渴络欣胶囊联合培哚普利治疗早期糖尿病肾病的临床研究

目的 探讨渴络欣胶囊联合培哚普利治疗早期糖尿病肾病的临床疗效。方法 选取2021年6月—2023年1月郑州大学第五附属医院收治的168例早期糖尿病肾病患者,按随机数字表法将患者分为对照组和治疗组,每组各84例。对照组晨服培哚普利叔丁胺片,4 mg/d,1次/d。治疗组在对照组基础上口服渴络欣胶囊,4粒/次,3次/d。两组疗程12周。比较两组临床疗效,治疗前后中医症状积分、肾功能指标[24 h尿蛋白定量（24 h UP）等]、相关量表[肾脏病生活质量量表1.3（KDQOL-SF 1.3）、简式抑郁-焦虑-压力量表（DASS-21）]评分及血清血管生成抑制蛋白1（VASH-1）、高迁移率族蛋白B1（HMGB1）、CXC趋化因子配体10（CXCL10）水平。结果 治疗后,治疗组总有效率是94.05%,显著高于对照组的84.52%（P＜0.05）。治疗后,两组气短乏力积分、咽干口渴积分、肢体麻木积分、肢体麻木积分、腰膝酸软积分、畏寒肢冷积分均较治疗前显著降低（P＜0.05）;治疗后,治疗组中医症状积分低于对照组（P＜0.05）。治疗后,两组血肌酐（Scr）、24 h UP、尿蛋白排泄率（UAER）低于同组治疗前（P＜0.05）;治疗后,治疗组肾功能指标改善优于对照组（P＜0.05）。治疗后,两组KDQOL-SF 1.3评分均显著增高,而DASS-21评分均显著降低（P＜0.05）;治疗后,治疗组KDQOL-SF 1.3评分和DASS-21评分改善优于对照组（P＜0.05）。治疗后,两组血清VASH-1、HMGB1、CXCL10水平均显著降低（P＜0.05）;治疗后,治疗组血清VASH-1、HMGB1、CXCL10水平低于对照组（P＜0.05）。结论 渴络欣胶囊联合培哚普利治疗早期糖尿病肾病具有良好的疗效,能有效缓解机体炎症反应、控制肾组织纤维化,在患者症状和负面情绪减轻、肾功能和生活质量改善方面获得更佳效果,值得临床推广应用。     

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.     

Crose氏改良根治术治疗乳癌

目的 探讨Crose氏改良根治术治疗乳癌的疗效。方法 对采用Crose氏改良根治术114例（C组）,Halsted根治术205例（H组）的乳癌患者的临床资料进行回顾性分析和对比。结果 319例中,278例获随访（C组98例,H组180例）,随访3－14年。随访3年以上278例（C组98例,H组180例）,5年以上216例（C组56例,H组160例）,10年以上69例（C组31例,H组38例）。C组和H组,3,5,10年生存率分别为100％,85．71％,70．97％和95．6％,83．13％,71．05％;3,5,10年局部复发率为4．08％,7．1％,6．45％和3．98％,6．88％,5．26％,3,5,10年远处转移率分别为6．1％,12．5％,12．9％和6．67％,11．25％,15．79％,两组各指标均无显著差异（P＞0．05）。而C组患者上肢活动功能较H组明显为佳（P＜0．01）。结论 Crose氏改良根治术治疗乳癌,其根治性疗效同Halsted根治术,而患侧上肢功能好,并发症少,是一种有效、满意的方法。     

LC-MS/MS方法研究新型酪氨酸酶抑制剂UP302的大鼠皮肤吸收量和皮肤代谢稳定性

目的建立大鼠皮肤中UP302定量的LC-MS/MS方法,并应用于研究UP302乳膏在大鼠皮肤局部给药24h后的皮肤吸收量,以及离体大鼠皮肤中UP302的代谢稳定性。方法 UP302用甲醇溶解稀释,皮肤样品用2倍体积甲醇沉淀处理,内标法进行定量。采用Hypersil Gold C18色谱柱,柱温30℃;甲醇为流动相A,5mmol.L-1甲酸铵水溶液为流动相B,以0.2mL.min-1梯度洗脱,进行色谱分离,运行时间6min。采用负离子电喷雾离子化电离源和选择反应监测（SRM）模式进行串联质谱分析,用于定量分析的离子反应分别为m/z 301.1→135.2（UP302）和m/z 252.9→132.0（内标大豆苷元）。结果 UP302皮肤标准样品在5～2000ng.mL-1的浓度范围内线性关系良好（r=0.9998）。UP302在大鼠皮肤匀浆中的最低定量限是5ng.mL-1。本方法日内准确度在100.00%～105.23%,日内精密度小于5.82%。结论本LC-MS/MS方法专属性强、灵敏度高、重现性好、操作简便、结果准确,可用于UP302在皮肤组织中含量的测定,以及UP302在大鼠皮肤组织中的代谢稳定性研究。     

COX-inhibiting nitric oxide donators (CINODs) -- a new paradigm in the treatment of pain and inflammation

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.     

Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-β superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild–moderate type I/IV human OI. In the postnatal study, 5-week-old wild-type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen-containing bisphosphonates (N-BPs), non-N-BP anti-osteoporosis medications, and no anti-osteoporosis medications after hip fracture. We studied a historical cohort using a population-wide database. Patients with first hip fracture during 2005–2015 were identified and matched by time-dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox-proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N-BPs and 11,802 without anti-osteoporosis medication were propensity score–matched. N-BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person-years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N-BPs were compared with non-N-BP anti-osteoporosis medications, the association remained significant. N-BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N-BPs, non–vaccine-based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.     

Polygenic Risk Score of Adolescent Idiopathic Scoliosis for Potential Clinical Use

Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 × 10⁻⁴⁰ with area under the receiver-operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 × 10⁻¹⁰) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 ± 0.054, p = 1.6 × 10⁻⁸), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 × 10⁻⁴). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Higher-Impact Physical Activity Is Associated With Maintenance of Bone Mineral Density But Not Reduced Incident Falls or Fractures in Older Men: The Concord Health and Aging in Men Project

High-impact physical activities with bone strains of high magnitude and frequency may benefit bone health. This study aimed to investigate the longitudinal associations between changes in loading intensities and application rates, estimated from self-reported physical activity, with bone mineral density (BMD) changes over 5 years and also with incident falls over 2 years and long-term incident fractures in community-dwelling older men. A total of 1599 men (mean age 76.8 ± 5.4 years) from the Concord Health and Aging in Men Project (CHAMP) were assessed at baseline (2005–2007) and at 2- and 5-year follow-up. At each time point, hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry, and physical activity energy expenditure over the past week was self-reported via the Physical Activity Scale for the Elderly (PASE) questionnaire. Sum effective load ratings (ELRs) and peak force were estimated from the PASE questionnaire, reflecting the total and highest loading intensity and application rate of physical activities, respectively. Participants were contacted every 4 months over 2 years to self-report falls and over 6.0 ± 2.2 years for fractures. Hip fractures were ascertained by data linkage for 8.9 ± 3.6 years. Compared with sum ELR and PASE scores, peak force demonstrated the greatest standardized effect size for BMD maintenance at the spine (β = 9.77 mg/cm²), total hip (β = 14.14 mg/cm²), and femoral neck (β = 13.72 mg/cm²) after adjustment for covariates, including PASE components (all p < .01). Only PASE scores were significantly associated with reduced falls risk (standardized incident rate ratio = 0.90, 95% confidence interval 0.81–1.00, p = .04). All physical activity measures were significantly associated with reduced incident fractures in univariate analyses, but none remained significant after multivariable adjustments. Older men who engaged in physical activity of high and rapid impact maintained higher BMD, while higher energy expenditure was associated with reduced falls risk. Coupling traditional physical activity data with bone loading estimates may improve understanding of the relationships between physical activity and bone health. © 2020 American Society for Bone and Mineral Research (ASBMR).