狭鳕鱼皮胶原多肽对去势大鼠骨微结构影响的研究

目的通过观察狭鳕鱼皮胶原多肽对去势大鼠骨质疏松模型骨微结构的影响，探讨其防治骨质疏松的可行性。方法成年 Wistar 雌性大鼠 60 只，体质量（250±10）g，随机分为 5 组（n=12），分别为正常对照组（A 组）、骨质疏松模型组（B 组）、骨质疏松模型+狭鳕鱼皮胶原多肽预防组（C 组）、骨质疏松模型+狭鳕鱼皮胶原多肽低剂量治疗组（D 组）、骨质疏松模型+狭鳕鱼皮胶原多肽高剂量治疗组（E 组），每组 12 只。B、C、D、E 组采用摘除双侧卵巢法制备大鼠骨质疏松模型。C 组从术前 4 周开始、D、E 组从术后 6 周开始，每天按照 1.0、0.5、1.0 g/kg 行狭鳕鱼皮胶原多肽灌胃，连续 6 周；A、B 组于术后同时间点给予等体积生理盐水灌胃。末次给药 24 h 后，A、B 组大鼠摄股骨 X 线片并测定灰度值；然后颈椎脱臼法处死各组大鼠，取左侧胫骨近端骨组织行 HE 染色，观察骨组织病理学改变，测量骨小梁数量（trabecular number，TN）、平均骨小梁厚度（mean trabecular plate thickness，MTPT）、平均骨小梁间距（mean trabecular plate spacing，MTPS）、骨小梁体积百分比（trabecular bone volume，TBV）、平均骨皮质厚度（mean bone cortical thickness，MBCT）；免疫组织化学染色观测降钙素受体（caltitonin receptor，CTR）及 IL-1 表达水平。 结果B 组大鼠股骨灰度值显著低于 A 组（t=45.130，P=0.000），表明去势大鼠骨质疏松模型制备成功。组织学观察示，A、C、E 组 TN、MTPS、TBV、MBCT 与 B 组比较，差异有统计学意义（P<0.05）；C 组各骨组织形态计量学参数与 D、E 组比较，差异均有统计学意义（P<0.05）；D 组 TN、MTPS、TBV、MBCT 与 A 组比较差异有统计学意义（P<0.05）；E 组仅 MTPS 与 A 组比较差异有统计学意义（P<0.05）；E 组 MTPS、TBV、MBCT 与 D 组比较，差异有统计学意义（P<0.05）。免疫组织化学染色观察示，A、C、D、E 组 CTR、IL-1 表达水平较 B 组降低，C、E 组低于 D 组，差异有统计学意义（P<0.05）；其余组间比较差异均无统计学意义（P>0.05）。 结论狭鳕鱼皮胶原多肽能够改善骨质疏松大鼠的骨微结构，其机制可能与抑制骨组织中 CTR、IL-1 表达有关，但尚未发现其对骨质疏松症有预防作用。     

改良推管在单侧椎弓根穿刺经皮椎体后凸成形术的应用

目的探讨改良推管用于单侧椎弓根穿刺经皮椎体后凸成形术（percutaneous kyphoplasty，PKP）的可行性及疗效。方法2012 年 1 月—2016 年 1 月，将收治并符合选择标准的 60 例（68 个椎体）骨质疏松椎体压缩性骨折（osteoporotic vertebral compression fractures，OVCF）患者随机分为两组：常规组 30 例（34 个椎体）及改良组 30 例（34 个椎体），分别采用常规推管及改良推管行单侧椎弓根穿刺 PKP。两组患者性别、年龄、病程、骨折节段及术前疼痛视觉模拟评分（VAS）、椎间高度等一般资料比较，差异均无统计学意义（P>0.05）。记录并比较两组手术时间、骨水泥注入量，术前及术后 2 d、末次随访 VAS 评分，术前及术后 2 d、1 年椎体高度，术后 2 d 骨水泥弥散系数。 结果术后两组患者穿刺点均愈合良好，均无严重并发症发生。两组手术时间以及骨水泥注入量比较，差异均无统计学意义（t=0.851，P=0.399；t=1.672，P=0.101）。两组各 2 例术中发生骨水泥渗漏。常规组骨水泥弥散系数低于改良组（t=13.049，P=0.000）。患者均获随访，随访时间 12～36 个月，平均 19 个月。两组术后两时间点 VAS 评分、椎体高度与术前比较，差异均有统计学意义（P<0.05）；组内术后两时间点间比较，差异无统计学意义（P>0.05）。两组间术后两时间点以上指标比较，差异均无统计学意义（P>0.05）。X 线片复查示，常规组 6 例、改良组 1 例患者随访期间发生其他节段椎体压缩性骨折。 结论单侧椎弓根穿刺 PKP 术中，采用改良推管注射骨水泥可以改善骨水泥在椎体内的弥散，恢复椎体高度，有效加强椎体内稳定，减少再骨折发生，疗效满意。     

Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.     

Role of Serum High-Sensitivity C-Reactive Protein as a Predictor of Therapeutic Response to Tadalafil in Patients With Erectile Dysfunction: A Prospective Observational Study

IntroductionHigh-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, is known to be elevated in patients with erectile dysfunction (ED). However, its role in predicting therapeutic response to phosphodiesterase-5 inhibitors is incompletely understood.AimThe aim of this study was to understand the relationship among hs-CRP, mechanism of ED, and therapeutic response of ED to tadalafil, a phosphodiesterase-5 inhibitor.MethodsA total of 282 men (mean age 36.6 ± 12.0 years) with ED were included. All subjects underwent detailed evaluation, including estimation of a 6-item abbreviated version of the International Index of Erectile Function (IIEF-6) score, penile Doppler studies, and measurement of hs-CRP. IIEF-6 scoring and hs-CRP measurement were repeated after 6 weeks of tadalafil therapy (10 mg/day). The patients were categorized into vasculogenic and nonvasculogenic ED groups based on penile Doppler findings.Main Outcome MeasureThe main outcome measure was the therapeutic response to tadalafil, in relation to the mechanism of ED and hs-CRP levels.ResultsVasculogenic ED was much less common (23.8% of the subjects) than non-vasculogenic ED. Subjects with vasculogenic ED were older, had higher prevalence of cardiovascular risk factors, had more severe (mean IIEF-6 score 9.2 ± 4.6 vs 14.8 ± 4.7; P < .001) and longer duration ED, and responded less favorably to therapy (response rate 10.4% vs 75.0%; P < .001). Those showing improvement with tadalafil had lower hs-CRP at baseline (median 1.5 mg/L [interquartile range 0.9?2.3] vs 2.0 mg/L [interquartile range 1.1?3.1; P = .034]) and had proportionately greater reduction in its level. However, on multivariate analysis, only shorter duration of ED (P = .008), non-vasculogenic origin (P = .025), and higher IIEF-6 score at baseline (P = .013) were independent predictors of response to treatment.Clinical ImplicationsSerum hs-CRP is elevated in patients who are less likely to respond to vasodilator therapy but does not have an independent predictive value for this purpose.Strengths & LimitationsThis is the largest study to evaluate the relationship among the mechanism of ED, serum hs-CRP level, and therapeutic response of ED to tadalafil. All patients underwent a penile Doppler study to characterize the type of ED. The limitations were nonrandomized nature of the study and nearly 22% dropout rate.ConclusionSerum hs-CRP level is higher in vasculogenic ED compared with non-vasculogenic ED, and is associated with poorer response to tadalafil therapy. However, this association is not independent of underlying risk factors and mechanism of ED.Jamaluddin, Bansal M, Srivastava GK, et al. Role of Serum High-Sensitivity C-Reactive Protein as a Predictor of Therapeutic Response to Tadalafil in Patients With Erectile Dysfunction: A Prospective Observational Study. J Sex Med 2019;16:1912–1921.     

Interstitial lung diseases in children

Interstitial lung disease (ILD) in children (chILD) is a heterogeneous group of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. The pathogenesis of the various chILD is complex and the diseases share common features of inflammatory and fibrotic changes of the lung parenchyma that impair gas exchanges. The etiologies of chILD are numerous. In this review, we chose to classify them as ILD related to exposure/environment insults, ILD related to systemic and immunological diseases, ILD related to primary lung parenchyma dysfunctions and ILD specific to infancy. A growing part of the etiologic spectrum of chILD is being attributed to molecular defects. Currently, the main genetic mutations associated with chILD are identified in the surfactant genes SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3 and NKX2-1. Other genetic contributors include mutations in MARS, CSF2RA and CSF2RB in pulmonary alveolar proteinosis, and mutations in TMEM173 and COPA in specific auto-inflammatory forms of chILD. However, only few genotype-phenotype correlations could be identified so far. Herein, information is provided about the clinical presentation and the diagnosis approach of chILD. Despite improvements in patient management, the therapeutic strategies are still relying mostly on corticosteroids although specific therapies are emerging. Larger longitudinal cohorts of patients are being gathered through ongoing international collaborations to improve disease knowledge and targeted therapies. Thus, it is expected that children with ILD will be able to reach the adulthood transition in a better condition.     

A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases

BackgroundOur aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature.MethodsWe performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature.ResultsOur patient is a six‐year‐old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non‐classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat‐soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0‐54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity.ConclusionThe first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.