DPP-4 inhibitors are new oral hypoglycemic drugs and hot spots developed and launched in recent years, and they pro-vide new choices for the clinical treatment of type 2 diabetes. In China, DPP-4 inhibitors that are approved to use in the treatment of type 2 diabetes are all imported products currently. In the paper, the current intellectual property situation of DPP-4 inhibitors that are developed and approved at home and abroad is researched and analyzed. Reasonable use of the patent information of DPP-4 inhibitors that is about to expire or have failed can provide good guidance for the subsequent development of DPP-4 inhibitors in domestic with promising curative effect and good market prospects, and can generate new patents in order to enhance the market competitiveness.

Child ; Community-Acquired Infections ; epidemiology ; Humans ; Pneumonia ; epidemiology

Parkinson's disease (PD) is the second major neurodegenerative disease.The pathogenesis of PI) is still unclear.It is generally believed that neural damage, mitochondrial dysfunction, inflammation, oxidative stress and autophagy dysfunction caused by the transmission and aggregation of a- synuclein play an important role in the occurrence and development of PD.More and more research show- that metabolic disorder is one of the pathogenesis of PD.We examined whether overexpression of a- synuclein could induce metabolic disorder in mice and the possible mechanisms.Mice were divided into two groups: Thyl-aSYN transgenic mice (TG) and the control wild-type (WT) group.The rotarod test was used to analyze motor function in mice.We detected the body weight, plasma insulin content, glucose tolerance and insulin tolerance in the two group mice.The morphology of islets in the two groups were observed by hematoxylin eosin (HE) staining, and the islets were isolated to detect the glucose- stimulated insulin secretion (GSIS).The results showed that compared with the WT group, exercise tolerance of 12-month-old TG group decreased by 23.1% (P < 0.05) , body weight increased by 7% (P < 0.01), glucose tolerance decreased (P < 0.05), insulin tolerance decreased (P < 0.05), and insulin contents in the peripheral blood decreased by 20% (P < 0.05).Compared with the WT group, the levels of ce -syn proteins in the pancreas of the TG group increased by 1.32 times (P < 0.05) , the area of islets in the TG group decreased (P < 0.05 ) , the number of islets decreased (P < 0.01) , and the insulin secretion function decreased (P< 0.01).This study showed that the role of a-synuclein in PD is not limited to the damage of dopaminergic neurons, it also can affect metabolism and the morphology and function of peripheral organs, which provides a new theoretical basis for the pathogenesis of PD.

Objective To develop an HPLC method for the determination of mycophenolic acid(MPA), mycophenolic acid glucuronide(MPAG) in plasma.Methods The samples were precipitated with zinc sulphate-methanol solution before injection.Carbamazepine was selected as internal standard,ZORBAX XDB C18 (4.6 mm ×250 mm,5 μm) column was used and the flow rate was 1 mL/min.The mobile phase consisted of methanol-acetonitrile-potassium dihydrogen phosphate buffer solution(gradient elution) .The column temperature was 30℃ and the detective wave length was 254 nm.And then the MPA,MPAG concentration of 32 patients in 7-14 days after renal transplantion were determined.Results The assay was linear within 0.2-50μg/mL for MPA, 2.5-500 μg/mL for MPAG(r>0.999).Absolute recovery rates of MPA,MPAG were more than 80%, the recoveries were between 90%-110%.The intra-day and inter-day RSDs were both lower than 10%.Totally 32 cases of renal transplantion patiens were with mycophenolate mofetil at the dose of 1-1.5 g/d,and MPA in plasma was within the range of 0.32-6.19μg/mL,MPAG in plasma was within the range of 9.52-149.25μg/mL.Conclusion The method is accurate, convenient and rapid, which could be used in the quantitative determination of plasma concentration of MPA,MPAG in renal transplantion patients.

OBJECTIVE:To explore the clinical related factors of leucopenia induced by azathioprine in the treatment of inflam-matory bowel disease (IBD). METHODS:Clinical information of 114 IBD patients were collected from our hospital during Jan. 2013-Mar. 2015. Steady concentration of AZA metabolite 6-thioguanine(6-TGNs)in red blood cell was determined by HPLC. The correlation of patient’s gender,age,diseases,AZA daily dose and blood concentration of 6-TGNs with leucopenia induced by AZA were investigated. The optimal critical value of leucopenia could be predicted with ROC curves. RESULTS:Among 114 IBD patients,40 patients suffered from leucopenia(35.1%). There was no statistical significance in the proportion of leucopenia among patients with different age,gender,diseases and AZA daily dose(P>0.05). There was statistical significance in the proportion of leucopenia among patients with different concentrations of 6-TGNs(P<0.05). Mean blood concentration of 6-TGNs in leukopenia patients [(407.82±262.88)pmol/(8×108)RBC] was higher than patients with normal leukocyte level [(275.85±118.37)pmol/(8× 108)RBC],with statistical significance(P<0.05). ROC curve predicted that the optimal critical value of leucopenia was blood con-centration of 6-TGNs>291.04 pmol/(8 × 108)RBC. CONCLUSIONS:AZA induced leucopenia may be related to the concentration of 6-TGNs in red blood cell of IBD patients,and high concentration of 6-TGNs is risk factors of leucopenia. Clinicians can provide AZA individual treatment for IBD patient to reduce the occurrence of leucopenia according to routine blood test and the concentra-tion of 6-TGNs.

Objective To detect the mutation of CARD15 gene in a patient with sarcoidosis and tuberculosis.Methods Clinical data were collected from a 32-year-old male patient with early-onset sarcoidosis and tuberculosis.Peripheral blood was obtained from the patient,both of his parents,and 102 healthy controls.All the 12 exons of the coding regions as well as flanking intronic sequences of the CARD15 gene were amplified by PCR followed by direct sequencing.The resulted sequences were blasted against the reference sequences of CARD15 gene.Results Both clinical features and histopathological findings of the patient were consistent with sarcoidosis.Furthermore,the patient presented with flexion contractures of fingers and toes,as well as iridocyclitis.A heterozygous missense recurrent mutation c.1000C ＞ T (p.R334W) was detected in exon 4 of the CARD15 gene in the patient,but not in either of his parents or any of the 102 healthy controls.Conclusions A p.R334W mutation in the CARD15 is identified in the patient,which may be responsible for the clinical phenotype of earlyonset sarcoidosis.Gene analysis may be a useful method to clarify the etiology of early-onset sarcoidosis.

Objective To observe the ultrastructural features of recessive dystrophic epidermolysis bullosa inversa(RDEB-Ⅰ)and to detect the mutations of COL7A1 gene in a family with RDEB-Ⅰ.Methods A 24-year-old male patient complained of recurrent vesicles in the skin for 24 years.The lesions began as generalized pruritic vesicles and bullae soon after birth,with a predilection for areas subject to friction,and showed a trend to be worse in summer but mild in winter.No photosensitivity was observed.When he was 3 to 4 years old,the lesions were decreased in number,with the only involvement of the trunk and abdomen;thereafter,the lesions were improved year by year.The patient suffered from nephritis at the age of 5 years,which progressed into renal failure at the age of 15 years.He received renal transplantation and was given long-term oral tacrolimus and mycophenolate mofetil,which leaded to an improvement in the lesions.The family history was unremarkable,and the marriage between her parents was not consanguineous.Dermatological examination revealed large areas of irregularly-marginated,hypopigmented,atrophic scar on the waist,back and abdomen with onychodystrophy involving multiple nails.No vesicles were observed.Immunofluorescence antigen mapping and transmission electron microscopy were conducted to observe the expression of type Ⅶ collagen in and ultrastructure of cutaneous lesions from the patient.Venous blood samples were obtained from the patient as well as his parents and 3 sisters,and drill biopsy specimens were obtained from the margin of vesicular lesions and unaffected anterior tibial skin of the patient.DNA specimens were obtained from the blood samples of the family members and 150 unrelated healthy controls,and RNA was extracted from the biopsy samples of the patient.PCR and direct sequencing were carried out to detect mutations in COL7A1 gene,and reverse transcription-PCR was conducted to confirm the mutation at mRNA level.Results Skin cleavage was observed under lamina densa in the dermis,with a decrease in anchoring fibrils and expression of type Ⅶ collagen in the lesions of the patient.A heterozygous synonymous mutation c.C5499T which created a new splicing site and leaded to a premature terminal codon,as well as a heterozygous missense mutation c.C6205T(C-T transition at codon 2069:CGT to TGT)which leaded to the substitution of arginine by cysteine,were identified in the COL7A1 gene of the proband and all of his sisters,but not in any of the unrelated controls.The c.C5499T and c.C6205T mutations were inherited from the patient's father and mother respectively.Conclusion The compound heterozygous mutations c.C6205T and c.C5499T may be responsible for RDEB-Ⅰ in this patient.

Objective To review the clinical features , diagnosis , prognosis and treatment of polycythemia vera ( PV) complicated with acute coronary syndrome ( ACS) .Methods The clinical data of 2 PV patients complicated with ACS admitted to Peking Union Medical College Hospital ( PUMCH ) were retrospectively analyzed and the recent literatures were reviewed .Results Case 1 was a 65-year old man who had been diagnosed PV with a positive JAK2V617F mutation 3 years ago.At presentation, the patient was suffering from recurrent angina pectoris , and coronary angiography revealed that there was a severe ( 80%) stenosis in the middle segment of left circumflex and a Xience V stent was implanted .After the percutaneous transluminal coronary intervention ( PCI ) , secondary prevention for coronary heart disease and hydroxyurea for PV were given and the patient has been followed up regularly for more than three years and he is going well.Case 2 is a 44-year old man who was diagnosed PV with a positive JAK 2 mutation 3 years ago and hydroxyurea, interferon, aspirin was prescribed.Then splenic infarction, thrombosis of splenic vein,regional portal hypertension , severe varices of fundus of stomach and upper gastrointestinal bleeding developed with him.Two months ago , an AMI of inferior wall occurred and the angiographic findings demonstrated an thrombotic lesion in the proximal segment of the right coronary artery with a moderate stenosis ( 60%);1 month ago an AMI of anterior wall developed and coronary angiography discovered that there were diffuse thrombus in the proximal segment of left anterior descending artery with a severe stenosis ( 90%) and a complete occlusion in the right coronary artery .After double antiplatelet therapy with anticoagulation therapy of warfarin was given , the patient recovered gradually .Conclusions PV complicated with ACS is relatively rare.According to recent studies, positive JAK2V617F mutation, leukocytosis, age >65 years and positive history of thrombosis are the most important predictors of cardiovascular events .Clinicians should design individualized treatment strategies for patients on the basis of clinical features , coronary angiography findings and complications .For those with thrombotic lesion in the coronary artery due to the hypercoagulative state caused by PV, it should be cautious to carry out a coronary revascularization treatment .

Objective To assess mutations in the ALDH3A2 gene in two patients with Sj(o)gren-Larsson syndrome manifesting primarily as congenital ichthyosis,mental retardation and spastic paraplegia.Methods Two patients,a 2-year-old girl and a 1.5-year-old boy,with Sj(o)gren-Larsson syndrome were included in this study.None of their family members suffered from this disease.Peripheral blood samples were collected from the two patients,their family members (an elder brother and both parents),and 100 unrelated healthy controls.DNA was extracted from the blood samples,and subjected to PCR for the amplification of 10 encoding exons and their flanking sequences of the ALDH3A2 gene followed by DNA sequencing.Results A homozygous missense mutation c.325G ＞ A,which leads to the substitution of glycine by arginine at position 109,was detected in the ALDH3A2 gene of patient 1,whose parents and elder brother were heterozygous carriers of this mutation.The patient 2 carried compound heterozygous mutations,including c.1157A ＞ G (p.Asn386Ser) inherited from his father and c.1294A ＞ T (p.Arg432X) inherited from his mother.None of these mutations was detected in the unrelated healthy controls.Conclusion The homozygous mutation p.Gly109Arg and compound heterozygous mutations p.Asn386Ser and p.Arg432X present in these patients may be associated with clinical phenotypes of Sj(o)grenLarsson syndrome.

Objective To investigate the efficacy of regional lymphadenectomy for patients with T2 gallbladder cancer. Methods From January 1990 to December 2009, 48 patients with T2 gallbladder cancer received regional lymphadenectomy following radical surgery at the Xinhua Hospital of Shanghai Jiaotong University, and their clinical data were retrospectively analyzed. Patients were divided into two groups according to the range of lymphadenectomy. Standard group (23 patients): lymph nodes in the regions of bile duct, common bile duct and hepatoduodenal ligament were dissected; extended group (25 patients): lymph nodes in the regions of hepatoduodenal ligament, head of pancreas, duodenum, portal vein, common hepatic artery and celiac axis were dissected).The condition of patients in the two groups were compared after the treatment. The morbidity and survival rate were analyzed by using Fisher exact test and Kaplan-Meier method, respectively, and the survival rates between the two groups were compared by using Log-rank test. Results No perioperative death was found in the two groups. The morbidities was 17% (4/23) in the standard group and 24% (6/25) in the extended group, with no significant difference between the two groups ( P ＞ 0.05 ). The 5-year cumulative survival rate and median survival time were 40% and 29.8 months in the standard group, and 66% and 53.2 months in the extended group, with significant differences between the two groups ( x2 = 4. 687, P ＜ 0.05 ). Conclusion Extended regional lymphadenectomy should be performed on patients with T2 gallbladder cancer if the primary lesions can be dissected radically.