月经及生殖状况与盆腔子宫内膜异位症关系的探讨

目的：探讨盆腔子宫内膜异位症（简称内异症）与月经及生殖状况的关系。方法：采用成组病例对照方法调查91例病例组及67例对照组病人的月经及生殖情况。结果：单因素分析结果显示，原发性痛经及继发性痛经均内异症发病的危险因素，t初孕年龄及t初产年龄≤24岁、N孕次≥2次及使用避孕器避孕这4个因素为可能的保护因素。非条件logistic多元回归分析显示，原发性痛经、继发性痛经为子宫内膜异位症的危险因素，t初孕年龄≤24岁与使用避孕器避孕有正交互作用，并对发病有保护作用。而单因素分析中，t初孕年龄≤24岁等4个可能的保护因素却未能显示与发病有联系。结论：原发性痛经是盆腔子宫内膜异位症可能的危险因素，积极有效地防治原发性痛经有助于预防内异症的发生。     

脾虚证计量诊断的前瞻性研究

以本研究所修订的“脾虚证诊断标准”为金标准，通过以整群抽样取得的５４９例各科各系统病人（包括脾虚２２９例，非脾虚３２０例）的四诊资料对笔者以往建立的“脾虚证诊断计分表”的诊断效果做了前瞻性的研究。该计分表诊断脾虚证的几项主要评价指标的结果为：患病率４１．７％，准确度９１．３％，敏感度９３．０％，特异度９０．０％，阳性预测值８６．９％，阴性预测值９４．７％，阳性拟然比９．３０，阴性拟然比０．０８，诊断效果满意。     

Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters

Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow

Bone marrow houses a multifunctional stromal cell population expressing C-X-C motif chemokine ligand 12 (CXCL12), termed CXCL12-abundant reticular (CAR) cells, that regulates osteogenesis and adipogenesis. The quiescent pre-adipocyte-like subset of CXCL12⁺ stromal cells (“Adipo-CAR” cells) is localized to sinusoidal surfaces and particularly enriched for hematopoiesis-supporting cytokines. However, detailed characteristics of these CXCL12⁺ pre-adipocyte-like stromal cells and how they contribute to marrow adipogenesis remain largely unknown. Here we highlight CXCL12-dependent physical coupling with hematopoietic cells as a potential mechanism regulating the adipogenic potential of CXCL12⁺ stromal cells. Single-cell computational analyses of RNA velocity and cell signaling reveal that Adipo-CAR cells exuberantly communicate with hematopoietic cells through CXCL12-CXCR4 ligand-receptor interactions but do not interconvert with Osteo-CAR cells. Consistent with this computational prediction, a substantial fraction of Cxcl12-creER⁺ pre-adipocyte-like cells intertwines with hematopoietic cells in vivo and in single-cell preparation in a protease-sensitive manner. Deletion of CXCL12 in these cells using Col2a1-cre leads to a reduction of stromal-hematopoietic coupling and extensive marrow adipogenesis in adult bone marrow, which appears to involve direct conversion of CXCL12⁺ cells to lipid-laden marrow adipocytes without altering mesenchymal progenitor cell fates. Therefore, these findings suggest that CXCL12⁺ pre-adipocyte-like marrow stromal cells prevent their premature differentiation by maintaining physical coupling with hematopoietic cells in a CXCL12-dependent manner, highlighting a possible cell-non-autonomous mechanism that regulates marrow adipogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Patient Outcomes in the Years After a DXA-BMD Treatment Monitoring Test: Improved Medication Adherence in Some,But Too Little Too Late

The role of mid-treatment monitoring dual-energy X-ray absorptiometry–bone mineral density (DXA-BMD) for bisphosphonate-treated patients with osteoporosis remains unsettled. A common reason for such monitoring is to encourage ongoing medication adherence. We sought to determine if a DXA-BMD treatment monitoring test was associated with improved medication adherence and whether improved adherence after a DXA-BMD treatment monitoring test was associated with subsequent reduction in fracture rates. Using linked administrative databases within Manitoba, Canada, we performed a retrospective cohort study of women starting and continuing antiresorptive therapy in whom a mid-treatment DXA-BMD monitoring test was performed. From the provincial pharmacy database, we estimated medication adherence by calculating annual medication possession ratio (MPR) and determining the change in MPR with respect to change (stable/decrease) in the DXA-BMD monitoring test, in addition to fracture rates before and after the test. The cohort comprised 3418 women, 90.7% treated with oral bisphosphonate, with pharmacy data for the 3 years before and after the mid-treatment DXA-BMD. Median (interquartile range) MPR was 0.84 (0.49–0.99) in the year before DXA-BMD and 0.84 (0.48–0.99) in the year after DXA-BMD (p = 0.37). Among those whose DXA-BMD declined, MPR in the prior year was 0.54 (0.04–0.92) but improved to 0.70 (0.31–0.92) in the year after DXA-BMD (p < 0.001). Among those whose DXA-BMD monitoring test was stable/improved, the fracture rate before the monitoring DXA-BMD was 10.1 per 1000 person-years and in those whose DXA-BMD monitoring test showed a decrease, the rate was 23.7 per 1000 person-years (p < 0.001). Despite improved adherence in those with DXA-BMD decline, the post DXA-BMD fracture rate was 22.4 per 1000 person-years versus 12.9 per 1000 person-years in those who had stable DXA-BMD (p < 0.001). A mid-treatment DXA-BMD reassessment strategy may be useful to focus attention upon adherence, but for optimal fracture outcomes, treatment adherence should be specifically addressed at the commencement of therapy. © 2021 American Society for Bone and Mineral Research (ASBMR).     

The role of Ureaplasma parvum serovar-3 or serovar-14 infection in female patients with chronic micturition urethral pain and recurrent microscopic hematuria

BackgroundUreaplasma parvum (UP) is commonly isolated in the genitor-urinary tract and may cause various clinical features, including microscopic hematuria (MH). Some UP serovars are more commonly related with specific urogenital disease, but the evidences have been conflicting. This study primarily aimed to research the possible associations between specific UP serotypes and genito-urinary pathogenicity in female patients showing MH with/without chronic micturition urethral pain (CMP).MethodsThis study retrospectively reviewed 276 female patients having MH with/without CMP, who visited health screening center or female infertility clinic. All patients underwent multiplex polymerase chain reaction (PCR) tests with vaginal and urine samples to evaluate the infection rate and serotypes of UP. The antimicrobial susceptibility of UP and the predictors of CMP among UP infected patients were also analyzed. All patients were followed up at least for 6-months.ResultsForty-nine patients (17.8%) showed urinary UP infection. Urinary UP serotyping showed the prevalence of seorvar-1, -3, -6 and -14 were 24.5%, 30.6%, 18.4% and 26.5%, respectively. 79.6% of the urinary UP positive patients accompanied vaginal UP infection. 22 patients of the cohort (8.0%) had CMP whereas serovars-3 and -14 accompanied CMP in 54.5% and 41.0% cases, respectively. No serovars-6 infection case had CMP. 26.4% of the cohort were infertile whereas 10.9% of these infertile patients were positive for urinary tract infection with UP serotype-3 or -14. Doxycycline, josamycin and pristinamycin were the most active antibiotics with the lowest rate of resistance (0.0%) for treating UP. At 1-month post-initial treatment with doxycycline, all UP serotypes were eradicated and no patient complained of urethral discomfort. However, simultaneous urinary and vaginal reinfection of serovar-3 (5 cases) and serovar-5 (1 case) were confirmed at 3-months post-initial doxycycline therapy. The logistic regression analyses revealed that serovars-3 [hazard ratio (HR) 1.354, P value 0.018] and -14 (HR 1.103, P value 0.046) were significantly associated with CMP in female patients having MH.ConclusionsUP serovars-3 and -14 infections could be associated with CMP in female patients having MH. Doxycycline, josamycin and pristinamycin were effective for treating UP. Serovar-3 showed higher reinfection rate than other serotypes after antibiotics treatment.     

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.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

Combined MEK Inhibition and BMP2 Treatment Promotes Osteoblast Differentiation and Bone Healing in Nf1Osx−/− Mice

Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase‐activating protein neurofibromin. Non‐bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo–based cell culture approach based on the use of Nf1^flox/flox bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell‐autonomous manner, independent of developmental growth plate–derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1‐deficient osteoprogenitors blunts the pro‐osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1‐deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1_osx^?/? mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol‐based delivery method. Collectively, these results provide novel evidence for a cell‐autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis. © 2014 American Society for Bone and Mineral Research.     

Urinary Tract Stones and Osteoporosis: Findings From the Women's Health Initiative

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow‐up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow‐up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis. © 2015 American Society for Bone and Mineral Research.