Objective To observe the effects of melatonin on autophagy in cortical neurons of neonatal rats with hypoxic-ischemic brain damage(HIBD)and to explore its mechanisms via the PI3K/AKT signaling pathway,aiming to provide a basis for the clinical application of melatonin.Methods Seven-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group,an HIBD group,and a melatonin group(n=9 each).The neonatal rat HIBD model was established using the classic Rice-Vannucci method.Neuronal morphology in the neonatal rat cerebral cortex was observed with hematoxylin-eosin staining and Nissl staining.Autophagy-related protein levels of microtubule-associated protein 1 light chain 3(LC3)and Beclin-1 were detected by immunofluorescence staining and Western blot analysis.Phosphorylated phosphoinositide 3-kinase(p-PI3K)and phosphorylated protein kinase B(p-AKT)protein expression levels were measured by immunohistochemistry and Western blot.The correlation between autophagy and the PI3K pathway in the melatonin group and the HIBD group was analyzed using Pearson correlation analysis.Results Twenty-four hours post-modeling,neurons in the sham operation group displayed normal size and orderly arrangement.In contrast,neurons in the HIBD group showed swelling and disorderly arrangement,while those in the melatonin group had relatively normal morphology and more orderly arrangement.Nissl bodies were normal in the sham operation group but distorted in the HIBD group;however,they remained relatively intact in the melatonin group.The average fluorescence intensity of LC3 and Beclin-1 was higher in the HIBD group compared to the sham operation group,but was reduced in the melatonin group compared to the HIBD group(P<0.05).The number of p-PI3K+and p-AKT+cells decreased in the HIBD group compared to the sham operation group but increased in the melatonin group compared to the HIBD group(P<0.05).LC3 and Beclin-1 protein expression levels were higher,and p-PI3K and p-AKT levels were lower in the HIBD group compared to the sham operation group(P<0.05);however,in the melatonin group,LC3 and Beclin-1 levels decreased,and p-PI3K and p-AKT increased compared to the HIBD group(P<0.05).The correlation analysis results showed that the difference of the mean fluorescence intensity of LC3 and Beclin-1 protein in the injured cerebral cortex between the melatonin and HIBD groups was negatively correlated with the difference of the number of p-PI3K+and p-AKT+cells between the two groups(P<0.05).Conclusions Melatonin can inhibit excessive autophagy in cortical neurons of neonatal rats with HIBD,thereby alleviating HIBD.This mechanism is associated with the PI3K/AKT pathway.

Objective: To investigate the characteristics of non-alcoholic fatty liver disease (NAFLD) and its associated factors in rheumatoid arthritis (RA) patients. Methods: This cross-sectional study recruited 385 RA patients [including 72 (18.7%) male and 313 (81.3%) female] who received abdominal sonographic examination from August 2015 to May 2021 at Department of Rheumatology, Sun Yat-Sen Memorial Hospital. There were 28 RA patients at 16-29 years old and 32, 80, 121, 99, 25 at 30-39, 40-49, 50-59, 60-69, ≥ 70 years old, respectively. Demographic and clinical data were collected including age, gender, history of alcohol consumption, disease duration, body mass index (BMI), waist circumference, blood pressure, RA disease activity indicators and previous medications. Logistic regression analyses were used to identify the associated factors of NAFLD in RA patients. Results: The prevalence of NAFLD was 24.2% (93/385) in RA patients, 26.3% (21/80) in 40-49 age group and 33.1% (40/121) in 50-59 age group. There were 22.1% (85/385) and 3.6% (14/385) RA patients with overweight and obese, in which the prevalence of NAFLD was 45.9% (39/85) and 78.6% (11/14) respectively, which was 2.6 folds and 4.5 folds that of RA patients with normal BMI. Although there was no significant difference of age, gender and RA disease activity indicators between RA patients with or without NAFLD, those with NAFLD had higher proportions of metabolic diseases including obese (11.8% vs. 1.0%), central obesity (47.3% vs. 16.8%), hypertension (45.2% vs. 29.8%) and type 2 diabetes mellitus (24.7% vs. 12.0%), consistent with higher levels of total cholesterol [(5.33±1.31) mmol/L vs. (4.73±1.12) mmol/L], triglyceride [(1.51±1.08) mmol/L vs. (0.98±0.54) mmol/L] and low-density lipoprotein cholesterol [(3.37±0.97) mmol/L vs. (2.97±0.78) mmol/L, all P<0.05]. Multivariate logistic regression analysis showed that BMI (OR=1.314) and triglyceride (OR=1.809) were the independent factors positively associated with NAFLD in RA patients. Conclusion: NAFLD is a common comorbidity in RA patients, especially in those with middle-aged, overweight or obese, which is associated with high BMI or high triglyceride. Screening and management of NAFLD in RA patients especially those with overweight, obese or dyslipidemia should be emphasized.
Adolescent ; Adult ; Aged ; Arthritis, Rheumatoid/epidemiology* ; Cholesterol, LDL ; Cross-Sectional Studies ; Female ; Humans ; Male ; Middle Aged ; Non-alcoholic Fatty Liver Disease/epidemiology* ; Obesity/epidemiology* ; Overweight/epidemiology* ; Triglycerides ; Young Adult

Objective:To explore the risk factors of paralytic ileus (PI) after simultaneous pancreas-kidney (SPK) transplantation.Methods:From January 2017 to December 2019, clinical data were reviewed retrospectively for 115 cases of SPK transplantation. The risk factors of PI after SPK were analyzed. According to the occurrence of PI, they were divided into two groups of occurrence and non-occurrence. One-way analysis of variance was utilized for analyzing such influencing factors as gender, age, body mass index (BMI), diabetic type, duration of diabetes, mode of dialysis, duration of dialysis, diabetic gastroenterology, history of open surgery, bowel preparation, operative duration, hemorrhagic volume, immunosuppressant and hypoproteinemia. Multivariate Logistic regression analysis was performed for screening the suspected risk factors.Results:Among them, 19 patients (16.5%) had PI. Univariate analysis showed that PI was associated with diabetic gastroenterology, operative duration, history of open surgery, no bowel preparation and hypoproteinemia ( P<0.05). Multivariate Logistic regression analysis revealed that the risk factors of PI after SPK included diabetic gastroenterology, operative duration time, history of open surgery and no bowel preparation ( P<0.05). Conclusions:Diabetic gastroenterology, operative duration, history of open surgery and no bowel preparation are risk factors for PI after SPK. Clinical interventions for the above factors are necessary.

On the basis of systematic evaluation of 32 provincial capital cities and municipalities in their capacity for preventing and controlling emerging infectious diseases, focus analysis is made on Wuhan in relation to its advantages and disadvantages as follows:There has been a legal basis for epidemic prevention according to law, but it has not translated into effective action.There has been an organizational basis for responding to epidemic, but coordination mechanism has not been effectively established.The management mechanism has been complete, but the division of responsibilities among different departments has not been clear.The monitoring network has been set up, but its role of "predictive warning" has not been played.Insufficiency of public health service delivery was observed owing to lack of financial investment.In cities of China, advantages and disadvantages have been both existent in their capacity to prevent and control of emerging infectious disease.We should be vigilant in this regard. It is imperative to "fill defects, stop leaks and strengthen weakness".There is a Chinese saying:"It is not too late to mend a fold after the sheep have been stolen".

ObjectiveThere is still controversy about which internal fixation method should be used in oblique lateral interbody fusion (OLIF). This paper aims to compare the biomechanical stability of OLIF with different internal fixation methods.MethodsA 31-year-old healthy male volunteer was selected to have a 64-slice spiral CT scan of his lumbar spine. Mimics 19.0, Geomagic Studio 2013, SolidWorks 2017 and other software were used to build a three-dimensional model of L3-L5, and OLIF surgery was simulated to build OLIF finite element models with five different fixation methods: pedicle screw (PS), lateral single rod screw (LSRS), lateral double rod screw (LDRS), lateral single rod screw+ipsilateral translaminar facet screw (LSRS+ITLFS), lateral single rod screw+contralateral translaminar facet screw (LSRS+CTLFS). After validating the validity of the model, the motion modes of spinal flexion, extension, lateral bending and rotation were simulated, and the fixed segment activity and stress distribution characteristics of each model were compared.ResultsIn terms of fixed segment activity, PS had the best fixation effect, and its range of motion (ROM) was the smallest in all 6 modes. The ROM of the vertebral body was maximized when the LSRS was fixed in all directions. LSRS+ITLFS, LSRS+CTLFS and PS had the similar ROM. In terms of maximum stress of cage, PS had the minimum one except in the left bending. LSRS+ITLFS had little stress in all directions except in flexion; LSRS+CTLFS had little stress in all directions except in extension. In terms of the maximum stress in internal fixation, PS had the least one in all directions; LSRS+CTLFS followed, and the maximum stress appeared in extension and right bending (123.05MPA and 91.74MPA, respectively).ConclusionIn OLIF surgery, PS has the best biomechanical effect. LSRS+CTLFS has the similar effect and its clinical operation is simple with relatively small surgical injury, thus providing a reference for clinical choice.

The outbreak of COVID-19 has exposed many shortcomings in disease control and prevention system (DCPS) of China.Resolving the problems and strengthening the DCPS became the top priority on China′s public policy agenda.This paper reveals the problems of the DCPS system regarding policy-making, regulations, operation mechanism and staff, and proposes several strategies from three aspects of legal construction, management system, and operation mechanism, including:"Prevention first" should be incorporated into the national legal system, all the departments should be engaged in "Healthy China 2030" initiative, laws and regulations should be amended, new disease prevention and control management institutions should be set up, a high-quality professional team should be retained, the regional health information exchange channels should be strengthened, the coordinated mechanism for disease prevention and control should be normalized, the long-term investment mechanism should be established, and the equipment renewal and reserve system should be improved.

OBJECTIVE: Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. METHODS: We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. RESULTS: Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. CONCLUSION Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.
Acrylamides/therapeutic use* ; Adult ; Aged ; Aminoquinolines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Breast Neoplasms/drug therapy* ; China ; Humans ; Middle Aged ; Neoplasm Metastasis ; Receptor, ErbB-2 ; Retrospective Studies ; Trastuzumab ; Treatment Outcome

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
Animals ; Blood Pressure ; physiology ; Excitatory Postsynaptic Potentials ; physiology ; Humans ; Hypertension ; physiopathology ; Hypothalamus ; physiology ; Neurons ; physiology ; Paraventricular Hypothalamic Nucleus ; physiology

OBJECTIVETo observe the effect differences among the comprehensive therapy, acupuncture and oral mecobalamine for senile sensorineural hearing loss.

METHODSA total of 126 senile sensorineural hearing loss patients were randomized into a comprehensive group, an acupuncture group and a western medication group, 42 cases in each group. After removing and discontinuing cases, 40 cases in each group were included in the analysis. Acupuncture, acupoint injection and auricular point pressing were used in the comprehensive group. Acupuncture for 2 courses was at the affected Tinggong (SI 19), Tinghui (GB 2), Yifeng (TE 17), etc, once every other day, 10 times as a course with one week rest between 2 courses, 3 times a week. Acupuncture as the comprehensive group was applied in the acupuncture group. Mecobalamin tablet was prescribed orally for 2 courses in the western medication group, 3 times a day, 0.5 mg a time, 3 weeks as a course, one week at the interval. Pure tone hearing threshold value and tinnitus grading were observed before and after intervention in the three groups. The clinical effects were compared.

RESULTSAfter treatment, pure tone hearing threshold value and tinnitus grading were better than those before treatment in the three groups (all <0.05), with better results in the comprehensive group than those in the other two groups (all <0.05). The total effective rate of pure tone hearing threshold value was 82.5% (33/40) in the comprehensive group, which was superior to 67.0% (27/40) in the acupuncture group and 62.5% (25/40) in the western medication group (both <0.05). The total effective rate of tinnitus was 83.3% (30/36) in the comprehensive group, which was superior to 69.7% (23/33) in the acupuncture group and 57.1% (20/35) in the western medication group (both <0.05).

CONCLUSIONThe clinical effects of comprehensive therapy on senile sensorineural hearing loss are superior to those of simple acupuncture and oral administration of mecobalamin in terms of pure tone hearing threshold value and tinnitus grading.

OBJECTIVETo establish osteoblast-osteoclast cell co-culture system in a Transwell chamber, and detect cell viability of osteoblasts and osteoclasts in system.

METHODSOsteoblast MC3T3-E1 and mouse monocytes RAW264.7 were cultivated in vitro. RANKL-induced mouse RAW264.7 monocytes differentiated into mature osteoclasts, osteoblast-osteoclast cell co-culture system was established in Transwell chamber. Cell activity of osteoblasts and osteoclasts were detected by CCK-8 experimenting, Alizarin Red staining, TRAP staining. The expression of OPG, ALP, RANKL, TGF-b1 gene and RANKL protein in osteoblast MC3T3-E1 were detected by PCR, Western-Blot methods. Also, the expression of RANK, NF-κB in gene and protein level in osteoclast were measured through the same method respectively.

RESULTSThe co-culture system of Mouse MC3T3-E1 cells and RAW264.7 cell were established in Transwell chamber. Co-culture system affected cell division activities of osteoblasts and osteoclasts. Differentiation of osteoblasts were increased, while differentiation of osteoclast division were slight decreased under microscope observation. OPG (0.65±0.08) and ALP (0.16±0.01) gene expression of co-culture system were less than single culture OPG(1.00±0.08) and ALP (1.01±0.16); TGF-b1(4.42±0.21) and RANKL(4.12±1.04) of osteoblasts in co-culture system were higher than TGF-b1(1.00±0.10) and RANKL(1.00±0.09) under single culture. However, gene expression of RANK(0.63±0.06) and NF-κB(0.64±0.08) in co-culture system were decreased than RANK(1.00±0.08) and NF-κB(1.00±0.09), in single culture, and had significant differences. Similarly, protein expression of OPG(0.43±0.05) and NF-κB(0.59±0.05) of co-culture system were less than OPG(0.84±0.06) and NF-κB(1.13±0.03) of single culture. While RANKL protein expression (0.54±0.03)of co-culture system was more than single culture RANKL(0.31±0.03), and had statistically differences, which was in agreement of the trend of gene expression change.

CONCLUSIONSCo-culture system of mouse MC3T3-E1 cells and RAW264.7 cell was viable in Transwell chamber, and the activity of osteoblasts is higher than osteoclasts in co-culture system.

3T3 Cells ; Animals ; Cell Differentiation ; Coculture Techniques ; Mice ; NF-kappa B ; metabolism ; Osteoblasts ; cytology ; Osteoclasts ; cytology ; Osteoprotegerin ; metabolism ; RANK Ligand ; metabolism ; RAW 264.7 Cells ; Receptor Activator of Nuclear Factor-kappa B ; metabolism ; Transforming Growth Factor beta1 ; metabolism