Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.
Mice ; Animals ; Hypoxia ; Oxidative Stress ; Autophagy ; Cognition ; Sirolimus/therapeutic use*

Drug-Eluting Stents ; Humans ; Polymers ; chemistry ; therapeutic use ; Sirolimus ; therapeutic use

Fibrosis ; drug therapy ; metabolism ; Humans ; Immunosuppressive Agents ; therapeutic use ; Models, Biological ; Sirolimus ; therapeutic use

Humans ; Sirolimus ; Cytarabine/therapeutic use* ; Erdheim-Chester Disease/drug therapy* ; Interferon-alpha/therapeutic use* ; Treatment Failure

Adult ; Coronary Restenosis ; surgery ; Drug-Eluting Stents ; Humans ; Male ; Sirolimus ; therapeutic use

BACKGROUNDDrug-eluting stents represent a major advance in interventional cardiology. However, the current drug-eluting stents have significant limitations. One of the major problems is very late stent thrombosis, which is likely caused by inflammation and a hypersensitivity reaction related to a polymer on the stent. A polymer-free sirolimus-eluting stent with a unique nano-porous surface has been developed. This study aimed to evaluate this novel polymer-free sirolimus-eluting stent for its efficacy and safety in a pig model.

METHODSStents were directly coated with sirolimus (a drug concentration of 2.2 µg/mm(2) on the stent surface). The polymer-free sirolimus-eluting stents (PFSES) were compared to standard polymer-coated sirolimus-eluting stents (PCSES) and bare-metal stents (BMS) in 18 pigs.

RESULTSAt one month the degree of neointimal hyperplasia was similar between the two sirolimus-eluting stent groups and was significantly less compared to BMS ((1.93 ± 0.51) mm(2), (1.57 ± 0.69) mm(2) vs. (4.45 ± 1.05) mm(2), P < 0.05) At three months, PFSES maintained the low level of neointima ((2.41 ± 0.99) mm(2) vs. (4.32 ± 1.16) mm(2), P < 0.05), whereas PCSES had developed significant neointimal proliferation similar to BMS. The inflammation level was significantly higher in PCSES when compared with BMS three months post-implantation (2.50 ± 0.55 vs. 0.83 ± 0.75, P < 0.05) whereas PFSES showed a low level of inflammation comparable to PCSES (1.33 ± 0.52 vs. 2.50 ± 0.55, P < 0.05).

CONCLUSIONThe PFSES is effective and safe, and appears to be superior to standard PCSEs.

Animals ; Drug-Eluting Stents ; adverse effects ; Neointima ; prevention & control ; Polymers ; chemistry ; Sirolimus ; therapeutic use ; Swine

Immune-mediated hemocytopenia is a common cytopenic diseases without bone marrow hematopoietic abnormalities, the patient's quality of life is significantly reduced when first-line treatments are ineffective. Rapamycin, possesses a clear mechanism of targeting mTOR protein, can upregulate regulatory T cells and induces apoptosis of specific cells, by regulating the lymphocyte subsets, so as to treat various types of immune-mediated hemocytopenia with a certain therapeutic effect. In this reviews, the action mechanism and clinical application of rapamycin in immune thrombocytopenia（ITP）, autoimmune hemolytic anemia（AIHA）, acquired aplastic anemia and autoimmune lymphoproliferative syndrome（ALPS） etc. are summarized.
Anemia, Aplastic ; Humans ; Quality of Life ; Sirolimus ; therapeutic use ; T-Lymphocytes, Regulatory ; TOR Serine-Threonine Kinases

OBJECTIVETo evaluate safety and efficacy of conversion of calcineurin inhibitors (CNI) to sirolimus (SRL) therapy for treatment of new-onset diabetes after kidney transplantation (NODAT).

METHODSOf 321 kidney transplant recipients, 34 patients who developed NODAT (10.59%) were divided into 3 groups to receive continued CNI therapy at a reduced dose (group A, 14 cases), sirolimus conversion therapy (group B, 12 cases), or oral hypoglycemic drugs (group C, 12 cases). All the patients had dietary and exercise therapies, and insulin injections were given in patients with postprandial (2 h) blood glucose over 14.0 mmol/L. The patients were followed up regularly for 5 years.

RESULTSThe mean blood glucose level was 13.02∓1.74 mol/L upon the diagnosis of NODAT in the 34 patients without significant differences between the 3 groups. At 6 months of therapy, fasting plasma glucose levels in the 3 groups decreased to 8.05 ∓2.45, 7.45∓2.44, and 9.30∓3.89 mmol/L, repsectively; at 12 months, blood glucose became normal in both groups A and B, but the patients in group A needed a greater daily insulin dose (P<0.05). In group B, the mean serum creatinine level was 165.1∓61.82 mmol/L at the conversion and lowered to 150∓53.05 mmol/L at 5 years (P<0.05), which were similar to those in group A at the two time points (152∓43.05 and 145.88∓53.05 mmol/L, respectively; P>0.05). In group C, creatinine level further increased after medication with oral hypoglycemic drugs. At 5 years, the patient and graft survival rates were 100% and 75% in group A, respectively, similar to those in group B (83.4% and 68%, respectively; P>0.05); group C showed lower patient and graft survival rates than groups B and C.

CONCLUSIONConversion from CNI to SLR therapy can significantly the metabolism of patients with NODAT without increasing the risk of acute graft rejection.

Blood Glucose ; Calcineurin Inhibitors ; therapeutic use ; Diabetes Mellitus ; Graft Rejection ; prevention & control ; Humans ; Hypoglycemic Agents ; Immunosuppressive Agents ; therapeutic use ; Kidney Transplantation ; Sirolimus ; therapeutic use

BACKGROUNDSirolimus-eluting stents (SES) are reported to be associated with reduced late lumen loss (LLL), resulting in less frequent restenosis when compared to bare-metal stent. The current study aimed to assess the difference in LLL between SES with biodegradable and with permanent polymer.

METHODSFrom March 2010 to June 2011, 300 consecutive patients having only biodegradable polymers or permanent polymer SES for all diseased vessels were included. Serial quantitative coronary analysis was performed on both the "in-stent" and "segment" area, including the stented segment, as well as both five mm margins proximal and distal to the stent. The primary endpoint was the LLL defined as the minimal lumen diameter (MLD) post-stenting minus the MLD at nine-month after the indexed procedure.

RESULTSLLL was comparable between the two stents. Importantly, LLL for the distal segment (median 0.05 mm, interquartile 0 to 0.09 mm) was less severe compared with in-stent (median 0.13 mm, interquartile 0.08 to 0.18 mm) and proximal segment LLL (median 0.12 mm, interquartile 0.06 to 0.14 mm, all P < 0.001). In general, the LLL was associated with the post-procedure MLD (b = 0.28, P = 0.002), hyperlipidemia (b = 0.14, P = 0.021), and calcified lesions (b = 0.58, P = 0.001). The R(2) and Radj of the multiple regression model were 0.651 and 0.625, respectively.

CONCLUSIONSSES with either biodegradable or permanent polymer had lower value of LLL. The small amount of LLL at the distal segment possibly contributed to the less distal edge stenosis.

Aged ; Aspirin ; therapeutic use ; Coronary Restenosis ; prevention & control ; Drug-Eluting Stents ; Female ; Humans ; Male ; Middle Aged ; Polymers ; chemistry ; Regression Analysis ; Sirolimus ; therapeutic use ; Ticlopidine ; analogs & derivatives ; therapeutic use

Aspirin ; therapeutic use ; Coronary Disease ; therapy ; Coronary Thrombosis ; chemically induced ; epidemiology ; mortality ; Drug-Eluting Stents ; adverse effects ; Humans ; Paclitaxel ; therapeutic use ; Platelet Aggregation Inhibitors ; therapeutic use ; Polymers ; chemistry ; Sirolimus ; therapeutic use ; Ticlopidine ; analogs & derivatives ; therapeutic use