Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Objective To investigate the effect of age on the incidence of cirrhosis and liver cancer in patients with chronic hepatitis B.Methods 279 patients with chronic hepatitis B were divided into the senior group and the younger group according to the age of the patients.The cumulative incidence of cirrhosis and liver cancer during 25 years of follow-up was calculated by using SPSS and R language through the long-term follow-up of HIS system,and the risk factors were analyzed by multivariate logistic regression.Results During follow-up,24 cases developed cirrhosis and 12 cases developed liver cancer.The cumulative incidence of liver cirrhosis was 1.5%,2.1%,5.4%,11.6%and 15.5%in the 5-year,10-year,15-year,20-year and 25-year group,and 5.5%,9.8%,22.9%,29.0%and 52.1%in the elderly,respectively.The difference between the younger age group and senior age group was statistically significant(P<0.001).A total of 2 risk factors(age and follow-up time)were included in the regression model.Two cases in the younger group developed into liver cancer after 17 and 21 years of follow-up,respectively.The cumulative incidence rates at 5,10,15,20 and 25 years were 1.8%,3.8%,18.5%,21.8%and 26.7%.A total of five factors(initial age,HBV-DNA load,HBV-DNA turned negative before the end-point,follow-up time,and sex)were included in the regression model.Conclusions The incidence of cirrhosis and liver cancer in CHB patients aged≥40 years,especially in male patients,is significantly higher than younger CHB patients.Timely initiation of antiviral therapy can delay disease progression and reduce the incidence of termi-nal liver disease.Whether antiviral therapy should be initiated for people aged 30 to 40 years remains to be studied.

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

Objective:To investigate the effect of vascular endothelial growth factor-A ( VEGF- A) gene mutation to neovascular age-related macular degeneration (nAMD) and the response to ranibizumab with this mutation in Chinese. Methods:This was a case-control study.We recruited 127 cases (diagnosed as nAMD) and 101 ethical, age and geographical area matched unrelated healthy controls in Beijing Hospital from February 2017 to January 2018.The patients with nAMD were divided into two subgroups: good response to intravitreal ranibizumab (IVR) and poor response to IVR based on whether gain 5 letters 3 months after therapy.Phenol chloroform method was used in purification of genomic DNA in the peripheral venous blood of each individual.All exons and 2 kb upstream and downstream sequence of VEGF-A was sequenced by using Sanger Sequenced method, and candidate variations were screened out.Restriction fragment length polymorphism (RFLP) method was used in genotyping of the case-control study.Hardy-Weinberg equilibrium was used to test the representativeness of the sample group.The differences of allele distribution frequency and genotype distribution frequency between the case group and control group, good response group and poor response group were compared.Written informed consent was obtained from each subject prior to entering the study cohort.The study protocol was approved by the Ethics Committee of Beijing Hospital (No.2017S-012).Results:The mutation (rs3025018) was located in 7th intron of VEGF-A.The allele were C, G, T and the genotype were CC, CT, CG, TT and TG.The allele distribution frequency between the case and control group were significantly different ( χ2=7.492, P=0.024). The allele G vs. C+ T distribution frequency between the case and control group were significantly different ( χ2=7.490, P=0.006). The genotype distribution frequency between the case group and control group were significantly different ( χ2=13.376, P=0.010). The genotype (CG+ GT vs. CC+ CT+ TT) distribution frequency between the case group and control group were significantly different ( χ2=8.335, P=0.004). The allele frequencies or genotype frequency were not significantly different between the good response group and poor response group (all at P>0.05). Conclusions:G allele of VEGF- A (rs3025018) carriers were less possible to occur nAMD compared with C and T allele.However, there is no effect of VEGF- A gene mutations (rs3025018) on response to ranibizumab for nAMD.

Objective: To explore the effects of multidisciplinary team based nursing intervention on nutritional status, muscle strength, physical function and daily living ability of super-aged patients with sarcopenia. Methods: A total of 29 super-aged patients with sarcopenia from July to November in 2017 in Department of Geriatric, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School were selected as the observation group with multidisciplinary team intervention. And 29 super-aged patients with sarcopenia from February to June 2017 were selected as the control group with routine management. Nutritional indicators, muscle strength, physical activity function and daily living ability scores were compared between the two groups at 1 and 6 months after intervention. Results: After 1 month of intervention, hemoglobin and serum albumin was (118.79±11.47), (35.86±5.73) g/Lin the observation group and (112.27±11.69), (31.35±5.48) g/L in the control group, the difference between the two groups was statistically significant (t value was 2.09, 2.98, P<0.05 or 0.01). After 6 months of intervention, hemoglobin, serum albumin, muscle strength, physical activity function and daily living ability was (124.66±13.52) g/L, (38.47±6.02) g/L, (23.75±3.61) g, (9.18±1.85) points, (86.19±14.36) points in the observation group, and (112.03±11.89) g/L, (31.01±5.91) g/L, (19.15±3.19) g, (6.14±1.69) points, (64.12±15.83) points in the control group, the difference between the two groups was statistically significant (t value was 3.68-6.37, all P<0.01). Conclusions Nursing intervention based on multidisciplinary team can improve the nutritional status, muscle strength,physical function and quality of life of super-aged patients with sarcopenia.

Coronary heart disease is one of the leading causes of death worldwide. Advanced age is associated with increased prevalence, morbidity and mortality of coronary heart disease. Older adults are at higher risk of complications and accelerated physical deterioration following cardiovascular events than youn-ger patients. In recent years, researchers have proposed that exercise-based cardiac rehabilitation is an im-portant part of the treatment of patients with coronary heart disease, especially contributing to the improve-ment of the quality of life of elderly patients. This review summarizes the current status and influence of car-diac rehabilitation on elderly patients with coronary heart disease.

Objective To compare the efficacy of intravitreal dexamethasone implant (OZURDEX（R）) in the treatment of macular edema (ME) caused by central retinal vein occlusion (CRVO) in different ages.Methods A retrospective case observation study was performed.Forty eyes of 40 patients diagnosed with ME secondary to CRVO were enrolled in the study.According to patient's age,all of the 40 eyes were divided into ＜40 years old group (20 eyes) and ≥40 years old group (20 eyes).All eyes went through best corrected visual acuity (BCVA),intraocular pressure (IOP) and optic coherence tomography (OCT) examinations.Early Treatment Diabetic Retinopathy Study chart was used to test visual acuity,and central macular thickness (CMT) was measured by OCT.Fundus fluorescein angiography (FFA) was proceeded selectively.All eyes went through intravitreal injections off intravitreal dexamethasone implant and BCVA,IOP,OCT were tested 1 month,2,3,6,9 and 12 months after injection.After 3 months follow-up,intravitreal dexamethasone implant or ranibizumab would be injected again for patients with ME recurrence or poor treatment effects.Changes of BCVA,IOP and CMT before and after injection were observed.Results BCVA and CMT in the ＜40 years old group and ≥40 years old group were compared at different time points,and the differences were significantly different (BCVA:Fgroup =2.071,P =0.044;Ftimc.=9.551,P ＜ 0.001.CMT:Fgroup =2.402,P=0.034;Ftime =13.175,P＜0.001),compared with before injection,the BCVA at each time point of post-injection was improved,and CMT was thinner than that before injection;at 2 months after injection,the BCVA was improved and CMT was thinner than those 1 month after injection,the differences were statistically significant (all at P＜0.05);at 12 months after injection,the BCVA in the ＜40 years old group was obviously better than that in the ≥40 years old group,the CMT was much thinner than that in the ≥40 years old group,the differences were statistically significant (both at P＜0.05).Compared with before injection,the IOP at 1 month,2 and 3 months after injection was increased,the IOP at 2 months after injection was higher than that at 1 month after injection,the differences were statistically significant (both at P＜0.05).The mean number of injections was (1.8±0.9) times in the ＜40 years old group and (2.7±1.4)times in the ≥40 years old group,with a statistical difference between them (t =2.569,P =0.014).Conclusions In different age groups,patients with ME caused by CRVO can be effectively treated by intravitreal dexamethasone implant,the therapeutic effect is significant at 1 month post-injection and most improvement is shown at 2 months post-injection.Compared with patients over 40 years of age,patients under 40 years of age have better long-term results,better visual improvement,thinner CMT and less intravitreal injections.

Objective To investigate the influences of maternal gestational diabetes mellitus (GDM) on amino acid levels in neonates.Methods From June 2016 to May 2017,393 pregnancies diagnosed with GDM in Changzhou Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University and 3 924 normal pregnancies were enrolled in this study.Clinical data of the gravidas and their newborns were collected.Heel blood samples were collected at 72 to 96 hours after birth.Tandem mass spectrometry was performed to detect the levels of 11 amino acids including alanine,arginine,citrulline,glycine,leucine/ isoleucine/hydroxyproline,methionine,ornithine,phenylalanine,proline,tyrosine and valine in neonatal heel blood.Differences in amino acid levels between the two groups were compared by t test.Influences of GDM on neonatal amino acid levels were analyzed by multivariate linear regression.Results Compared with the healthy pregnancy group,neonates in the GDM group had higher levels of methionine [(21.01 ±6.30) vs (19.93±6.47) μmol/L,t=3.159,P=0.002] and phenylalanine [(47.19±9.19) vs (45.78±8.58) μ mol/L,t=3.076,P=0.002],but lower levels of alanine [(280.51 ±64.54) vs (290.15±68.40) μ mol/L,t=2.678,P=0.007],proline [(147.64±30.64) vs (152.36±33.57) μ mol/L,t=2.680,P=0.007],tyrosine [(85.21 ±29.50) vs (90.60± 33.32) μ mol/L,t=3.089,P=0.002] and ornithine [(101.22±28.79) vs (105.83±30.10) μmol/L,t=2.906,P=0.004].Multivariate linear regression analysis showed that GDM was responsible for the increase of methionine (β=0.69,95％CI:0.02 to 1.37,P=0.044) and phenylalanine (β=1.60,95％CI:0.69 to 2.51,P=0.001),and the decrease of tyrosine (β=-4.98,95％CI:-8.42 to-1.54,P=0.005) and ornithine (β=-3.16,95％CI:-6.30 to-0.02,P=0.048) in neonates.Conclusions GDM neonates has increased of methionine and phenylalanine levels and decreased tyrosine and omithine levels.

Objective To evaluate the efficacy and safety of dexamethasone intravitreal implant (Ozurdex) in the treatment of macular edema (ME) secondary to retinal vein occlusion (RVO).Methods Thirty-nine patients (39 eyes) with ME secondary to RVO were enrolles in this study.Of the patients,27 were male and 12 were female.The mean age was (41.9 ± 16.3) years.The mean course of disease was (5.0± 5.3) months.The best corrected visual acuity (BCVA),intraocular pressure and optical coherence tomography (OCT) were performed.BCVA was measured by Early Treatment Diabetic Retinopathy Study charts.Central macular thickness (CMT) was measured by OCT.The mean BCVA was (13.4± 15.3) letters.The mean intraocular pressure (IOP) was (14.1 ±2.8) mmHg (1 mmHg=0.133 kPa).The mean CMT was (876.1 ±437.9) μm.Of the 39 eyes,33 were central RVO,6 were branch RVO.Patients were categorized into ischemic (18 eyes)/non-ischemic (21 eyes) groups and previous treatment (22 eyes)/treatment naive (17 eyes) groups.All eyes underwent intravitreal 0.7 mg Ozurdex injections.BCVA,IOP and CMT were assessed at 1,2,3,6,9,12 months after injection.Three months after injection,intravitreal injections of Ozurdex,triamcinolone acetonide or ranibizumab could be considered for patients with ME recurrence or poor treatment effects.Change of BCVA,IOP and CMT were evaluated with paired t test.The presence of ocular and systemic adverse events were assessed.Results BCVA,IOP significantly increased and CMT significantly decreased at 1 month after injection compared to baseline in all groups (t=3.70,3.69,4.32,3.08,4.25,6.09,6.25,4.02,5.49,8.18,6.54,5.73;P＜0.05).Two months after injection,change of BCVA,IOP and CMT was most significant (t=4.93,6.80,6.71,5.53,4.97,5.89,5.13,7.68,7.31,8.67,8.31,5.82;P＜0.05).Twelve months after injection,there was no statistical difference regarding BCVA of ischemic RVO group and previous treatment group,compared to baseline (t=1.86,0.67;P＞0.05);BCVA ofnon-ischemic RVO group and treatment naive group significantly increased compared to baseline (t=2.27,2.30;P＜0.05);IOP significantly increased and CMT significantly decreased in all groups (t=0.30,0.13,4.60,3.26,0.64,1.53,3.00,4.87;P＜0.05).Twenty-seven eyes (69.2％) experiences ME recurrence (4.5± 1.5) months after injection.Most common side-effect was secondary glaucoma.41.0％ eyes had IOP more than 25 mmHg,most of which were lowered to normal range with use of topical IOP lowering drugs.Four eyes (10.3％) presented with significant cataract progression and needed surgical treatment,all were central RVO eyes.No serious ocular or systemic adverse events such as vitreous hemorrhage,retinal detachment or endophthalmitis were noted.Conclusions Intravitreal injection of Ozurdex for patients with ME secondary to RVO is effective in increasing BCVA and lowering CMT in the first few months.Significant treatment effect could be seen at 1 month after injection and was most significant at 2 months after injection.The long-term vision of eyes in non-ischemic RVO group and treatment naive group are better.69.2％ eyes experience ME recurrence at 4 months after injection.Short term adverse events were mostly secondary glaucoma and long term adverse events are mostly cataract progression.

Objective To investigate the factors associated with short-term elevation ofintraocular pressure after ranibizumab intravitreal injection.Methods 292 eyes of 292 patients who were diagnosed retinopathy and suitable to receive ranibizumab intravitreal injection were enrolled in this prospective clinical study.There were 157 males and 135 females.193 patients diagnosed with age-related macular degeneration and 99 other retinopathy patients.Mean age of patients was 62.75 ± 13.74 years.All subjects underwent systemic and comprehensive ophthalmology examinations.The mean BCVA was 0.68± 0.47 logMAR.Mean basal intraocular pressure was 18.1 mmHg (1 mmHg=0.133 kPa).All patients received intravitreal injection with 0.05 ml of ranibizumab (0.5 mg).The intraocular pressure were measured by non-contact tonometer at 10,30,120 minutes and 1 day after injection in a sitting position.The patients were grouped by the changes ofintraocular pressure 10 minutes after injection.The elevation was more than 10 mmHg as elevation group and less than 10 mmHg as stable group.Analyze the possible related factors with elevation of intraocular pressure after ranibizumab intravitreal injection by comparing the different datum of two groups.Results The mean intraocular pressure were 23.8,20.5,19.9 and 17.4 mmHg at 10,30,120 minutes and 1 day after injection.The significant elevation level were 5.8,2.4,1.8,-0.7 mmHg compared with basal intraocular pressure.Among 292 eyes,intraocular pressure elevation in 68 eyes and stabled in 224 eyes.The age (Z=-0.732),gender (x2=1.929),right or left eye (x2=2.910),BCVA (Z=-0.039),diseases ((2=2.088) were no significant difference between two groups (P＞0.05).The injection number (Z=-2.413,P=0.001),basal intraocular pressure (Z=-3.405,P=0.016) and elevations after injection (Z=-11.501,-8.366,-5.135,-3.568;P＜0.01) were significantly different comparing two groups (P＜0.05).By logistic regression analysis,basal intraocular pressure was positively correlated with the elevation of intraocular pressure 10 minutes after injection (B=-0.844,OR=0.43,95％CI 0.24-0.76,P=0.004).Patients with higher basal intraocular pressure may occur intraocular pressure elevation after ranibizumab intravitreal injection much probably.Conclusions The factors associated with short-term elevation of intraocular pressure after ranibizumab intravitreal injection were basal intraocular pressure.The higher basal intraocular pressure,the higher risk to gain elevation of intraocular pressure after injection.