2016年 · 第96卷第38期

In early 2015, US President Barack Obama officially announced the launch of the "Precision Medicine Program" in his State of the Union address. For a time, precision medicine quickly became a global health hot word and a new concept to promote the development of medicine. The so-called precision medicine is a new medical model characterized by individualized medicine and based on genome sequencing technology and bioinformation and big data analysis. The aim is to analyze, identify, verify and apply biomarkers to large sample populations and specific disease types by using omics technology and cutting-edge medical technology, so as to accurately find disease causes and therapeutic targets, and accurately classify diseases by subtypes, and finally realize personalized precision treatment for diseases and specific patients^[1,2]。

With the rapid growth of China's economy and the substantial improvement of national living standards, the public demand for high-quality medical services is also increasingly strong. Due to the two-way pressure of China's population and finance, the government's investment in the medical field is very limited, which leads to the serious shortage of the number of medical institutions and the supply of medical services, which objectively causes the situation of "difficult to see a doctor". In this round of public hospital reform, the drug addition that hospitals depend on for survival will be completely banned, the phenomenon of supporting doctors with medicines will no longer exist, and the development funds of hospitals will mainly come from government compensation. However, as China's economy enters a new normal, the downward pressure on the economy increases, and the financial operation becomes increasingly tense. Full compensation for public hospitals can only be a moon in the water and a flower in the mirror. In order to maintain the basic operation and development needs of hospitals, if public hospitals pass on the funding gap to patients, the phenomenon of "expensive medical treatment" will not only not be corrected, but will also become more and more severe; Or by changing ideas, bravely innovating, actively looking for other financial support channels. Since the reform and opening up, while the state-owned economic strength continues to grow, private enterprises have also completed the primitive accumulation, and have good financial strength and strong development momentum. However, a large amount of private capital in China is idle, and the public is eagerly looking forward to new investment fields. In this way, the mode of cooperation between government, social capital and Public hospitals (Public-Private Partnership, PPP mode) came into being. After the PPP model enters the practice of public hospitals, it will surely break the traditional operation mode of public hospitals, which may lead to a series of problems such as property rights changes and loss of state-owned assets. Therefore, this paper will explore the possible problems from the property right system reform, state-owned assets protection and human resources construction, and put forward corresponding legal countermeasures to ensure the smooth implementation of PPP mode in the application of public hospital projects.

Congenital adrenocortical hyperplasia (CAH) is a group of diseases caused by mutations in genes encoding enzymes essential for corticosteroid synthesis, resulting in disorders in the synthesis of adrenocortical steroids. Different degrees of enzyme deficiency also have different clinical manifestations. In recent years, with the continuous development of imaging technology, the detection rate of adrenal accidental tumor (AIs) has increased year by year^[1,2,3]。 There are reports in the world that AIs (often large tumor) was first diagnosed, and after clinical evaluation and longitudinal follow-up observation, the final diagnosis of non-classical CAH was confirmed^[4,5,6,7]； Studies on CYP21A2 gene mutation analysis in AIs patients also confirmed that 16% of AIs patients carried CAH mutation gene, and 2% were diagnosed with CAH^[8]。 We also encountered similar cases in our clinical work. After clinical evaluation and follow-up, it was finally confirmed that they were non-classical CAH. Whether it was an internationally reported case or a case confirmed by our hospital, there was misdiagnosis or missed diagnosis at the beginning, which suggests that clinicians should be more vigilant. Four patients admitted to the Department of Endocrinology of the General Hospital of the People's Liberation Army are reported as follows and related literatures are reviewed to improve clinicians' understanding of this disease.

A 53-year-old female was admitted to our hospital on June 5, 2014 due to "proposed acute myeloid leukemia (AML) for more than 2 months and after 2 cycles of chemotherapy". The patient went to the local hospital 2 months ago for persistent periumbilical pain. Blood routine showed: WBC 24.19×10⁹/L, hemoglobin 77 g/L, platelets 397×10⁹/L; Bone marrow image: hyperplasia was obviously active, with blast granulocytes accounting for 32.4%; Cytochemical staining: peroxidase (POX) staining was positive, chlorinated acetate AS-D naphtholesterase staining was partially positive, α-naphtholesterase acetate (α-NAE) staining was negative, alkaline phosphatase (NAP) positive rate was 82%, and the score was 264; Gene mutation: FLT3-ITD positive; Fusion gene screening was all negative; Chromosome normal karyotype; They were diagnosed as "AML-M2A with FLT3-ITD mutation, high risk group", and were given chemotherapy with DA regimen [daunorubicin 60 mg/d, days 1 to 3; cytarabine 100 mg every 12 hours, days 1 to 7) and CAT regimen (cyclophosphamide 300 mg every 12 hours, days 1 to 3; cytarabine 300 mg every 12 hours, days 2 to 6; topotecan 1.5 mg/d, days 2 to 6) on April 10, 2014 and May 4, 2014, respectively. After the end of chemotherapy, the bone marrow images reexamined showed no remission, and the proportion of blasts was 42% and 18%, respectively. Then he went to our hospital on June 5, 2014, and no obvious abnormalities were found in the admission physical examination. Blood routine: white blood cells 18.25×10⁹/L, hemoglobin 66 g/L, platelets 59×10⁹/L; There were no abnormalities in blood biochemistry; Bone marrow image: hyperplasia is obviously active, primitive and naive monocytes account for 78%, and mature monocytes account for 11.6%; Cytochemical staining: weakly positive for POX, positive for α-NAE, positive for sodium fluoride (NAF) inhibition test; Immunophenotype was detected by flow cytometry: the abnormal cell population accounted for 90.4% of nuclear cells, expressing CD117, CD13, CD33, CD36, and partially expressing CD38, conforming to the phenotype of AML; Gene mutation: FLT3-ITD positive; The modified diagnosis was "AML-M5 with FLT3-ITD mutation, high risk group" and sorafenib 400 mg was administered orally twice daily on 06 Jun 2014. On June 9, 2014, he was given chemotherapy with CLAG regimen [cladribine 7.5 mg/d continuous intravenous infusion, days 1 to 5; cytarabine 1.5 g every 12 hours, days 1 to 5; granulocyte colony stimulating factor (G-CSF) 300 μ g/d, days 0 to 5]. After chemotherapy, the bone marrow image was re-examined: hyperplasia was extremely reduced, and no blasts were seen. On July 9, 2014, the bone marrow image was re-examined: the hyperplasia was obviously active, and no blasts were seen; Blood routine on 20 Jul 2014: white blood cells 2.52×10⁹/L, hemoglobin 87 g/L, platelets 99×10⁹/L, neutrophils 1.51×10⁹/L, suggesting complete remission (CR). All-consistent allogeneic hematopoietic stem cell transplantation was followed.

Stress ulcer (SU) is a disease characterized by acute gastrointestinal erosion, ulcer and other lesions, which can eventually lead to gastrointestinal bleeding and perforation, and worsen the original lesions under various severe stress states such as severe trauma and critical diseases^[1]。 As early as 1999, the American Pharmacists Association (ASHP) issued the first guidelines for the prevention and treatment of stress ulcers, pointing out risk factors and preventive measures for SU, which are applicable to patients in intensive care units; In 2002, the editorial committee of Chinese medical journal formulated the interim standard for the prevention and treatment of stress ulcer^[2],The etiology, mechanism, clinical manifestations, diagnostic methods and preventive measures of SU were expounded. In recent years, domestic and foreign medical associations have revised the guidelines many times, and added the adapted objects and risk factors of drug prevention of SU. In 2009, the Department of General Surgery issued "Prevention and Treatment of Stress Mucosal Lesions in General Surgery-Suggestions of Chinese General Surgery Experts"^[3]The etiology, risk factors, diagnosis and preventive measures of stress mucosal lesions (SRMD) were given. In 2015, Bai Yu, Ren Xu, Li Zhaoshen and other expert groups on the prevention and treatment of stress ulcers updated the expert recommendations on the prevention and treatment of stress ulcers^[1]The Surgery Branch of the Chinese Medical Association also updated the expert consensus on the prevention and treatment of stress mucosal lesions^[4]It is again suggested that attention should be paid to the occurrence and development of SU in critically ill patients and the prevention of related complications. The above two guidelines are the current clinical prevention guidelines for SU in China, which give the prevention core of SU and SRMD and the treatment principles of complications in detail, and give the indications, strategies and measures of drug prevention. For the prevention of severe trauma and high-risk groups, proton pump inhibitors (PPIs) should be infused intravenously after the onset of the disease, so that the pH value in the stomach rapidly rises above 4.0, such as omeprazole (40 mg, twice/d). Prevention of SU is an important link in the prevention and treatment of gastrointestinal perforation and bleeding in critically ill patients. Rational use of PPIs to prevent stress ulcer is the key to successful treatment.

In 1922, Banting and Best successfully discovered insulin, declaring that diabetes was no longer an incurable disease, marking a new era of diabetes treatment. Since then, with the advent of various hypoglycemic drugs, the life span of diabetic patients has been significantly prolonged, but the harm of chronic complications of diabetes has gradually appeared, especially cardiovascular and cerebrovascular diseases, which have become the main cause of disability and death of diabetic patients. According to the British Diabetes Prospective Study (UKPDS), every 1% increase in glycosylated hemoglobin (HbA1c) can significantly increase the risk of myocardial infarction, heart failure, stroke, amputation, death and other events in patients with type 2 diabetes (T2DM)^[1]。 A large-scale observational study on complications and concomitant diseases of 239,000 patients with T2DM in 606 hospitals in China showed that common cardiovascular related diseases of T2DM include hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, etc. The prevalence rate of hypertension is as high as 33%, and the prevalence rate of coronary heart disease is 11%^[2]。 The ultimate goal of diabetes treatment is not only to achieve the standard of blood sugar control, but also to manage the risk of diabetic complications, especially the risk of cardiovascular diseases. Therefore, when evaluating hypoglycemic drugs, whether it can reduce or at least not increase the risk of cardiovascular events in patients is an issue that we must pay attention to.

Almost all nucleotide sequences in the human genome are transcribed, but less than 2% of the sequences are finally translated into proteins, and the vast majority of the remaining sequences are transcribed into non-coding RNA (ncRNA). According to their functions, ncRNAs can be divided into housekeeping ncRNAs, such as ribosomal RNA, transport RNA, and regulatory ncRNA, which can be divided into long non-coding RNA (lncRNA) and short chain ncRNA according to their length. Short-chain ncRNAs include well-known interfering RNAs (siRNAs), microRNAs (miRNAs), RNAs that interact with Piwi protein (piRNAs), and the like, and play an important role in mediating gene silencing at the transcriptional and post-transcriptional levels. lncRNA is a class of ncRNA with a length greater than 200 nucleotides. As early as the 1990s, it was found that lncRNA Xist was involved in the inactivation of X chromosome, and lncRNA H19 was involved in gene imprinting. With the implementation of the Human Genome Project and the widespread application of second-generation high-throughput sequencing technology, more and more lncRNAs have been discovered, and more than 28,000 lncRNA transcripts have been annotated at present (gencodegenes.org/stats/current.html). Most lncRNAs have similar structures to mRNA, but lack effective long open reading frames, have low conservation and high spatiotemporal specificity, and their expression is related to neighboring coding genes. According to their relationship with neighboring coding genes, they can be divided into cissense lncRNA, antisense lncRNA, bidirectional lncRNA, intron-derived lncRNA, and intergenic region-derived lncRNA (lincRNA). Through interaction with DNA, RNA and protein, they participate in various cellular processes such as gene imprinting, chromatin remodeling, mRNA splicing, synthesis and degradation, cell cycle regulation, etc., and regulate gene expression in many fields such as epigenetics, transcription and post-transcription, thus playing an important role in individual development and disease development^[1]。

Glucocorticoids are effective anti-inflammatory therapeutic agents for many inflammatory and immune diseases, especially inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus, and others. However, some patients, even with large doses of glucocorticoids, still experience unresponsive or poor treatment effects^[1]This phenomenon is called glucocorticoid resistance. Due to the broad disease spectrum and increasing prevalence of chronic inflammatory diseases, the problem of glucocorticoid resistance also increases. It has been found that several mechanisms of glucocorticoid resistance have been described, including decreased expression of total glucocorticoid receptor (GR), increased expression of GR β, defects in GR binding ligand and nuclear transfer, activation of mitogen-activated protein (MAP) kinase pathway mediated by certain cytokines, overactivation of transcription factor activated protein 1, decreased expression of histone deacetvlase-2 (HDAC2), increased macrophage migration inhibitor, and increased drug excretion mediated by P-glycoprotein, etc^[1,2,3]。 It is well known that Th17 cells are involved in the pathophysiological processes of various inflammatory diseases and autoimmune diseases. Recent studies have found that glucocorticoid resistance is closely related to Th17 cells. Recent studies have shown that a specific phenotype of Th17 subtype-multidrug resistance gene 1 (MDR1)^＋Th17 cells play an important role in glucocorticoid resistance. In this paper, the recent advances in the study of glucocorticoid resistance mediated by Th17 cells are reviewed, with the aim of seeking strategies to reverse glucocorticoid resistance.

inflammatory bowel disease (IBD) is a class of chronic non-specific inflammatory diseases of the intestine, mainly including ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological studies show that there are currently about 1 million CD patients and 1.4 million UC patients in Europe, while there are about 1.3 million IBD patients in the United States^[1]And the number of patients is still climbing. As an incurable disease, increasing IBD poses a serious challenge to patients' quality of life and global healthcare^[2]。 The incidence of IBD in China is increasing year by year, and related research started late, but developed rapidly in recent years. The pathogenesis of IBD has not been fully elucidated, and it is mainly caused by the interaction of environmental, genetic, infectious and immune factors^[3]。 At present, the main therapeutic drugs are aminosalicylic acids, glucocorticoids, immunosuppressants and biological agents, etc., all of which have different degrees of adverse reactions and treatment failure rates. It is urgent to explore effective therapeutic drugs to induce remission and maintenance therapy. Elafin is an endogenous serine protease inhibitor, which is a secreted protein and exists in mucosal epithelial cells and blood. Elafin can be used as an endogenous serine protease inhibitor to inhibit elastase, protease 3, pancreatic elastase and endogenous vascular elastase, and has the functions of anti-inflammation, immune regulation, anti-microbial infection, anti-cell proliferation, vascular remodeling, and participating in tissue damage repair^[4,5,6,7]。 In recent years, there are more and more studies on Elafin, and the research progress of Elafin in IBD will be reviewed.