Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.     

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

PurposeRare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation.MethodsWe obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine–based classifier distinguishing CDK13-RD and non–CDK13-RD samples.ResultsWe reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance.ConclusionWe describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.     

A mutation update on the LDS‐associated genes TGFB2/3 and SMAD2/3

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor‐β (TGF‐β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF‐β signaling. More recently, TGF‐β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF‐β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF‐β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.     

Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

大块充填树脂在牙体修复中的应用与研究进展

传统复合树脂在临床应用中分层充填,步骤较多,树脂的聚合收缩可导致修复体边缘微渗漏、术后敏感等,导致修复失败.2009年,大块充填树脂(bulk-fill resin-based composite)应运而生,改良的基质单体、改性强化的纳米混合填料以及独特的光引发剂,使得大块充填树脂能够一层充填4 mm,其简化操作步骤、节约椅旁时间、并能显著降低聚合收缩和聚合应力.本文就大块充填树脂的分类、固化原理、性能等方面进行阐述和讨论,并提出大块充填树脂的应用发展方向.     

淫羊藿素对 SD 大鼠骨髓基质细胞增殖与成骨分化的影响

目的：研究淫羊藿素（ICT）对体外培养 SD 大鼠骨髓基质细胞（rBMSCs）增殖与成骨分化的影响。方法：体外分离培养 rBMSCs,传代至第4代作多向分化鉴定。分别以10－9、10－8、10－7、10－6、10－5 mol／L ICT 刺激 rBMSCs 后3、6、9 d,分别用 cck-8及碱性磷酸酶 ALP 试剂盒检测 rBMSCs 的增殖及 ALP 活性;10－9 mol／L ICT 处理 rBMSCs 后21 d 作茜素红（AR）染色以判断钙结节的形成。结果：原代培养的 rBMSCs 贴壁生长、呈梭形,能多向分化;ICT 明显抑制了 rBMSCs 的增殖;但增高其 ALP 活性、钙结节形成。结论：ICT 以剂量依赖方式抑制 rBMSCs 的增殖但促进其分化和矿化。     

Addition of obliquely crossed spherocylindrical lenses

This paper presents a three-step method for the addition of obliquely crossed spherocylinders. Contrary to other methods it does not require algorithms or complicated abstract concepts to secure the consistency of the results.     

Priming and boosting of the rabbit intestinal immune system with live and killed, smooth and rough Vibrio cholerae cells

Cholera disease can be induced in the rabbit by ligation of the cecum (C) followed by duodenal inoculation (DI) of virulent Vibrio cholerae organisms (DIC model). When the cecum is not ligated, DI does not induce disease. In contrast, the animals are primed which becomes apparent upon challenge with live V. cholerae in the DIC model. Such animals are vibriocidally protected. This protection is characterized by absence of disease symptoms, rapid disappearance of V. cholerae from the feces and presence of high levels of anti-lipopolysaccharide Immunoglobulin A in the bile. The present study shows that primed rabbits can also be boosted by duodenal administration of killed, smooth V. cholerae cells. On the other hand, killed cells cannot prime. The minimal lethal dose of a rough derivative of a smooth strain C5, designated R5 and lacking the O antigen part of the LPS, was 100,000 times higher than that of its parent strain C5, in the DIC model. Rabbits which had been duodenally immunized with strain R5 and were subsequently challenged with the smooth strain C5, all developed diarrhea and two out of eight died. This result supports an earlier observation that the specific O antigen part of the V. cholerae LPS is an essential prerequisite for the induction of protective immunity in the rabbit.     

A menopause-specific quality of life questionnaire: development and psychometric properties

Objective:

to develop a condition-specific quality of life questionnaire for the menopause with documented psychometric properties, based on women's experience. Methods: Subjects: Women 2–7 years post-menopause with a uterus and not currently on hormone replacement therapy. Questionnaire development: A list of 106 menopause symptoms was reduced using the importance score method. Replies to the item-reduction questionnaire from 88 women resulted in a 30-item questionnaire with four domains, vasomotor, physical, psychosocial and sexual, and a global quality of life question. Psychometric properties: A separate sample of 20 women was used to determine face validity, and a panel of experts was used to confirm content validity. Reliability, responsiveness and construct validity were determined within the context of a randomized controlled trial.Construct validation involved comparison with the Neugarten and Kraines' Somatic, Psychosomatic and Psychologic subscales, the reported intensity of hot flushes, the General Well-Being Schedule, Channon and Ballinger's Vaginal Symptoms Score and Libido Index, and the Life Satisfaction Index.

Results:

The face validity score was 4.7 out of a possible 5. Content validity was confirmed. Test-retest reliability measures, using intraclass correlation coefficients were 0.81, 0.79, 0.70 and 0.55 for the physical, psychosocial, sexual domains and the quality of life question. The intraclass correlation coefficient for the vasomotor domain was 0.37 but there is evidence of systematic change. Discriminative construct validity showed correlation coefficients of 0.69 for the physical domain, 0.66 and 0.40 for the vasomotor domain, 0.65 and −0.71 for the psychosocial domain, 0.48 and 0.38 for the sexual domain, and 0.57 for the quality of life question. Evaluative construct validity showed correlation coefficients of 0.60 for the physical domain, 0.28 for the vasomotor domain, 0.55 and −0.54 for the psychosocial domain, 0.54 and 0.32 for the sexual domain, and 0.12 for the quality of life question. Responsiveness scores ranged from 0.78 to 1.34.

Conclusions:

The MENQOL (Menopause-Specific Quality of Life) questionnaire is a self-administered instrument which functions well in differentiating between women according to their quality of life and in measuring changes in their quality of life.