood stasis, purging turbid, and eliminating pathogenic factors can be used in the middle stage; reducing blood stasis and removing toxic materials should be used in the late stage, supplemented with warming yang and increasing urine excretion; astringing yang,generating body fluids, tonifying qi and yang should be used in the end stage. At the same time of treating by stages, attention should be paid to adhering to a holistic concept and dialectical treatment; pay attention to timing and flexible medication; adopting a combination of Chinese and Western approaches and integrating them.

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Objective To explore the anatomic basis for and clinical outcomes of the internal fixation which preserves the pronator quadratus (PQ) for distal radius fractures.Methods Twenty cadaveric specimens of adult upper extremity were used for this study (14 males and 6 females).The radial and ulnar lengths of PQ,the distal and proximal widths of PQ,the distances from the distal end of PQ to the articular surface of the distal radius and to the transverse line of the wrist,and the width of the bony tunnel of PQ were dissected and measured to study the anatomical features of PQ.A retrospective study was conducted of the 18 distal radius fractures which had been treated from March 2015 to March 2017 by internal fixation with T-shaped anatomic locking compression plate (LCP) with PQ preserved.They were 8 males and 10 females,with an average age of 52.7 years (range,from 28 to 65 years).According to the AO classification,there were 8 cases of type 23-A,5 ones of type 23-B and 5 ones of type 23-C1.The functional outcomes of the wrist were assessed using the Cooney scoring system at the last follow-ups.Results The PQ muscle was flat and like a right angle trapezoid with rich blood vessels.The radial and ulnar lengths of PQ were about 4.60 cm and 4.46 cm;the distal and proximal widths of PQ were about 4.41 cm and 4.48 cm;the distance from the distal end of PQ to the transverse line of the wrist was about 3.61 cm;the widths of the distal and proximal bony tunnels were about 3.08 cm and 1.91 cm.The 18 patients were followed up for 6 to 36 months (average,11.5 months).Bone union was achieved in all the patients after a mean time of 2.5 months (range,from 2 to 3 months).The mean Cooney score for the wrist function was 97.7 (range,from 95 to 100) at the last follow-up,yielding an excellent rate of 100％.Conclusions The transverse line of the distal radius fracture is located between 1/4 and 1/2 of the distal PQ.The bony tunnel of PQ is wide enough.It is feasible to preserve the distal PQ muscle in the internal fixation of distal radius fractures of types 23-A,23-B and 23-C1,because it may lead to rapid recovery of the patients and satisfactory wrist function.

Objective To investigate the clinicopathologic characteristics and prognosis of medullary breast carcinoma.Methods We conducted a retrospective analysis on clinical and pathologic data of 166 patients with medullary breast cancer.Results All the patients were female with a median age of 52 years old.The proportion of patients with stage Ⅰ,Ⅱ and Ⅲ disease was 16.9％,68.1％,15.0％,respectively.The Luminal,HER-2 overexpressing and triple-negative subtypes constituted 31.3％,8.4％,and 60.3％,respectively.There was significant difference in regional lymph node status of medullary breast cancer patients with different molecular types (x2 =18.248,P =0.003),but not in tumor size,TNM stage,histological grade,and expression of Ki67 (all P ＞ 0.05).Multivariate survival analysis indicated that TNM stage was an independent predictor in the prognosis of medullary breast cancer (HR =5.664,P =0.001).All the patients were followed up from 15 months to 145 months with a median follow-up time of 108 months.The 5-year survival rate was 91.5％ and the 10-year survival rate was 87.2％.Conclusions The prognosis of medullary breast cancer is favorable.Personalized treatment according to the TNM stage and histopathologic characteristics achieve a favorable prognosis.

Objective To explore the clinicopathological characteristics and prognosis of invasive micropapillary carcinoma of the breast (IMPC),and the distinction between IMPC and invasive ductal carcinoma of the breast (IDC).Methods From February 2004 to November 2013,195 IMPC patients and 420 IDC patients were analyzed retrospectively.Results There were significant differences in mammilla invasion,lymph vessel invasion,orange peel sign,soft tissue encroachment,neoadjuvant chemotherapy,radical mastcctomy,lymph node metastasis,clinical stages,tumor size,lymph node staging,estrogen receptor (ER),progestin receptor (PR),human epidermal growth factor receptor 2 (HER2),molecular subtyping,ratio of radiation,ratio of endocrine therapy,disease-free survival (DFS),overall survival (OS)between the two groups,all P ＜0.05.Patients with IMPC had lower 5-year DFS and OS rates (68.2％ and 73.8％,respectively) than IDC patients (85.7％ and 88.6％,respectively),all P ＜ 0.05.In IMPC patients with positive ER/PR,HER2-negative,smaller tumor volume,less lymph node metastasis,negative nipple invasion,negative lymphatic vessel tumor thrombus,negative orange peel change had higher 5-year DFS and OS rates than those with negative ER/PR,HER2 overexpression,larger tumor volume,more lymph node metastasis,positive nipple invasion,positive lymphatic vessel tumor thrombus,positive orange peel change,all P ＜ 0.05.Besides,the patients with pathologic stage Ⅰ had higher OS than those with stage Ⅲ (P ＜ 0.05).Cox regression analysis found that orange peel change,lymph vessel invasion and HER2 were the independent risk factors for the survival time of patients with IMPC.Conclusions IMPC patients have lower DFS and OS compared with IDC.

Objective: To investigate the seroprevalence and epidemiological characteristics of hepatitis E virus (HEV) infection in pregnant women in Xiamen. Methods: Sera samples of 910 pregnant women were collected from September 2014 to June 2015 in Xiamen Huli District Maternity and Child Care Hospital. Those who intended to give birth in target hospital were included in a subgroup which was asked to collect the second serum sample. All samples were tested for anti-HEV IgM and IgG antibody by enzyme linked immunosorbent assay (ELISA). HEV RNA was tested by reverse transcription-polymerase chain reaction (RT-PCR) for the positive samples of anti-HEV IgM antibody, meanwhile, the quantitative detections for anti-HEV IgG were conducted in specimens positive for anti-HEV IgG. Results: Of the 910 pregnant women, 8 (0.88%, 95%CI 0.45%-1.73%) were anti-HEV IgM positive. HEV RNA was found in 3 cases through RT-PCR and viral load values were between 600 and 700 copies/ml; 140 (15.38%, 95%CI 13.19%-17.68%) were anti-HEV IgG positive and geometric mean concentration of the samples was 0.385 Wu/mL (95%CI 0.332-0.445 Wu/ml). The positive rate of anti-HEV IgG increased with age (P=0.004). In the subgroup, 150 pregnant women were included and followed up, 4 of those were defined as 'new HEV infection cases’ and the incidence was evaluated as 10.7/100 person-year (95%CI 3.39-25.7/100 person-year). Conclusions There were a low percentage of HEV carriers in pregnant women in Xiamen, but the risk of new primary infection in pregnant women during pregnancy was much higher than the general population, suggesting that it is necessary to expand sample size to clarify the burden of HEV infection during pregnancy.

Objective To investigate the clinical and pathologic features of squamous cell carcinoma of the breast.Methods The clinical and pathologic data of 23 squamous cell carcinoma of the breast patients admitted between 1984 and 2013 to Tianjin Medical University Cancer Hospital was analyzed retrospectively.Results Primary squamous cell carcinoma of the breast was a very rare tumor accounting for 0.06％ of all breast cancers.All of the 23 patients were females aged 28 years to 87 years(median age 49 years).Average tumor size was 4.5 cm.9 patients suffered from lymph node metastasis at admission (39.1％).The positive rates of estrogen receptor (ER),progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) were 13.6％ (3/23),4.5％ (1/23) and 0 (0/20) respectively.With a follow-up time varying from 5 months to 36 months recurrence or metastasis were found in 8 patients,and another 1 patient was found having distant metastasis at admission.Lung metastasis (7/9) was most common.6 patients died.Conclusions Squamous cell carcinoma of the breast is highly invasive,with low rate of positive receptors and early distant metastasis or recurrence after operation,and poor patients' survival.