OBJECTIVE:To establish the pharmacokinetic-pharmacodynamic(PK-PD) model of Nisoldipine controlled-release patches(NCRP)in spontaneously hypertensive rats(SHR). METHODS:SHR were randomized into a patch(NCRP)group and a tablet(Nisoldipine tablets)group,with 6 rats in each group. The microdialysis probes were implanted in SHR. Each rat was given 5 mg nisoldipine. Plasma microdialysate was collected within 36 h after administration. HPLC was adopted to determine the plasma concentration of nisoldipine,and WinNonlin 5.3 was employed to calculate Pharmacokinetic parameters. With heart rate and blood pressure as pharmacodynamic indexes,PK-PD model study was conducted. RESULTS:Vs. nisoldipine tablets,NCRP has con-trolled release effect. The relationship between NCRP drug effect and effect-site concentration met the Sigmoid-Emax model. The main parameters of the PK-PD model for heart rate and systolic blood pressure were as follows as Emax of (2.65 ± 0.06) and (10.71 ± 0.87),EC50 of (83.65 ± 35.25) and (1.29 ± 0.26) ng/ml,γ of (0.83 ± 0.91) and (1.2 ± 0.35),Keo of (0.37 ± 0.53) and (0.91±0.24)h-1. CONCLUSIONS:PK-PD model of NCRP in SHR has been established successfully.

Spinal muscular atrophy (SMA) is a group of neuromuscular disorders, caused by degeneration of the motor neurons in the anterior horn of the spinal cord, with prevalence of about 1 in 6000 to 1 in 10000 in newborn. The gene carrying frequency is about 1 in 40 to 1 in 50 all over the world. SMA is one of the most common autosomal recessive diseases causing infant death. SMA mainly refers to SMN1 dependent caused by SMN1 gene mutations. Noninvasiveness and specificity make genetic testing a recommended method for diagnosis of SMA. In addition to conventional methods such as neural nutrition, muscle exercise, etc., there is no specific treatment for SMA up to now. Nevertheless, HDAC inhibitors deserve attention as they are the only drugs completed Phase Ⅲ clinical trials to date. Furthermore, other ways as small-molecule SMN enhancers, induced pluripotent stem cell (iPSC), antisense oligonucleotides to correct SMN2 splicing, etc, were still on the way of in vitro stage at present.

Objective To investigate the relevance between expectations before treatment, new symptoms and satisfaction after treatment of the pelvic organ prolapse (POP) patients. Methods Made a collection of 75 cases of POP patients at Peking University Third Hospital, who were affected by the POP symptoms and came to our clinic for treatment from January to December in 2013. Prospectively investigate the patients′expectations before treatment, which were the most troubling symptoms to be solved. According to treatment we divided the patients into surgery and pessary groups. Two groups were followed up with the degree to achieve the desired goals using patient global impression of improvement (PGI-I), new symptoms and satisfaction after treatment, try to find the relevance between expectations before treatment, new symptoms and satisfaction after treatment. Results There were 47 (63%, 47/75) patients in the surgical group and 28 (37%, 28/75) patients in the pessary group. The top three problems for patients were friction when walking (25%, 19/75), dysuria (23%, 17/75) and the feeling of vaginal prolapse (19%, 14/75). The follow-up rate was of 93% (70/75), follow-up time was (5 ± 4) months. Satisfaction score after treatment of surgical group was higher than that of pessary group [(4.9±0.4) versus (4.0±1.3) scores, P<0.01]. There was no statistically significant difference between two groups of PGI-I score [(6.7±0.6) versus (6.6±0.9) scores, P=0.886]. The top three new symptoms after treatment were increased secretion, urinary incontinence and dysuria. PGI-I and satisfaction scores was relevant (P=0.021). The availability of new symptoms and satisfaction scores was relevant (P=0.001). Conclusion When achieving higher expectations to the treatment and no more new symptoms, the satisfaction score after treatment is higher.

Objective To evaluate the therapeutic effect and influence factors of silicone pessary in treatment of pelvic organ prolapse ( POP).Methods From October 2005 to October 2010,132 with symptomatic POP managed by pessary were enrolled in this retrospective study.Validated prolapse quality of life questionnaire (pelvic floor distress inventory short form 20,PFDI-20),pelvic floor impact questionnaire short form 7 (PFIQ-7) and the patients' satisfaction degree were used to evaluate the therapeutic effect.Clinical characteristic of the patients with successful using for more than 6 months ( successful fitting group),giving up within 6 months (giving up group),unsuccessful fitting (unsuccessful fitting group)were compared.Factors influencing satisfaction degree and causing discontinuation were investigated.Results One hundred and six among 132 ( 106/132,80.3％ ) patients were in successful fitting group,26 (26/132,19.7％ ) patients were in the unsuccessful fitting group.In the successful fitting group,86.8％ (92/106) patients were followed up,the median follow-up time was 12.5 months.And 78.3％ ( 72/92 ) patients continued to use pessary with the wearing time ranged 3 -69 months; 21.7％ (20/92) patients discontinued with the wearing time ranged 1 -38 month,14 patients (14/20) gave up in the initial 6 months.The median scores of PFDI-20 and PFIQ-7 questionnaires before pessary use were 50.0 and 47.6,which decreased to 8.9 and 0.0 after pessary use (P＜0.05).And 87.1％ (61/70) patients were satisfied.There was no significantly difference among 3 groups on clinical characteristics,such as age,body mass index ( BMI ),pelvic surgery and so on (P ＞ 0.05 ).The main factor influencing satisfaction degree and causing discontinuation was difficulties in placing and removing.Conclusions Silicone pessary is effective for patients with POP.It could relieve discomfort symptoms and improve quality of life.The main factorinfluencing pessary use is difficulties in placing and removing.Thus,More suggestions are needed for patients in the initial 6 months.

Objective To investigated the efficacy and toxic effects of combined chemotherapy of vinorelbine plus cisplatin or carboplatin in patients aged ≥ 70 years and with non-small cell lung cancer (NSCLC).Methods One hundred patients with lung cancer aged ≥70 years were enrolled in the study.Fifty patients in chemotherapy group were assigned to receive vinorelbine 25 mg/m2 at the first day and the fifth day plus cisplatin 60-70 mg/m2 or carboplatin 250 mg/m2 at the second day.All treatments were repeated every 3 or 4 weeks.Another fifty patients aged ≥ 70 years were taken as control group, not receiving treatment.The primary endpoint was survival.Results Forty-five patients were evaluable for response and the partial remission rate was 35.6% (16/45).One year survival rate was 37.8% and median survival time was 9.75 months in chemotherapy group.The median survival time was 4.0 months for patients in control group.All 50 patients in chemotherapy group were evaluable for toxic side effects.WHO grade Ⅲ incidences of leucopoenia, neutropenia and anemia were 38.0%, 52.0% and 2.2%, respectively.Grade IV incidence of neutropenia was 35.5%.WHO grade Ⅲ incidences of fatigue, constipation and vomit were 22.0%, 8.0% and 14.8%,respectively.Five patients failed to complete the treatment due to side effects.Conclusions Combined chemotherapy of vinorelbine plus platinum drugs is effective and tolerated in patients aged over 70 years with advanced NSCLC.Even patients with stable clinical effects shows benefit of survival time.

Objective To investigate the factors influencing therapy decision of surgery or pessary in patients with severe pelvic organ prolapse (POP). Methods Totally 419 cases ofⅢtoⅣdegree POP patients were studied retrospectively. Patients were divided into surgery and pessary groups according to their own choice. Clinical characters were compared such as age, body mass index (BMI), age of onset and disease duration, POP stage, complications. Results 67.5%(283/419) patients were in the surgical group and 32.5%(136/419) patients in the pessary group. Patients in surgical group had higher BMI [(25.1 ± 3.5) versus (23.8±2.6) kg/m2], elder age of onset [(62±12) versus (57±11) years old], longer disease duration [(5± 8) versus (11±11) years] and higher POP staging of middle compartment and less cardiac disease [20.1%(57/283) versus 30.9% (42/136)] than those in pessary group, all had significant difference (P<0.05). Logistic regression analysis on the above factors showed a statistically significant difference between two groups, BMI, disease duration and POP staging of middle compartment were independent factors (OR=1.141, 0.932, 1.389;all P<0.01). Conclusions Patients with higher BMI, higher POP staging of middle compartment and less cardiac disease tended to choose surgery. Patients with younger age of onset and longer disease duration tended to choose pessary. Factors as age, POP staging of anterior and posterior compartment, history of POP surgery, complicated with hypertension and diabetes, showed no influence on treatment choice.

Objective: To investigate the epidemiological characteristics of malaria in Hangzhou City from 2004 to 2021, so as to provide the evidence for formulating the post-elimination control strategy for malaria in Hangzhou City. Methods: The epidemic situation of malaria in Hangzhou City from 2004 to 2021 were collected from the National Information System for Disease Control and Prevention in China, and the temporal, spatial and human distributions of malaria cases and the source of malaria infections were analyzed in Hangzhou City during the pre-elimination stage (2004 to 2009), the elimination stage (2010 to 2015) and the post-elimination stage (2016 to 2021). Results: Totally 602 malaria cases were reported in Hangzhou City from 2004 to 2021,and the annual mean incidence of malaria was 0.22/105, 0.20/105 and 0.18/105 during the pre-elimination, elimination and post-elimination stages, appearing a tendency towards a decline. Men accounted for 63.96%, 85.07% and 93.75% of all malaria cases and there were 67.86%, 82.84% and 80.00% of cases at ages of 18 to 50 years during the pre-elimination, elimination and post-elimination stages, both appearing a tendency towards a decline (χ2trend=56.748, P<0.001; χ2trend=39.971, P<0.001). The predominant occupation of malaria cases shifted from farmers or migrant workers to multiple occupations, and the proportion of commercial servants increased from 4.87% during the pre-elimination stage to 24.38% during the post-elimination stage (χ2trend=73.308, P<0.001). The proportion of Plasmodium vivax malaria cases reduced from 96.43% during the pre-elimination stage to 7.50% during the post-elimination stage, and the proportion of P. falciparum malaria cases increased from 3.57% to 71.25%, while P. ovale, P. malariae and mixed infections were identified since 2010. There was a significant season-specific incidence of P. vivax malaria during the pre-elimination stage, and the period between May and October was an epidemic season; however, there was no season-specific incidence of P. vivax malaria during the elimination and post-elimination stages. The regional distribution of malaria cases presented a tendency towards a shift from suburb and rural areas to urban areas (χ2trend=74.229, P<0.001). No local cases were detected in Hangzhou City since 2010, and 94.22% of malaria cases were overseas imported cases after malaria elimination, including 90.61% from Africa. Conclusions oung and middle-aged men were high-risk populations for malaria in Hangzhou City from 2004 to 2021, and overseas commercial servants gradually became the predominant source of malaria infections, with malaria parasite species tending to be diverse. Improving the management of overseas imported cases and timely identification and treatment of cases are major interventions to consolidate malaria elimination achievements in Hangzhou City.

Objective To analyze the etiological factor and genetic feature of a familial hemophagocytic lymphohistiocytosis patient with PRF1 mutation (FHL2) with human herpesvirus 7 (HHV7)infection and its family constellation. Methods Clinical characteristics, laboratory examinations of a FHL2 case with HHV7 infection were reported. HHV1-HHV8 virus DNA was screened by PCR; NK cell function was analyzed by flow cytometry; PRF1 gene mutations were analyzed by PCR and direct sequencing, structure of mutant PRF1 proteins were analyzed using ExPasy and I-TASSER server and genetics pedigree were analyzed. Results The patient's HHV7 viral was detected positive with DNA copy number of 350/106 peripheral nucleated cells. Flow cytometry analysis showed decrease both in proportion of perforin positive NK cells and perforin protein expression. Genetic testing showed PRF1 biallelic heterozygote mutations (c. 503G ＞ A/p. S168N and c. 1177T ＞ C/p. C393R) and pedigree analysis showed they were inherited. The patient was then treated with antivirus therapy, dexamethasone and VP16 therapy, but only achieved partial response. The patient was then followed by human leukocyte antigen 10/10 allele identical nonconsanguinity allogeneic hematopoietic stem cell transplantations (allo-HSCT) and soon the successful implantation of donor hematopoietic cells and persistent recovery was achieved. The patient was now surviving without recurrence for 9 months after allo-HSCT. Conclusions FHL is prone to be misdiagnosed as lymphoma. Genetic analysis of related gene mutation and herpes simplex virus detection will help in early and accurate diagnosis. Allo-HSCT is a fundamental treatment of FHL.

Objective Although the ocular motility examination has been traditionally used in the diagnosis of complex strabismus resulting from cranial nerve (CN) and extraocular muscles (EOM) abnormalities, magnetic resonance imaging (MRI) now permits the direct imaging of lesions in CNs and EOMs. Methods Twenty-six patients with complex strabismus underwent MRI examination on 1.5 T MR unit (Twinspeed, GE). Nerves to EOMs were imaged with T1 weighted in orbits in all patients using phase array surface colls. Results Patients with Duane syndrome ( 15 cases, 19 eyes) all exhibited absence or hypoplasia of abducens nerve (CN6), always with mild hypoplasia and apparent misdirection of oculomotor nerve ( CN3 ) to the lateral rectus muscle in the orbit, and there were no hypoplasia of EOMs. Patients with congenital fibrosis of EOMs (9 cases, 16 eyes) exhibited severe hypoplasia of CN3 and CN6, and EOMs appeared hypoplasia to a different degree, particularly severe for the superior rectus and levated palpted muscles. Multiple nerves displayed aplasia in patients with Mobius syndrome (1 case, 2 eyes) and there was abnormal branch from CN3 to lateral rectus. The tendons of bilateral superior oblique muscles were thin in the patients with Brown syndrome ( 1 case, 2 eyes). Conclusion MRI can directly demonstrate absence or hypoplasia of CNs and corresponding EOM abnormalities in congenital complex strabismus, which suggests that the mechanism of congenital complex strabismus is perhaps abnormal innervation or displasia of the ocular motor nerves.

ObjectiveTo investigate the CT and MRI characteristic features of neuroendocrine carcinoma in paranasal sinuses.MethodsCT and MRI findings of 10 patients with proved neuroendocrine carcinoma by pathology were retrospectively reviewed. All patients underwent plain and enhanced MRI scanning,and 9 patients also underwent CT manning.ResultsThere were 5 males and 5 females with mean age of (48 ± 9 ) years old,ranging from 27 to 57 years.The treatment time after symptoms onset ranged from 1 to 4 months,with the median of 2 months.Clinical symptoms were headache and vision loss,hyposmia and yellow nasal discharge,and exophthalmos.The lesions were located in the ethmoidal sinus ( n =6 ),maxillary sinus ( n =2),and bilateral sphenoid sinus ( n =5 ).The lesions were symmetrical in the sphenoid sinus.Pathology type included typical carcinoid tumor ( n =1 ),atypical carcinoid ( n =1 ),and neuroendocrine carcinoma not otherwise specified ( n =8 ). Immunohistochemical staining showed that neurospecific enolase,synaptophysin,cytokeratin and P53 were all positive.On CT images,lesions showed isointensity (n =1 ),iso- to hypointense (n =4 ),and iso- to hyperintense (n =4 ) with hypointense or hyperintense spots.Bone changes included bony absorption and sclerosis ( n =1 ) with a clear margin in typical carcinoid tumor,and moth-eaten bone destruction in other 8 cases( n =8).The lesions were isointense on T1-weighted images,and isointense (n =4) or mixed iso- to hyperintense on T2-weighted images (n =6).Lesions showed mild to medium heterogeneous enhancement ( n =7 ) or marked enhancement ( n =3 )on gadolinium-enhanced images.Time-signal intensity curve ( TIC ) showed plateau type in 2 cases.The aggressive nature of the tumors was demonstrated by invasion of adjacent structures,involvement of nasal cavity( n =9 ),orbits ( n =7 ),pterygopalatine fossa ( n =4 ),ethmoidalsinus and sphenoid ( n =3 ),clivus ossis occipitalis(n =2),cavernous sinus and internal carotid canal(n =2),optic canal(n =2),jugular fossa ( n =1 ),anterior fossa ( n =1 ),apex partis petrosae ossis temporalis ( n =1 ),meninges ( n =1 ),temporal fossa and infratemporal fossa ( n =1 ),pharyngonasal cavity and parapharyngeal space ( n =1 ).ConclusionsThere are different CT features in different pathological types of neuroendocrine carcinoma of the paranasal sinuses,and MRI can demonstrate the invasive extent accurately. CT combined MRI can provide more comprehensive information in the diagnosis and therapy.