Effect of IL-17 on pulmonary artery smooth muscle cells and connective tissue disease-associated pulmonary arterial hypertension.

OBJECTIVE: To explore the role of interleukin (IL)-17 in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and to investigate its possible mechanism on pulmonary artery smooth muscle cells (PASMCs). METHODS: Enzyme-linked immunosorbent assay (ELISA) were used to compare levels of serum IL-17 in patients with CTD-PAH and healthy controls (HCs). After treatment for 3 months, the serum IL-17 levels were tested in CTD-PAH. ELISA and immunohistochemistry were used to compare levels of serum IL-17 and numbers of pulmonary artery IL-17+ cells, respectively, in a rat model of monocrotaline-induced PAH and untreated rats. Proliferation, migration, and inflammatory factors expression of PASMCs were assessed after stimulation with different concentrations of IL-17 for various time periods. Proteins in the mitogen-activated protein kinase (MAPK) pathway were examined by western blot. RESULTS: Levels of IL-17 were upregulated in patients with CTD-PAH compared to HCs. After 3 months of treatment, serum IL-17 levels were downregulated with pulmonary artery pressure amelioration. Moreover, serum IL-17 levels and numbers of IL-17+ cells infiltrating lung arterioles were increased in PAH model rats. IL-17 could dose- and time-dependently promote proliferation and migration of PASMCs as well as time-dependently induce IL-6 and intercellular cell adhesion molecule-1 (ICAM-1) expression. The levels of MKK6 increased after IL-17 treatment. Inhibition of MAPK decreased proliferation of PASMCs. CONCLUSION: Levels of IL-17 may increase in CTD-PAH, and IL-17 promotes proliferation, migration, and secretion of IL-6 and ICAM in PASMCs, respectively, which likely involves the p-38 MAPK pathway.

Adeno-Associated Virus Serotype 2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two-Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial.

PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human choroideremia (CHM)-encoding cDNA in CHM. DESIGN: Prospective, open-label, nonrandomized, dose-escalation, phase I/II clinical trial. PARTICIPANTS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS: Patients received uniocular subfoveal injections of low-dose (up to 5 × 1010 vector genome [vg] per eye, n = 5) or high-dose (up to 1 × 1011 vg per eye, n = 10) of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA (AAV2-hCHM). Patients were evaluated preoperatively and postoperatively for 2 years with ophthalmic examinations, multimodal retinal imaging, and psychophysical testing. MAIN OUTCOME MEASURES: Visual acuity, perimetry (10-2 protocol), spectral-domain OCT (SD-OCT), and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. Visual acuity returned to within 15 letters of baseline in all but 2 patients (1 developed acute foveal thinning, and 1 developed a macular hole); the rest showed no gross changes in foveal structure at 2 years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry or in the lateral extent of retinal pigment epithelium relative preservation by SD-OCT and SW-FAF. Microperimetry showed nonsignificant (< 3 standard deviations of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: Visual acuity was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13 of 15 patients. Acute foveal thinning with unchanged perifoveal function in 1 patient and macular hole in 1 patient suggest foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

A novel palmitic acid hydroxy stearic acid (5-PAHSA) plays a neuroprotective role by inhibiting phosphorylation of the m-TOR-ULK1 pathway and regulating autophagy.

AIMS: Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. METHODS: 5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. RESULTS: Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA. CONCLUSION: We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.

Cerebral infarction After Laparoscopic Right Lung Wedge or Segment Resection: A Report of Four Cases.

Several cases have been reported of patients who experienced cerebral infarction following thoracoscope left lobectomy. Compared with right lung surgery, the pulmonary veins stump after left lobe surgery were longer and thrombosis was more likely. Besides, cases of cerebral infarction after right lung surgery are rarely reported. Left lobectomy is therefore considered as the main risk factor for postoperative cerebral infarction. However, here we report four cases of cerebral infarction after thoracoscopic wedge or segment resection of right lobe, which cause less damage to the pulmonary vein compared with lobectomy. Magnetic resonance imaging and computed tomography scan reveal intracranial vascular obstruction and cerebral infarction. The case 1 had a poor prognosis because doctors lacked experience treating such complications. In the case 2, the sequela of cerebral infarction was obvious due to the large cerebral infarction area. Benefiting from timely treatment, the rest recovered better.

m6A RNA methylation regulators can contribute to malignant progression and impact the prognosis of bladder cancer.

N6-methyladenosine (m6A) is the most common form of messenger RNA (mRNA) modification. An increasing number of studies have proven that m6A RNA methylation regulators are overexpressed in many cancers and participate in the development of cancer through the dynamic regulation of m6A RNA methylation regulators. However, the prognostic role of m6A RNA methylation regulators in bladder cancer (BC) is poorly understood. In the present study, we downloaded the mRNA expression data from The Cancer Genome Atlas (TCGA) database and the corresponding clinical and prognostic information. The relationship between m6A RNA methylation regulators and clinicopathological variables of BC patients was assessed by the Kolmogorov-Smirnov test. The expression of the m6A RNA methylation regulators was differentially associated with different clinicopathological variables of BC patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was then applied to identify three m6A RNA methylation regulators. The risk signature was constructed as follows: 0.164FTO - (0.081YTHDC1+0.032WTAP). Based on the risk signature, the risk score of each patient was calculated, and the patients were divided into a high-risk group and a low-risk group. The overall survival (OS) rate of the high-risk group was significantly lower than that of the low-risk group. The risk signature was not only an independent prognostic marker for BC patients but also a predictor of clinicopathological variables. In conclusion, m6A RNA methylation regulators can participate in the malignant progression of BC, and a risk signature with three selected m6A RNA methylation regulators may be a promising prognostic biomarker to guide personalized treatment for BC patients.

Thymic epithelial tumor complicated by immunological abnormalities: results from a single-center retrospective study in China.

BACKGROUND: To describe the clinical manifestations, immunological features, treatments, and outcomes of patients with thymic epithelial tumor (TET) complicated by immunological abnormalities, and to improve knowledge on immunological abnormalities in this rare disease. METHODS: Patients with pathologically confirmed TET at Beijing Chaoyang Hospital between January 2013 and May 2018 were included in this study, and clinical data were analyzed retrospectively. Immunological abnormalities were classified into two groups as follows: Good syndrome (GS) and autoimmune disease (AD). RESULTS: Fifty-nine TET patients were enrolled; twenty-two patients (37.3%) had immune dysfunction. There were no gender, age, or histological type differences between groups with or without immunological abnormalities. Six patients had GS, of whom four patients were diagnosed after thymectomy. Recurrent respiratory infections, particularly opportunistic infections, were the most common manifestation. Three GS patients developed a second cancer (50%; P=0.011). Anti-infective therapy and immunoglobulin supplements effectively treated GS. Seventeen patients developed ADs, including myasthenia gravis (MG) (n=13), Hashimoto's thyroiditis (n=4), Sjogren's syndrome (n=1), rheumatoid arthritis (n=1), pemphigus (n=1), and Evans syndrome (n=1). One patient developed both MG and GS and 4 patients presented with two ADs. Three AD cases occurred after thymectomy. Pemphigus and 80% (8/10) of MG cases were resolved following thymectomy. CONCLUSIONS: There is a strong association between immunological abnormalities and TET, which may present at any time point during the disease, even after thymectomy. In addition to infection, GS patients are more likely to develop a second cancer. Thymectomy may produce favorable outcomes for MG in this study, while surgery does not improve immunodeficiency in GS patients.

Anesthetic management of off-pump simultaneous coronary artery bypass grafting and lobectomy: Case report and literature review.

RATIONALE: Survey data show approximately 10% patients with lung cancer may present concomitant coronary heart disease. Simultaneous surgery is a challenge for anesthetist. We review our experience in the anesthesia with 5 patients who required simultaneous off-pump coronary artery bypass grafting (OPCABG) and pulmonary resection for lung cancer. PATIENT CONCERNS: Between 2014 and 2016, 5 patients with ASA (American Society of Anesthesiologists) grade II or III, underwent combined OPCABG and lung resection in the first Affiliated Hospital, Zhejiang University School of Medicine. DIAGNOSES: All five patients were diagnosed with coronary heart disease and peripheral pulmonary carcinoma INTERVENTIONS:: Five patients received general anesthesia with double-lumen endobronchial tube for lung separation. The anesthetics were used, which caused slight hemodynamic fluctuations during induction of anesthesia; while during the maintenance of anesthesia, supplemented by Dexmedetomidine, the drug doses were titrated according to the depth of anesthesia. Guided by cardiac index (CI), stroke volume variation (SVV) and oxygen delivery (DO2), different strategies were taken at the different stage of surgery, during lung resection, SVV was kept about 13% to 15%, and less than 10% during OPCABG. OUTCOMES: Five patients were transferred to intensive care unit (ICU) with intubation after surgery, duration of ventilation was 10 to 18 hours, and length of ICU stay and hospital stay were 1.8 to 2.5 ds and 11 to 16 ds, respectively. All of patients were discharged with not any perioperative complication. LESSONS: In summary, anesthetists should focus on the maintenance of the balance between oxygen supply and demanding, which was achieved by close monitoring, titration of anesthetics and goal-directed fluid therapy during surgical procedures.

[Human umbilical cord blood mononuclear cell transplantation promotes long-term neurobehavioral functional development of newborn SD rats with hypoxic ischemic brain injury].

OBJECTIVE: To explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI). METHOD: A modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery. RESULT: Newborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group. CONCLUSION: Human UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.

Diagnosis and treatment of pulmonary mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Primary non-Hodgkin's lymphoma in lung is very rare, and the most common among them is mucosa-associated lymphoid tissue lymphoma (MALToma), whose clinical features and laboratory characteristics are poorly defined, making diagnosis difficult. The purpose of this study was to study the diagnosis and treatment of pulmonary MALToma. METHODS: The clinical data of 12 patients treated for MALToma between August 1992 and December 2005 were analyzed. RESULTS: No specific symptoms or signs, or results of bronchoscopy, ultrasonagraphy or bone marrow examination could be found in the 12 patients. Only radiography was useful in diagnosis, though the final diagnosis of all the patients was based on histology and immunohistochemistry. Two patients also had gastric MALToma. Operations were performed on 6 patients, including 5 radical operations and 1 partial resection: 4 patients also received adjuvant chemotherapy. One patient experienced recurrence 152 months after the operation, while the other 5 patients have survived disease-free. Four patients were treated with chemotherapy alone, two of whom experienced complete remission and the others partial remission. The final 2 patients received no treatment and had survived for 7 and 27 months respectively. All the patients were still alive at the most recent follow-up, 7 to 160 months (mean 71.3 months). CONCLUSIONS: Except radiography, no specific clinical manifestations could be identified for pulmonary MALToma. The final diagnosis should be based on histology and immunohistochemistry. Several treatment methods can be used to achieve good outcomes.

Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.

Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95. In mice lacking Mpp4, PMCAs were lost from rod photoreceptor presynaptic membranes. Synaptic ribbons were enlarged, a phenomenon known to correlate with higher Ca(2+). SERCA2 (sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase, type 2), which pumps cytosolic Ca(2+) into intracellular Ca(2+) stores and localizes next to the ribbons, was increased. The distribution of IP(3)RII (InsP(3) receptor, type 2), which releases Ca(2+) from the stores, was shifted away from the synaptic terminals. Synaptic transmission to second-order neurons was maintained but was reduced in amplitude. These data suggest that loss of Mpp4 disrupts a Ca(2+) extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca(2+) homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca(2+) homeostasis and synaptic transmission in rod photoreceptors.

A new rubidium beryllium borate, RbBe4(BO3)3.

Single crystals of a new rubidium beryllium borate, RbBe4(BO3)3, have been obtained by spontaneous nucleation from a high-temperature melt. This new orthorhombic (Pnma) structure type contains [Be2BO4]- rings, made of two BeO4 tetrahedra and one BO3 triangle, which constitute the basic structural units. The m plane runs through the B and one of the O atoms and intersects the ring. These rings form chains in the a direction, which are connected in the b and c directions to form zeolite-type cages in which the Rb+ cations are located, at sites of m symmetry.

[Protective effects of ginaton against ischemia-reperfusion injury on the autograft after lung autotransplantation: experiment with rabbits].

OBJECTIVE: To investigate the effects of ginaton against ischemia-reperfusion injury on the autograft after lung autotransplantation. METHODS: Models of lung autotransplantation were established in 18 New Zealand rabbits were established. The 18 rabbits were randomly divided into 3 equal groups: group of simple ischemia-reperfusion (group I/R), undergoing ischemia by blocking the left pulmonary artery for 2 h and then re-perfusion for 90 min; group with perfusion of low potassium dextran solution (group LPD), undergoing perfusion of LSD solution before ischemia; and group with treatment of ginaton (group LPD + E), undergoing intravenous injection of ginaton 15 min before ischemia. Arterial blood samples were collected before ischemia, and 15, 60, and 90 min after re-perfusion to examine the alveolar oxygen pressure (PaO2). Serum tumor necrosis factor-alpha (TNF-alpha) was monitored before ischemia, and 30, 60, and 90 min after re-perfusion. Then the left lungs were taken out to undergo detection of dry/wet ratio (D/W), pathological examination, and contents of myeloperoxidase (MPO) and the malondialdehyde (MDA) in the lung tissues. RESULTS: (1) The PaO2 decreased significantly after reperfusion in all groups. And the PaO2 values at different time points of Group LPD + E were all significantly higher than those of Group I/R (all P < 0.01), however, there were no significant differences between Group LPD and Group LPD + E. (2) The TNF-alpha level after reperfusion increased in Group I/R and Group LPD, while in Group LPD + E it increased only 60 min and 90 min after the reperfusion. The TNF-alpha levels after reperfusion at all time points of Group LPD + E were all significantly lower than those of the other 2 groups (all P < 0.05). (3) The MPO and MDA levels at all time points after re-perfusion of Group LPD + E were all significantly lower than those of the other 2 groups (all P < 0.01). (4) The value of D/W ratio of Group LPD + E was significantly higher than those of the other 2 groups (both P < 0.01). (5) Pathological examination showed that the lung tissue lesion of Group I/R was severe. Interstitial inflammatory cell infiltration, intra-alveolar inflammatory cell aggregation, exudation and even hemorrhage could be observed. The pathological lesion of Group LPD + E was mild, no significant inflammatory cell infiltration or exudation was observed. CONCLUSION: Ginaton provides a protective effect against ischemia-reperfusion injury on the autograft after lung autotransplantation. The mechanism may be related with antioxidation, inhibition of neutrophil aggregation, and TNF-releasing.

Enhanced shutoff of phototransduction in transgenic mice expressing palmitoylation-deficient rhodopsin.

Palmitoylation is a reversible, post-translational modification observed in a number of G-protein-coupled receptors. To gain a better understanding of its role in visual transduction, we produced transgenic knock-in mice that expressed a palmitoylation-deficient rhodopsin (Palm(-/-)). The mutant rhodopsin was expressed at wild-type levels and showed normal cellular localization to rod outer segments, indicating that neither rhodopsin stability nor its intracellular trafficking were compromised. But Palm(-/-) rods had briefer flash responses and reduced sensitivity to flashes and to steps of light. Upon exposure to light, rhodopsin became phosphorylated at a faster rate in mutant than in wild-type retinas. Since quench of rhodopsin begins with its phosphorylation, these results suggest that palmitoylation may modulate rod photoreceptor sensitivity by permitting rhodopsin to remain active for a longer period.

Plasma levels of tumor necrotic factor-alpha and interleukin-6, -8 during orthotopic liver transplantation and their relations to postoperative pulmonary complications.

BACKGROUND: Pulmonary complications after orthotopic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ischemia and reperfusion are induced by pro-inflammatory cytokines. The high level of inflammatory cytokines might additionally influence pulmonary capillary fluid filtration. The objectives of this study were to measure the concentrations of tumor necrotic factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) during OLT and to investigate the relationship between these cytokines and postoperative pulmonary complications. METHODS: Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consisting of 8 patients with postoperative pulmonary complications, and group B consisting of 14 patients without postoperative pulmonary complications. Enzyme-linked immunoassay (ELISA) was used to determine serum TNF-alpha, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0), clamping and cross-clamping of the inferior cava and portal vein (T1, T2), 90 minutes and 3 hours after reperfusion (T3, T4) and 24 hours after operation (T5). RESULTS: The level of PaO2/FiO2 in group A was lower than that in group B (P<0.05). The concentrations of TNF-alpha, IL-6 and IL-8 in the two groups increased rapidly at T2, peaked at T3, decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-alpha, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4 (P<0.05). CONCLUSION: After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-alpha, IL-6 and IL-8 increased may be related to pulmonary injury after hepatic ischemic reperfusion.

Histological study of vas deferens following intravasal laser irradiation.

AIM: To study the histologic changes of the vas deferens following Nd: YAG laser irradiation. METHODS: Intravasal laser irradiation was given to (i) 52 segments of rabbit (laser dosage: 2 seconds at 40 W approximately 50 W) and 16 segments of human (3 seconds at 45 W approximately 55 W) vas deferens in vitro, (ii) 25 rabbit vasa (2 seconds approximately 2.5 seconds at 40 W approximately 45 W) in vivo and (iii) 2 human vasa (3 seconds at 55 W) in vivo. Segments of vasa were removed from the in vivo irradiated vasa deferentia 15 days approximately 180 days (rabbit) or 15 days (man) after the exposure. All vas segments were embedded in methacrylate resin. Serial sections (thickness 25 microm approximately 30 microm) were obtained and observed under a light microscope. RESULTS: (i) Laser-induced damage reached the muscularis layer in 27% and 94% of the rabbit and human vas segments in vitro, respectively. (ii) Fourteen of the 25 in vivo rabbit vasa were completely occluded by fibrous tissue and the longer the time interval after treatment, the more likely was the vas occluded. Those unoccluded vasa had either a normal histology or a mucosal damage. (iii) One in vivo human vas was almost completely occluded by the fibrous tissue but the other had a relatively large lumen packed with sperm granulomatous tissue and partial destruction of the smooth muscle layer. CONCLUSION: Laser irradiation can induce long-term vas occlusion; for rapid occlusion, laser doses just completely destroying the mucosal layer will be advisable.