Abstract BACKGROUND Polymorphic light eruption (PLE) is the commonest photosensitive disorder, characterized by pruritus, erythematous papules, plaques or blister lesions that occur within hours of exposure to ultraviolet radiation. However, the etiology and pathogenesis of PLE are still uncertain. The current study aims to identify the relationship between HLA and PLE, and analyze the discrepancies between Han and Tibetan males on the association of HLA with PLE. METHODS Polymerase chain reaction sequence-based typing (PCR-SBT) method was used to determine the distribution of HLA-DPA1 and -DQA1 alleles among 62 male patients with PLE (45 Hans and 17 Tibetans) and 66 healthy males (52 Hans and 14 Tibetans) in Qinghai region. RESULTS 4 HLA-DPA1 and 11 HLA-DQA1 genotypes were detected in all samples. The allele frequency of HLA-DPA1*01:03 in healthy Han men was significantly higher than that in healthy Tibetan men (Pc=0.008), while the HLA-DPA1*02:01 was significantly lower than that in Tibetan men (Pc=0.04). The frequency of HLA-DQA1*03:03 allele (OR=2.7891, Pc=0.011) was significantly increased in Han men with PLE compared with Han controls , and HLA-DPA1*01:03 allele (OR=7.217, Pc=0.0076) was significantly increased in Tibetan men with PLE than Tibetan controls, whereas HLA-DPA1*02:01 (OR=0.154, Pc=0.008) allele frequency was highly decreased in Tibetan men with PLE. CONCLUSIONS There were racial differences between Han and Tibetan men in HLA gene polymorphism. The HLA-DQA1*03:03 allele could be a susceptible allele of PLE in Han men, and the HLA-DPA1*01:03 allele could be a susceptible allele of PLE in Tibetan men, while the HLA-DPA1*02:01 allele could be a protective allele in Tibetan men.

Background: The aim of this work is to analyze the effect of a positive cumulative fluid balance and relative clinical indicators on the prognosis of patients with sepsis in the Xining area, China. Methods: The clinical data of 480 sepsis patients (313 males and 167 females, aged 52–77 (65) years) admitted between January 2017 and December 2019 were retrospectively analyzed. The APACHE II score, SOFA score, SIRS score and clinical laboratory test indicators of the patients were collected. Receiver operating characteristic (ROC) curves were used to analyze the sensitivity and specificity of each indicator in predicting the poor prognosis of patients with sepsis, and the maximum Youden index was used to determine threshold values. Cox regression analysis was performed to assess patient prognosis using data from patients with different fluid balances. Results: The following clinical indicators were significantly different between the 2 groups (P<0.05): APACHE II score, SOFA score, SIRS score, PCT, IL-6, BNP, CRP, PLT, BUN, CREA, Lac and total fluid balance from days 1 to 5. The area under the ROC curve (AUC) for total fluid balance from days 1 to 5 was 0.558, the cut-off value was 2120.5 mL, the sensitivity was 54.0%, and the specificity was 58.1%. The survival rates were different between the 2 groups (60.9% vs 48.9%, P<0.05). Total fluid balance was significantly higher in patients with septic shock and with Lac>2.0 mmol/L (P<0.05). Cox regression analysis indicated that APACHE II score, SOFA score, PLT score, Lac, and total fluid balance from days 1 to 5 were independent risk factors for poor prognosis. Conclusion: A positive fluid balance from days 1 to 5 after ICU admission was associated with poor patient outcomes and was an independent risk factor for poor patient prognosis.

AimsMemantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia.Main methodswe made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine.Key findingsOur results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved.SignificancePresent study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.

Background: This study aimed to evaluate changes in microcirculation, physiological characteristics, and the pathomechanism of and potential treatment alternatives for severe septic shock among healthy individuals residing at different altitudes.Methods: Seventy individuals, 35 from Xining and 35 from Nanjing, were recruited, and their body temperature, pulse, respiration, mean arterial pressure, peripheral blood oxygen saturation, and blood cell parameters were determined. Microcirculation indices of sublingual microcirculation were monitored using the sidestream dark field method.Results: Erythrocyte counts and hemoglobin levels were significantly higher among individuals from Xining than among those from Nanjing (P < 0.05); however, platelet counts were significantly lower among those from Xining (P < 0.05). Microcirculation indices of total vessel density, perfused vessel density, and the proportion of perfused vessels were significantly higher among individuals from Xining than among those from Nanjing; however, the microvascular flow index was lower among those from Xining. Microvascular density was significantly higher among individuals from Xining than among those from Nanjing.Conclusion: Microvascular densit may be a physiological adaptation among populations at moderate-to-high altitudes.

To evaluate the effect of dance on vascular-related factors and cerebral hemodynamics in elderly individuals in Qinghai-Tibetan plateau regions (mean altitude ≥2,300 m). Thirty elderly individuals, who practiced traditional Tibetan Guozhuang dance or did not, were enrolled, respectively. Serum PGC-1α, HCY, FSTL-1, VEGF and HIF-1α were measured by ELISA assays. Carotid artery stenosis and plaque, IMT, extracranial internal carotid artery stenosis and cerebral arteriosclerosis were evaluated using CUS and TCD. Body weight, BMI, heart rate, systolic pressure, and diastolic pressure, serum BGS, TC, LDL, HIF-1α, VEGF, and HCY in the dance group were significantly lower than the no-dance group. FSTL-1 levels, SO2 and SO2/heart rate ratio in the dance group were significantly higher than the no-dance group. Incidence of extracranial internal carotid artery stenosis, carotid stenosis and plaque in the dance group was significantly lower than the no-dance group. IMT was a significant positive correlation between PGC-1α and HCY in the no-dance group. Elderly individuals who regularly practiced Tibetan dance had improved blood vessel functionality and cerebral hemodynamic at high altitudes.

Oval cells, a kind of hepatic progenitor cell quiescent at normal condition, activates to proliferate and differentiate into hepatocytes under severe and long-term liver injury, which usually raises severe inflammation. However, how oval cell survives in the inflammatory milieu interne is still unclear. Tumor necrosis factor α (TNFα), mimicking inflammatory hepatic milieu interne, was used to treat oval cell line, WB-F344, to test the protective function of matrilin-2. In this study, our data suggested that matrilin-2 prevented TNFα-induced apoptosis in WB-F344 cells via inhibiting ASK1/MKK7/JNK pathway. In conclusion, we determined that matrilin-2 plays the key role in maintaining the survival of oval cell and guarantees its proliferation under various injury factors.

Background The aim of this work is to detect and compare the peripheral blood miRNA expression profiles in patients with severe traumatic brain injury (sTBI) 2, 12, 24, 48, and 72 h after injury at high altitude and to predict the target genes of differential expressed miRNAs. Methods Twenty sTBI patients from high-altitude areas were randomly selected according to the inclusion and exclusion criteria and were divided into five groups: the 2-h group, 12-h group, 24-h group, 48-h group, and 72-h group. Peripheral blood miRNA expression profiles were detected using real-time quantitative PCR (qRT-PCR). Results The expression levels of miR-18a, miR-203, miR-146a, miR-149, miR-23b, and miR-let-7b in peripheral blood showed significant differences between the 2-h group and the 12-h group. The expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f in peripheral blood were up-regulated in the 24-h group. In the 48-h group, the expression levels of miR-181d, miR-29a, and miR-18b were upregulated. In the 72-h group, the expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f changed. The main target genes of the differentiation expressed miRNAs were genes that regulate inflammatory responses, apoptosis, and DNA damage/repair. Conclusions miRNAs may be involved in the pathogenesis of sTBI by dynamically regulating the target genes that regulate inflammatory responses, apoptosis, and DNA damage/repair pathways.

To understand the improvement of recruitment maneuvers and extravascular lung water in oxygenation of high altitude acute respiratory distress syndrome, 30 HARDS patients were enrolled in the study from May 2012 to October 2013 from Qinghai Provincial People’s Hospital. All the patients received recruitment maneuvers and Pulse Contour Cardiac Output, hemodynamics monitoring including intrathoracic Blood Volume Index; Global End-diastolic Volume Index; Global ejection fraction; Pulmonary Vascular Permeability Index; Extravascular Lung Water Index; Pulse indicates cardiac Index; Stroke Volume Variation; Pulse pressure variation; Maximum pressure to increase speed; Systemic Venous Resistance Index, oxygenation and hemodynamics were determined before and after 72 hours of recruitment maneuvers. The results showed that after treatment with recruitment maneuvers and capacity limitation, PaO2/FiO2 was increased significantly compared with those before treatment [PaO2/FiO2 (mmHg): 124.70±43.37 vs 186.87±41.20, t=9.43, P<0.001], ITBVI, GEDVI, PVPI, EVLWI, SVV were reduced significantly compared with those before treatment[ITBVI (ml/m2): 1031.00±275.88 vs 907.13±242.56, t=1.26, P=0.041; GEDVI (ml/m2): 822.40±143.30 vs 722.83±169.65, t=1.75, P=0.016; PVPI (ml/kg): 2.71±1.21 vs 1.98±0.65, t=2.86, P=0.001; EVLWI (ml/kg): 12.30±4.19 vs 8.12±2.94, t=8.27, P<0.001; SVV (%):17.30±5.65 vs 10.33±3.47, t=9.17, P<0.001]. Our results indicated that recruitment maneuvers and capacity limitation have been improved oxygenation in HARDS, extravascular lung water reduced, and lung capillary permeability also improved.

Pulmonary hypertension (PH) is defined as the mean pulmonary artery pressure (mPAP) ≥25 mmHg under the sea level in resting state. ROCK1 and ROCK2 can be combined to cause the damage of vascular endothelial function. To explore the differences of ROCK1 and ROCK2 in subjects with pulmonary hypertension or normal pulmonary artery pressure in plateau area, and to further understand the mechanism of Rho/rho-kinase pathway activation for promoting pulmonary hypertension, we collected 64 patients with pulmonary hypertension and 87 normal pulmonary artery healthy controls. All subjects were hospitalized in Cardiology or Respiration Department of Qinghai Provincial Peoples’ Hospital from December 2016 to June 2017. The pulmonary artery systolic pressure was measured by Doppler ultrasound, and serum ROCK1 and ROCK2 levels were tested by enzyme linked immunosorbent assay (ELISA). We found that the serum ROCK2 concentration in the pulmonary hypertension group was significantly higher than that in the control group, but serum ROCK1 level had no significant difference. ROCK2 plays a leading role in pulmonary hypertension in the plateau region, so selective ROCK2 inhibitors will be more effective in improving pulmonary hypertension.

BACKGROUND:Many studies have demonstrated that a higher radiotherapy dose is associated with improved outcomes in non-small-cell lung cancer (NSCLC). We performed a dosimetric planning study to assess the dosimetric feasibility of intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) in locally advanced NSCLC.METHODS:We enrolled twenty patients. Five different dose plans were generated for each patient. All plans were prescribed a dose of 60 Gy to the planning tumor volume (PTV). In the three SIB groups, the prescribed dose was 69 Gy, 75 Gy, and 81 Gy in 30 fractions to the internal gross tumor volume (iGTV).RESULTS:The SIB-IMRT plans were associated with a significant increase in the iGTV dose (P < 0.05), without increased normal tissue exposure or prolonged overall treatment time. Significant differences were not observed in the dose to the normal lung in terms of the V5 and V20 among the four IMRT plans. The maximum dose (Dmax) in the esophagus moderately increased along with the prescribed dose (P < 0.05).CONCLUSIONS:Our results indicated that escalating the dose by SIB-IMRT is dosimetrically feasible; however, systematic evaluations via clinical trials are still warranted. We have designed a further clinical study (which is registered with ClinicalTrials.gov, number NCT02841228).

Synchronous gastric tumors that consist of both gastrointestinal stromal tumor (GIST) and adenocarcinoma are rare. We studied the clinicopathological and molecular characteristics of six cases containing both gastric adenocarcinoma and GIST. By means of immunohistochemical analysis, all GIST cells expressed CD117, CD34 and Dog1 in all six synchronous gastric adenocarcinomas with GIST, and in GIST alone. Sequencing analysis demonstrated that exon 11 c-kit mutations were present in two of six synchronous tumors and four of five GISTs. One of the two exon 11 c-kit mutations in synchronous adenocarcinomas with GISTs was an uncommon mutation of CTT > CCA at amino acid 576, and the other was a GTT deletion at amino acid 560. The mutation was a homozygous A > G mutation in exon 12 (amino acid 567) of PDGFR-α . We concluded that the exon 11 mutations were the most important in both cases of synchronous gastric adenocarcinoma with GIST and GIST alone. The mutation rate was higher in GIST alone than in synchronous adenocarcinoma with GIST.

This study aimed at evaluating the effect of high glucose on the expression of extracellular matrix (ECM) protein Matrilin-2 and the mechanism underlying this effect by using a mouse mesangial cell line. Mouse mesangial cells (MMCs) were cultured in media containing normal (5 mM d-glucose) or high concentrations of glucose (30 mM d-glucose). The expression of Matrilin-2 was assessed by either RT-PCR or western blot. Additionally, transforming growth factor beta 1 (TGF-β1) inhibitors and TGF-β1 were used to determine whether glucose-regulated Matrilin-2 expression was mediated by the TGF-β1/Smad3 signaling pathway. Our data demonstrated that Matrilin-2 expression was markedly induced by high glucose and TGF-β1. High glucose-induced Matrilin-2 expression was inhibited by TGF-β1/Smad3 inhibitors, indicating that Matrilin-2 was markedly induced by high glucose and this induction was mediated by the TGF-β1/Smad3 pathway. Taken together, our results showed that high-glucose-induced Matrilin-2 expression that was mediated by the TGF-β1/Smad3 signaling pathway might play a role in Diabetic nephropathy (DN) pathogenesis and our finding provided a potential diagnostic and/or therapeutic target for DN.

Matrilins are cartilage abandon molecules which are a 4 member of family of non-collagen filamentous network proteins. In cartilage, extracellular matrix (ECM) occupied 95% space which determines the histoarchitecture specific to organ plays dominant role in chondrocyte functions. Matrilins can form collagen dependent and collagen independent filamentous network in extracellular matrix which involved cell-matrix and matrix-matrix communication, and provide cells with crucial information on migration, adhesion, differentiation, matrix homeostasis, and endoplasmic reticulum stress, etc. Although the matrilins gene-deficient mice show no gross abnormalities during embryonic or adult development with normal lifespan, there were several osteochondrodysplasias and degenerative joint diseases are related the point mutations of matrilins, especially matrilin-3. In this article, we reviewed most recently work on the family of matrilin and cartilage diseases.

The aim of the present study was to examine cerebral vasoconstriction in patients with chronic high altitude disease [cerebrovascular reactivity (CVR)], and to evaluate differences in alterations of brain vascular contractile reactivity of chronic mountain sickness (CMS) patients and healthy controls. Alterations of endothelin (ET) and its receptor, as well as endothelial nitric oxide synthase (eNOS) levels in the plasma were examined to determine the cerebral reservation capacities in CMS patients. Transcranial Doppler ultrasound and carbon dioxide analysis methods were used to detect the CVR variances. At the same time, enzyme-linked immunosorbent assay approaches were utilized to detect the ET and ET B receptor and the eNOS levels in serum of the CMS patients and healthy controls. CVR and CVRI levels in CMS patients were lower than those of the healthy control subjects and the difference was statistically significant (P<0.05). By contrast, eNOS and ET-1 levels were not statistically significant for CMS and healthy controls (P>0.05). However, the ET receptor concentration level was higher in CMS than the healthy controls. Thus, ET-1 may not be a direct etiological variation but may play compensatory roles in CMS patients. The results of the study may provide scientific clues for the prevention and treatment of CMS with higher blood coagulation states of cerebral infarction in patients with chronic high altitude disease.

Radiation pulmonary injury is related to the accumulation of extracellular matrix proteins in the alveolar interstitial space. Matrilin-2 as a component of extracellular filamentous networks, present higher level in the lung tissue from irradiated mice and irradiated pulmonary epithelial cell line, HPAEpiC cells. Knockdown of endogenous matrilin-2 prevents the apoptosis of HPAEpiC cell induced by the irradiation injury. Consistently, over-expression of matrilin-2 reduced the proliferation and induced apoptosis of HPAEpiC cells. Matrilin-2 promotes the expression of p21 via increasing the transcriptional activity of p53, by which induces the G1 phase arresting in HPAEpiC cells. In summary, matrilin-2, increased by irradiation, reduced the proliferation and induces apoptosis of pulmonary epithelial cells via p53/p21 pathway.

Mutations in matrilin-3 are associated with common skeletal diseases, such as hand osteoarthritis (HOA), as well as rare chondrodysplasias, such as multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). In the present study, we constructed the mutations R116W [at the von Willebrand factor, type A (vWFA) domain], T298M [at the first epidermal growth factor (EGF) domain] and C299S (at the first EGF domain), according to the mouse sequence, which are associated with human MED, HOA and SEMD, respectively, by overlap extension PCR and inserted them into an expression vector (pcDNA3.1/v5-His). We transfected these contructs into the COS-1 or MCT cells, and the results revealed that the HOA-related matrilin-3 mutation (T298M) leads to a high expression level of growth arrest DNA damage-inducible gene 153 (GADD153, also known as CHOP; an endoplasmic reticulum stress marker), as shown by western blot analysis and does not significantly affect protein secretion, as shown by immunofluorescence staining; however, osteochondroplasia, i.e., MED-related (R116W) and SEMD-related (C299S) mutations lead to both high levels of GADD153 expression and protein trafficking into the cytoplasm and form multiple vacuoles in cells, which in turn leads to insufficient protein secretion.

Objective: The purpose of this study is to observe neuroprotective effects of hypoxia preconditioning（HP）in primary culture newborn SD rat hippocampus neurons and 3-n-butylphalide（NBP) against oxygen glucose deprivation/ reoxygenation (OGD/R) injury, and investigate the possible mechanisms against ischemic reperfusion injury. Methods: After 7-days culture, the hippocampal neurons were initially divided into three groups: normal control group, simple hypoxia group and HP group. Later, we established OGD30min/R8h model. So, the hippocampal neurons were eventually divided into five groups: normal control group, OGD/R model group, OGD/R+3-n-butylphalide (NBP) groups（0.1μmol/L, 1μmol/L and 10μmol/L). Bcl-2 and neuroglobin (NGB) expression of cells in each group were analyzed by immunocytochemistry. The mRNA expression of Bcl-2 and NGB in each group was analyzed by RT-PCR. Results: The results showed that the protein and mRNA levels of Bcl-2 and NGB were significantly increased in the HP group compared to the hypoxia group (P < 0.01). In the OGD/R model, NBP groups also showed a significantly increased expression of proteins Bcl-2 and NGB compared to the OGD/R (P < 0.05); Different concentration of NBP drugs showed a significantly increased expression of proteins Bcl-2 and NGB with the increase in NBP concentration (P < 0.01). Conclusion: The neuroprotection of HP and NBP may share the same possible mechanisms and have endogenous neuroprotection by up regulating the mRNA and protein expression of Bcl-2 and NGB. Keywords: 3-N-butylphalide, Bcl-2, hippocampal neurons, HP, neuroglobin, OGD/R.

The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42-46°C and 50-55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50-55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.