女性致密性骨炎血清骨转换生化标志物水平变化研究

背景 致密性骨炎（OCI）和其他疾病有时难以鉴别，探讨血清骨转换生化标志物可为OCI的鉴别诊断提供依据。 目的 探索女性OCI患者的血清骨转换生化标志物的水平变化及临床意义。 方法 回顾性选取2013年6月至2022年2月在北京积水潭医院门诊及住院诊断为OCI的61例女性患者作为观察组，年龄15~50岁，平均（33.8±6.6）岁，病程2周~15年。选择同期61例女性体检健康者作为对照组，年龄15~48岁，平均（35.6±7.6）岁。比较两组一般临床资料和血清骨转换生化标志物水平，并对血清骨转换生化标志物与病情相关指标进行相关性分析。 结果 观察组血清白蛋白（45.4±2.9）g/L低于对照组（46.5±2.8）g/L（t=2.190，P<0.05）。血清骨转换生化标志物比较结果显示，观察组血清1型胶原羧基末端肽β特殊序列（β-CTX）〔0.28（0.23，0.37）μg/L〕、N-端骨钙素（OC）〔13.1（11.2，16.2）μg/L〕、25-羟维生素D3〔25-（OH）VD3〕〔（14.1±5.1）μg/L〕低于对照组〔0.36（0.29，0.48）μg/L，15.6（13.7，17.3）μg/L，（17.5±6.6）μg/L〕（Z=-2.983、-3.255，t=3.081，P<0.05）。长病程亚组OC水平〔14.6（12.4，18.5）μg/L〕高于短病程亚组〔11.7（10.2，14.0）μg/L〕（Z=-2.407，P<0.05）。多孕亚组β-CTX〔0.25（0.22，0.32）μg/L〕、OC水平〔12.2（10.3，15.0）μg/L〕低于非多孕亚组〔0.33（0.26，0.44）μg/L、13.4（12.0，18.8）μg/L〕（Z=-2.486、-1.897，P<0.05）。相关性分析显示，观察组血清1型前胶原氨基端延长肽（tP1NP）与妊娠次数、生产次数均呈负相关（rs=-0.276、-0.298，P<0.05），OC与体质指数（BMI）、视觉模拟评分法（VAS）评分、妊娠次数均呈负相关（rs=-0.284、-0.374、-0.360，P<0.05），25-（OH）VD3水平与BMI呈正相关（rs=0.275，P<0.05）。 结论 女性OCI患者血清OC、β-CTX水平明显降低，可为鉴别其他疾病提供依据；血清OC水平可以反映OCI患者的严重程度，同时OC水平与患者妊娠次数相关；tP1NP与妊娠次数、生产次数相关。     

Evidence for reduced cerebellar volumes in trichotillomania.

BACKGROUND: Limited knowledge exists regarding the neurobiology of trichotillomania (TTM). Cerebellum (CBM) volumes were explored, given its role in complex, coordinated motor sequences. METHODS: Morphometric magnetic resonance imaging (MRI) scans were obtained for 14 female subjects with DSM-IV diagnoses of TTM and 12 age-, education-, and gender-matched normal control (NC) participants. Parcellation was performed utilizing a recently developed methodology to measure subterritory volumes of the CBM. Regions were defined based on knowledge of the structural and functional subunits of the CBM. RESULTS: As predicted, significant group differences were reported for CBM raw cortical volumes (p = .008) that survived correction for total brain volume (TBV; p = .037) and head circumference (HC; p = .011). A priori and post hoc group raw volume comparisons for CBM subterritories and functional clusters revealed many significant differences. However, most differences failed to withstand correction for total CBM volumes (TCV). Smaller volumes were consistently reported for the TTM versus NC cohorts. Total Massachusetts General Hospital Hair Pulling Scale (MGHHPS) scores were significantly inversely correlated with left primary sensorimotor cluster volumes (p = .008), with smaller volumes associated with more severe TTM symptoms. CONCLUSIONS: These findings implicate the CBM in the neurobiology of TTM, with reduced subterritory volumes reported for the TTM versus NC groups.     

RAB1A在晚期卵巢癌中的表达及与预后的关系

目的 探讨晚期卵巢上皮癌患者RAB1A表达水平与患者预后之间的关系。方法 收集2010年6月至2018年6月181例病理确诊的Ⅲ期或Ⅳ期卵巢癌患者病理标本。采用荧光定量PCR检测方法对癌组织中RAB1A的表达量进行检测,依据检测结果将患者分为两组(高表达组和低表达组),进一步分析RAB1A表达量与晚期卵巢癌患者临床特征及生存期之间的关系;通过检测RAB1A的表达为卵巢癌患者制定个体化治疗方案。结果 RAB1A高表达与晚期上皮性卵巢癌患者年龄(P=0.009)、吸烟(P=0.010)、肿瘤临床分期(P=0.011)、是否淋巴结转移(P＜0.001)、是否远端转移(P=0.014)有关;RAB1A高表达晚期卵巢癌患者生存期明显缩短(P＜0.001)。结论 RAB1A在卵巢癌中高表达,且高表达将缩短卵巢癌患者生存期。     

Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium,cartilage, and bone in the LITHE study

Objective

We investigated the effects of tocilizumab (TCZ) on joint tissue remodeling in patients with moderate to severely active RA by measuring tissue-specific biomarker.

Methods

The LITHE biomarker study (n = 740) was a phase III study of 4- and 8-mg/kg TCZ in combination with MTX. Early response was evaluated at week 16 as ±20% improvement in swollen/tender joint counts; and ACR50 was evaluated at week 52. Biomarkers (tissue inflammation: C3M, CRPM, and VICM; cartilage degradation: C2M; and bone turnover: CTx and osteocalcin) were tested in serum from baseline, week 4, 16, 24, and 52, and dose-dependent effect was investigated. Patients were divided into the following three groups: early non-responders (ENR), ACR50 responders, and non-responders; their biomarker profiles were compared.

Results

At week 52, CRP was inhibited to 4% and 40% of baseline by TCZ8 and TCZ4, respectively. CRPM (63%), C2M (84%), C3M (69%), and VICM (42%) were significantly (p < 0.05) reduced by TCZ8, but not by TCZ4. MMP3 and osteocalcin changed to <58% and >111%, respectively, in response to TCZ. CTx was not changed significantly. ENRs had significantly less inhibition of CRPM (p < 0.05), C2M (p < 0.01), and C3M (p < 0.01) compared to early responders. There was a significant difference in the C2M, C3M, and CRPM profiles of the ENRs, non-responders, and responders. ACR50 responders had significantly inhibited levels (p < 0.001), irrespective of dose.

Conclusions

TCZ8 strongly inhibited the biomarkers of joint tissue remodeling suggesting that TCZ actively suppresses key pathobiological processes at the site of inflammation in RA patients. The differences in biomarkers' profiles of responders and non-responders indicate that specific responder profiles exist.     

Tamoxifen induces resistance to activated protein C

Introduction

The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.

Materials and Methods

Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.

Results

APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.

Conclusions

This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.     

Normal reference ranges of antithrombin,protein C and protein S: Effect of sex,age and hormonal status

Introduction

Antithrombin (AT), protein C (PC) and protein S (PS) deficiencies are risk factors for venous thromboembolism. Overlapping values between heterozygous carriers and normal individuals often make a correct classification of a deficiency difficult. The aim of this study was to investigate the effect of sex, age, menopause and hormone therapy on natural anticoagulant plasma levels in a large group of healthy individuals, and to evaluate the need of separate reference ranges.

Materials and Methods

AT and PC were measured with a chromogenic assay, antigenic free PS with an ELISA test. To evaluate the effect of sex, age, oral contraception, hormonal status (and their interaction) on AT, PC and PS levels, linear regression models were used. Biological relevance and the value of the normal deviate z were chosen as rules to decide for separate reference ranges.

Results

The study population consisted of 1837 healthy adult individuals (741 men, 1096 women), aged 18-85 years (median age: 44 years). In men AT levels decreased after the age of 50 years. Men had higher levels of PS than women, particularly at young ages. In women, after correction for menopause, only PC levels increased with age. Menopause affected AT and PS, but not PC levels. Oral contraceptive intake was associated with a decrease of AT and PS, and an increase of PC levels.

Conclusions

For AT, PC and PS, sex- and age-specific normal reference ranges can be useful, in order to better discriminate true carriers of a natural anticoagulant deficiency.     

Enhanced thrombin generation in women with a history of oral contraception-related venous thrombosis

Introduction

In women who suffer venous thrombosis (VT) during oral contraceptive (OC) use, a transient risk factor (OC) is removed during the acute event, while most co-existing forms of thrombophilia persist and presumably continue to maintain hypercoagulability. The aim of this study was to establish if hypercoagulability persists long after OC-related VT and if it could be attributed to thrombophilia.

Materials and Methods

60 women (age 33.0 ± 8.5 years) were investigated 5 – 64 (median 33) months after OC-related VT (patients) and compared to 63 apparently healthy women (controls). All women were tested for thrombophilia, activated partial thromboplastin time (APTT), fibrinogen, D-dimer, P-selectin and C-reactive protein. Thrombin generation was measured by Technothrombin® TGA assay. Overall haemostasis potential (OHP) assay with overall coagulation potential (OCP) and overall fibrinolytic potential (OFP) as supplementary parameters were measured by repeated fibrin formation and degradation registration.

Results

In patients increased endogenous thrombin potential (4205 ± 440 nM x min vs 4015 ± 421 nM x min, p = 0.017), increased OCP (22.6 ± 4.6 Abs-sum vs 20.8 ± 4.1 Abs-sum, p = 0.025), shorter APTT (30.9 ± 3.8 s vs 33.4 ± 3.6 s, p < 0.001) and lower antithrombin activity (99, 93-105% vs 104, 100-109%, p < 0.05) were observed. Thrombophilia was observed in 22/60 (36%) patients and in 5/63 (7.9%, p < 0.001) controls. The only significant difference between thrombophilic and non-thrombophilic patients was higher soluble P-selectin in the former subgroup (22, 20-33 μg/L vs 17, 12-22 μg/L, p = 0.012).

Conclusions

In women with a history of OC-related VT persistent hypercoagulability was observed, which, however was not augmented by the presence of thrombophilia.     

Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus,Respiratory Syncytial Virus and Influenza A Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca²⁺ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.