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 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 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 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 investigate the effects of preserving continence important structures during Studer pouch surgery. Methods Radical cystectomy and Studer orthotopic neobladder surgeries were performed on 68 male patients with muscle invasive bladder cancer.The anatomic configuration of the rhabdosphincter complex,pudendal nerve supply,and musculofascial support system to the proximal urethra were carefully preserved.The neobladder functions were then evaluated. Results The pathological classification of the 68 patients was as follows:T3a N0M0 in 20 cases and T2N0M0 in 48 cases.The patients were followed up for 6 to 36mon(mean 12 mon).Complete urinary continence was achieved in 67 patients 24 hours a day and the remained one had nocturnal incontinence.Of these patients,59 patients could urinate well without residual urine and the other 9 patients had residual urine of 20 to 30 ml. Conclusions A well-performed Studer pouch should pay specific attention to the anatomic configuration of the rhabdosphincter complex,pudendal nerve supply,and musculofascial support system to the proximal urethra to achieve the goal of maximizing continence preservation.

Objective To discuss the value of different staging systems for gallbladder cancer.Methods The clinical data of 132 patients with gallbladder cancer who had been admitted to Xinhua Hospital from October 1992 to December 2006 were retrospectively analyzed.The clinical stage and postoperative survival of patients in each stage were analyzed by Nevin staging system,staging systems of AJCC 5th and 6th edition.The survivals of patients were analyzed by Kaplan-Meier method and the comparison between groups was analyzed by Log-rank test.Results According to the Nevin staging system,the accumulative survivals of patients with stages Ⅰ,Ⅱ,Ⅲ,Ⅳ or Ⅴ were 80.3%,75.6%,43.2%,16.2% and 6.5%,respectively.The accumulative survivals of patients with stages Ⅰ,Ⅱ or Ⅲ were significantly higherthan those with stages Ⅳ or Ⅴ(χ~2=7.239,6.152,3.992,12.354,13.171,15.084,P＜0.05).According to the AJCC 5th edition staging system,the accumulative survivals of patients with stagesⅠ,Ⅱ,Ⅲ or Ⅳ were 71.4%,40.9%,10.2% and 5.8%,respectively.The accumulative survivals of patients with stages Ⅰ or Ⅱ were significantly higher than those with stages Ⅲ or Ⅳ (χ~2=18.286,23.729,5.541,13.607,P＜0.05),and the survivals of patients with stage Ⅲ were significantly higher than those with stage Ⅳ (χ~2=7.758,P＜0.05).According to the AJCC 6th edition staging system,the accumulative survivals of patients with stages Ⅰ,Ⅱ,Ⅲ or Ⅳ were 51.1%,11.7%,8.2% and 6.5%,respectively.Patients with stages Ⅰ or Ⅱ had a comparatively low survival,while the survivals of patients with stage Ⅰ were significantly higher than those with stages Ⅱ,Ⅲ or Ⅳ(χ~2=15.300,21.956,31.397,P＜0.05).Patients with stage Ⅱ had a higher survival than those with stage Ⅳ(χ~2=8.789,P＜0.05).There was no significant difference in survival between patients with stage Ⅱ and Ⅲ,and between patients with stage Ⅲ and Ⅳ.Conclusions The AJCC 5th edition staging system is still the perfect staging system of gallbladder cancer.The Nevin staging system is not integrating enough,while AJCC 6th edition staging system is too strict.

Objective To evaluate the contribution of puboprostatic ligament-sparing technique in urinary continence after radical retropubic prostatectomy (RRP). Methods A total of 74 men with clinically localized prostate cancer underwent RRP. Of whom, 50 patients were performed pubo-prostatic ligament-sparing technique(group A), while 24 patients were not(group B). Patients were evaluated by independent observer questionnaire to determine their urinary continence status. Results Mean patient age [(61.3±2.4) vs (60.8±2.1)years], serum prostate-specific antigen (PSA) values [14.3±1.2)ng/ml vs (14.7±1.3) ng/ml], operative time [(110.5±10.4)min vs (109.7±10.6) mini, estimated blood loss [(250.5±23.4) ml vs (253.4±22.3) ml], and positive surgical margin rate (6% vs 8%) were not significantly different between group A and B(P>0.05). The urinary con-tinence rate with the puboprostatic ligament-sparing technique at 1-year follow-up was significantly higher than that of the control group (P<0.05). Concision The puboprostatic ligament-sparing technique significantly enhances post-operative urinary continence after RRP.

Objective To study cutaneous ultrastructural changes and FERMT1 gene mutations in a patient with Kindler syndrome. Methods Clinical data were collected, and tissue samples obtained from the lesions of poikiloderma were observed by using transmission electron microscopy. Fifteen coding exons and their flanking sequences of the FERMT1 gene were amplified by PCR and DNA sequencing was followed.Results Reduplication of lamina densa was seen between the dermal-epidermal junctions of the lesional skin. The patient was found to be homozygous for a novel splice-site mutation (IVS9 + 1G ＞ A) in FERMT1 gene, and his parents were heterozygous for it. The mutation was undetected in fifty normal control individuals.Conclusions Transmission electron microscopy may serve as an ancillary examination for the diagnosis of Kindler syndrome. The IVS9+1G＞A mutation of FERMT1 gene may contribute to the clinical phenotype of Kindler syndrome in this patient.