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Tang L.Y.,Chinese University of Hong Kong | Li L.,Chinese University of Hong Kong | Borchert A.,University of Medicine Berlin | Lau C.B.S.,Chinese University of Hong Kong | And 2 more authors.
Molecular Human Reproduction | Year: 2012

Largehead Atractylodes Rhizome (LAR) is the most commonly used Chinese herbal medicine for threatened miscarriage. Potential reproductive toxicity of LAR was identified in early pregnancy in animals. Skeletal anomalies including loss of ulna and distal digits, shortening of humerus and radius were observed in higher clinical dose groups. Here, we aimed to study the molecular mechanism of the congenital malformation induced by LAR. In vitro whole mouse embryo culture was used to confirm the embryotoxicity effects of LAR on developing limb buds during early organogenesis. A pregnant mouse model was employed to study the developmental gene expression by quantitative PCR and whole hybridization and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling staining, in the forelimbs and hindlimbs during development in vivo. Severe growth retardation, multiple embryonic malformations and delayed limb bud development were observed. Limb-specific Tbx gene expressions in both developing forelimbs and hindlimbs were significantly decreased. Increased developmental apoptosis in apical ectodermal ridge and mesenchymal mesoderm of the developing limb buds was identified. Overexpressions of Tbx2 and Tbx3 in embryos in vitro rescued LAR-induced abnormal limb development and reduced apoptosis in the developing forelimb buds. In conclusion, LAR affects limb development by suppressing the expression of limb developmental genes and disturbing programmed cell death during limb formation in mice. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Jacobs J.W.G.,University Utrecht | Da Silva J.A.P.,University of Coimbra | Armbrecht G.,University of Medicine Berlin | Bijlsma J.W.J.,University Utrecht | Verstappen S.M.M.,University Utrecht
Journal of Rheumatology | Year: 2010

Objective. To investigate basic assumptions of prediction models for future vertebral fractures. Methods. Lateral radiographs of the spine were obtained from 314 Portuguese individuals aged 60 years or older (205 women and 109 men) with bone mineral density (BMD) measurements at several sites. Associations between BMD at various sites, participant characteristics, and vertebral fractures were investigated. For men and women separately, logistic regression analyses and analyses of areas under the receiver-operating characteristic (ROC) curves were performed to determine the accuracy of BMD measurment at predicting the presence of vertebral deformities. Results. BMD measurements at all sites significantly predicted the presence of osteoporotic vertebral deformities in women but not in men. Similarly, in analyses of areas under ROC curves, BMD assessments were statistically significantly related to vertebral deformities in women but not in men. In multivariate analyses, BMD measurements of the lumbar spine and of the forearm, adjusted for gender, age, and body mass index, significantly predicted the presence of vertebral deformity, but BMD of the hip sites did not. Conclusion. Prediction of fractures is specific for gender and site of BMD measurement. This challenges the use of similar algorithms for men and women as well as the use of hip BMD data to accurately estimate future vertebral fracture risk. The Journal of Rheumatology Copyright © 2010. All rights reserved.

Tiburzy B.,University of Lubeck | Kulkarni U.,University of Lubeck | Hauser A.E.,University of Medicine Berlin | Abram M.,University of Marburg | Manz R.A.,University of Lubeck
Seminars in Immunopathology | Year: 2014

Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells. © 2014 Springer-Verlag.

Oude Ophuis C.M.C.,Netherlands Cancer Institute | Verhoef C.,Netherlands Cancer Institute | Rutkowski P.,Center of Oncology of Poland | Powell B.W.E.M.,St Georges, University of London | And 9 more authors.
European Journal of Surgical Oncology | Year: 2016

Background: Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. Aim: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Methods: Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Results: Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00 mm (1.90-5.00 mm) vs 3.00 mm (1.90-4.43 mm) (p = 0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p = 0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS. Conclusions: Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients. © 2016.

Schmidt S.C.,University of Medicine Berlin | Schumacher G.,University of Medicine Berlin | Klage N.,Clinic for General and Visceral Surgery | Chopra S.,University of Medicine Berlin | And 2 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2010

Background: In recent years, laparoscopic hepatic resection is performed by an increasing number of surgeons. Despite many advantages of the laparoscopic procedure, it is unclear whether the pneumoperitoneum affects the postoperative liver regeneration after liver resection. The current study aimed to investigate the influence of a carbon dioxide (CO2) pneumoperitoneum on liver regeneration in a rat model. Methods: In this study, 60 male Wistar rats were subjected to 70% partial hepatic resection. Of these 60 animals, 30 underwent preoperative pneumoperitoneum at 9 mmHg for 60 min. After hepatic resection, the rats were killed at 12, 24, and 48 h, and on days 4 and 7. The outcome parameters were hepatocellular injury (plasma aminotransferases), oxidative stress (plasma malondialdehyde), interleukin-6 (IL-6), and liver regeneration (mitotic index, KI-67; regenerating liver mass). Results: The mitotic index was significantly lower in the pneumoperitoneum group than in the group without pneumoperitoneum at all time points (p < 0.05). In the pneumoperitoneum group, KI-67 was significantly lower on day 4 (p < 0.05). The liver regeneration rate was significantly lower for the animals with pneumoperitoneum on days 2 and 4 (p < 0.05). The postoperative hepatocellular injury was significantly greater after pneumoperitoneum at 12, 24, and 48 h (p < 0.05). Plasma malondialdehyde and IL-6 were significantly higher in the pneumoperitoneum group at 24 h and on day 4 (p < 0.05). Conclusion: This study showed that pneumoperitoneum before extended liver resection impaired postoperative liver regeneration. Oxidative stress reaction and hepatocellular damage was markedly higher after pneumoperitoneum. Further investigations, especially with patients that have impaired liver function, are necessary for clinical consequences to be drawn from these results. © 2009 Springer Science+Business Media, LLC.

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