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Introduction: Locally implanted antibiotic-eluting carriers may be a valuable adjuvant to the management of prosthetic joint infections. Aim: to assess local and plasma antibiotic concentrations as well as cumulative antibiotic urine excretion associated with clinical use of a gentamicin - or vancomycin-loaded mineral composite antibiotic carrier.Methods: 32 patients (male/female=19/13, mean age=56; 21-82 years) were prospectively followed after implantation of gentamicin (n=11), vancomycin (n=15), or a combination (n=7), using an antibiotic carrier (CERAMENT™|G or CERAMENT™|V, mean amount 11 (3-20) mL) during resection arthroplasty of the hip/knee. We measured antibiotic concentrations in plasma (1h, 3h, 24h, 48h and 72h post-implantation), urine (24h, 48h and 72h post-implantation) and in drain (n=15).Results: We observed low antibiotic concentrations in plasma (Gentamicin: 0.33 mg/L (95%-CI: 0.25-0.44) and vancomycin: 1.33 mg/L (95%-CI: 1.02-1.66)) and high concentrations in drain (Gentamicin: mean 57.8 mg/L (95%-CI: 45.8-69.7) and vancomycin: mean 234.4 mg/L (95%-CI: 198.9-269.7)). Use of a drain was associated with a statistically significant reduction in vancomycin urine excretion (55.6% (95% CI: 36.45-74.92) to 28.71% (95% CI: 13.07-44.35), p=0.042). A similar trend was observed for gentamicin (34.17% (95% CI: 24.62-43.72) to 16.22% (95% CI: 0-33.86), p=0.078).Conclusions: CERAMENT™G/V was associated with safe plasma concentrations and high local concentrations above minimum inhibitory concentration. Installation of a surgical drain results in removal of a substantial amount of antibiotics and reduces antibiotic urine excretion.

Objectives: The objective is to present the antibiotic elution from a locally implanted gentamicin containing hydroxyapatite and calcium sulphate bone substitute with an extended follow up of 30 days.We also compare the pharmacokinetics of the ceramic bone substitute with a published study on gentamicin containing poly (methyl methacrylate) (PMMA) bone cement used in primary total hip arthroplasty.Methods: Gentamicin release was measured in the urine for a month and the serum for 4 days in 10 patients operated for trochanteric hip fractures and 10 patients in uncemented hip revisions. 17 patients were followed up at one year and 3 patients at 6 months.Results and Discussion: The gentamicin concentrations measured in serum were low and approximately 100 times less than in urine during the first days, indicating high local concentrations at the implant site. The elution from the biphasic bone substitute showed a stronger burst and higher gentamicin concentrations for the first week compared to that reported for PMMA used in hip arthroplasty. Also, for the bone substitute a complete gentamicin elution was obtained after 30 days, while for the PMMA cement sub-inhibitory MIC levels of gentamicin were still present in urine 60 days past surgery. No infections were detected.Conclusions: A new biphasic bone substitute containing antibiotics could potentially be used to prevent infection in patients treated for trochanteric hip fractures or uncemented hip revisions. The gentamicin elution from the bone substitute is efficient with high initial local gentamicin concentrations and complete release at 30 days.

Gamma irradiation induces DNA damage to mature bovine spermatozoa but does not affect motility, membrane integrity, or function (Fatehi et al. 2006 J. Androl. 27, 176–188), making it a useful model to evaluate the effect of fertilization with DNA-damaged spermatozoa. The objective of the present study was to analyze the fertilizing capacity of frozen–thawed gamma-irradiated sperm from 2 bulls: a bull with a high sperm quality and fertilization rate (bull A), and a bull with a low sperm quality and fertilization rate (bull B). To ensure that DNA damage was induced, frozen–thawed semen was exposed to a high dose of irradiation (90 Gy). Cumulus–oocyte complexes were obtained from abattoir ovaries and were in vitro-matured (IVM) using standard procedures (23 h in DMEM with 5% serum and eCG/hCG). For each treatment group, 3 to 5 straws of semen from the same ejaculate were used. After thawing, semen from the 2 bulls was either irradiated or held at room temperature before 1:1 dilution in sperm-TALP. During irradiation, semen was kept in the straws. The irradiated and nonirradiated sperm were used for IVF (23 h in IVF-TALP) within 1 h of thawing. IVM and IVF were carried out at 38.5C in 5% CO2 in air. After IVF, presumptive zygotes were whole mount-fixed and 24 h later were stained with 1% aceto-orcein followed by determination of fertilization status. Fertilization was considered normal if 2 pronuclei (PN) were present. A total of 4 replicates were performed and 286 zygotes analyzed. No difference was detected between replicates, and the results were pooled. Fisher''s exact test was used to determine effect of treatment. More zygotes had 2 PN after fertilization with semen from bull A (47/67 = 70%), compared with that from bull B (16/71 = 23%; P < 0.0001) using nonirradiated sperm. Irradiation of sperm significantly increased the fraction of zygotes with 2 PN from bull A (61/70 = 87%; P = 0.03), but decreased the 2 PN fractions in zygotes fertilized with sperm from bull B (2/75 = 3%; P = 0.0002). Ideally, to avoid straw variation, semen should have been pooled and divided into groups before irradiation. The variation between straws might explain the higher fertilization rates in bull A using irradiated sperm compared with nonirradiated sperm. In conclusion, there appear to be differences in fertilizing ability between bulls after irradiation of frozen–thawed sperm. This could be due to suboptimal DNA packaging, which made sperm from bull B more susceptible to radiation-induced damage. The potential irradiation-induced increase in DNA fragmentation in sperm from bull B compared with that from bull A might delay or prevent the formation of the 2 PN. Further studies are needed to investigate differences in fertilization and early embryonic development using sperm with intact or damaged DNA. [ABSTRACT FROM AUTHOR]

In a prospective study, we evaluated the adaptive bone remodelling pattern of the distal femur using dual energy X-ray absorptiometry (DEXA) after total knee arthroplasty (TKA). Eleven patients underwent TKA with insertion of an Interax total knee system (Howmedica) because of primary osteoarthrosis of the knee. All patients received an uncemented femoral component with an uncoated cast-mesh ingrowth surface. The components had a 20-mm long central peg placed anteriorly just behind the anterior flange. DEXA scans were performed postoperatively at 2 weeks and at 3, 6, 12 and 24 months in the mediolateral plane of the distal femur and in the anteroposterior plane of the distal tibia and fibula. Compared to the immediate 2-week postoperative bone mineral density (BMD) value, we found no significant changes in BMD in 4 regions of interest (ROI) in the distal femur during the 2-year follow-up at 3 months. A temporary but significant decrease in BMD of 11.2% (95% CL, -17.3% to -5.0%) was observed in the most distal ROI just posterior to the fixation peg. Bone mineral content (BMC) of the distal tibia and fibula showed no significant changes in the operated and contralateral legs during the follow-up. The adaptive bone remodelling of the distal femur after TKA using an uncemented femoral component not previously examined by DEXA induced only a very limited and temporary loss of bone mineral. [ABSTRACT FROM AUTHOR]

Background and Purpose: Revision total hip arthroplasty (rTHA) is a challenging procedure especially in the presence of severe bone loss where implant fixation is compromised. The aim of this study was to evaluate implant survival, clinical outcome, and midterm results in a group of complex patients after femoral revision using an uncemented modular implant design. Patients and Methods: We performed a retrospective study including 100 patients (101 hips) treated with revision THA using an uncemented modular implant design. We identified 51 hips as Paprosky types I-II and 50 hips as Paprosky III-IV bone defects. We reviewed operative reports and radiographs. Patients underwent a clinical examination to assess the Harris Hip Score (HHS) and completed patient-reported outcome measures (PROM), including the Oxford Hip Score (OHS) and the EQ-5D Visual Analog Scale (VAS). Minimum follow-up was 2 years (average, 5.8 years; range, 2.0-9.4 years). Results: Among the cases, 46 hips were revised for infection in a 2-stage procedure and 44 hips for aseptic loosening. 11 hips had periprosthetic fractures of Vancouver type B2 or B3. A total of 5 hips required revision with removal of the femoral implant and 11 patients experienced complications resulting in fracture ( n  = 1), dislocation ( n  = 10), and soft tissue revision ( n  = 1). The 5-year implant survival estimated by Kaplan-Meier survival analysis was 95% (95%-CI: 91%-99%). All hips had radiographic evidence of osseointegration and no one with subsidence greater than 5 mm. Additionally, 80% showed radiographic evidence of restoration of proximal femoral bone. Mean HHS was 78. Conclusion: In complex cases of revision THA, using a modular revision femoral system yielded promising results. The 5-year implant survival estimated by Kaplan-Meier survival analysis was 95% (95%-CI: 91%-99%), with all hips demonstrating radiographic evidence of osseointegration and no one with subsidence greater than 5 mm. Notably 80% showed radiographic evidence of restoration of proximal femoral bone., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Sebastian Winther et al.)

Introduction: New Zealand's shortage of medical imaging technicians has intensified due to factors like illness, the pandemic, and an ageing workforce. Addressing staff retention issues requires attention to intrinsic factors like workplace satisfaction and work-life balance. Self-rostering has proven effective in healthcare by enhancing work-life balance, job satisfaction, and retention, but it has not been implemented widely in radiology. This study aimed to explore the perceptions, benefits, and challenges of implementing AI-generated self-rostering in a radiology department through simulated trials., Methods: This study simulated an AI-generated roster in a regional New Zealand radiology department, engaging 23 staff members. A mixed-methods approach included surveys and discussion groups. Community-based participatory action methodology guided discussion groups and informed modifications., Results: The AI-generated self-rostering method demonstrated success by meeting a high percentage of shift preferences while fulfilling service demands. Participants perceived potential benefits in work-life balance and autonomy, though uncertainties persisted regarding implementation and fairness. Despite staff reservations, we found that an AI-generated self-rostering system may be fairer than manual self-rostering, while saving radiology staff time and cost., Conclusion: AI-generated self-rostering offers an innovative solution to an old problem. This self-rostering system provides a fair way for staff to have a say in the shifts they do, which increases feelings of work-life balance and autonomy. In this simulation, AI-generated self-rostering was well received, and most staff were receptive to moving to pilot the programme., Implications for Practice: Self-rostering could be a potential solution to staff retention issues in radiology; we recommend a pilot study is implemented. When switching to self-rostering, departments should consider implementing one-on-one support systems to assist staff with entering preferences. Education is essential to encourage staff understanding and cooperation., Competing Interests: Conflict of interest statement None., (Copyright © 2024 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Purpose: Recurrence is a known complication to inguinal herniotomy with an incidence of 10 to 15 percent (Hernia Surge Group in Hernia 22:165, 2018). Previous studies have shown that direct hernia or large defects are risk factors for postoperative seroma formation (Morito et al. in Surg Endosc https://doi.org/10.1007/s00464-021-08814-2 , 2021). These types of defects are often closed during open herniotomy (Rosenberg et al. in Dan Med Bull 58: C4243, 2011). This is not routine during laparoscopic surgery. A recent study has indicated that closure of the medial defect during laparoscopy may reduce recurrence and seroma formation. As a result, we performed the present systematic review to evaluate the efficacy of this add on to the standard procedure., Methods: An extensive search was carried out in PubMed and Embase. All studies involving adults undergoing laparoscopic direct hernioplasty were enrolled and screened with predefined inclusion criteria, to be part of a systematic review with data synthesis and meta-analysis., Results: The search identified 108 publications of which four met the inclusion criteria. Two studies (Ng et al. in Hernia 24:1093-1098, 2020; Usmani et al. in Hernia 24:167-171, 2020) showed reduced risk of recurrence. The remaining studies (Zhu et al. in Surg Laparosc Endosc Percutan Tech 29:18-21, 2019; Li and Zhang in Surg Endosc 32:1082-1086, 2018) reported no recurrence in any of the patients included. Two articles (Usmani et al. in Hernia 24:167-171, 2020; Zhu et al. in Surg Laparosc Endosc Percutan Tech 29:18-21, 2019) showed a decrease in risk of postoperative seroma, one showed a significant increase (Ng et al. in Hernia 24:1093-1098, 2020). None of the included studies showed an increase in the risk of postoperative pain or postoperative complications., Conclusion: This review suggests that closure versus non-closure of the medial hernia defect in laparoscopic inguinal hernioplasty reduces the risk of recurrence and seroma formation without an increase in postoperative pain or complications. Further randomized controlled trials are needed for further evaluation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Four large community-randomized trials examining universal testing and treatment (UTT) to reduce HIV transmission were conducted between 2012-2018 in Botswana, Kenya, Uganda, Zambia and South Africa. In 2014, the UNAIDS 90-90-90 targets were adopted as a useful metric to monitor coverage. We systematically review the approaches used by the trials to measure intervention delivery, and estimate coverage against the 90-90-90 targets. We aim to provide in-depth understanding of the background contexts and complexities that affect estimation of population-level coverage related to the 90-90-90 targets., Methods: Estimates were based predominantly on "process" data obtained during delivery of the interventions which included a combination of home-based and community-based services. Cascade coverage data included routine electronic health records, self-reported data, survey data, and active ascertainment of HIV viral load measurements in the field., Results: The estimated total adult populations of trial intervention communities included in this study ranged from 4,290 (TasP) to 142,250 (Zambian PopART Arm-B). The estimated total numbers of PLHIV ranged from 1,283 (TasP) to 20,541 (Zambian PopART Arm-B). By the end of intervention delivery, the first-90 target (knowledge of HIV status among all PLHIV) was met by all the trials (89.2%-94.0%). Three of the four trials also achieved the second- and third-90 targets, and viral suppression in BCPP and SEARCH exceeded the UNAIDS target of 73%, while viral suppression in the Zambian PopART Arm-A and B communities was within a small margin (~ 3%) of the target., Conclusions: All four UTT trials aimed to implement wide-scale testing and treatment for HIV prevention at population level and showed substantial increases in testing and treatment for HIV in the intervention communities. This study has not uncovered any one estimation approach which is superior, rather that several approaches are available and researchers or policy makers seeking to measure coverage should reflect on background contexts and complexities that affect estimation of population-level coverage in their specific settings. All four trials surpassed UNAIDS targets for universal testing in their intervention communities ahead of the 2020 milestone. All but one of the trials also achieved the 90-90 targets for treatment and viral suppression. UTT is a realistic option to achieve 95-95-95 by 2030 and fast-track the end of the HIV epidemic., (© 2022. The Author(s).)

Objective: Sunscreens play a major role in the EU sun protection strategy in order to prevent humans from UV light-induced skin damage. In recent years, the demand for high-quality sunscreen products including aspects of broad range and photostability of the UV protection, showing good spreadability onto human skin and excellent sensorial properties during and after application has increased. Environmental aspects are considered. Sunscreens are complex compositions, with UV filters being the key element in the formulations reaching up to about 30% in content in the final product. Some of these ingredients, however, may be regarded as hazardous for the aquatic environment. Nevertheless, the aquatic ecosystem represents only a single environmental compartment, which may be impacted by UV filters. Therefore, the EcoSun Pass (ESP) tool was developed in order to assess the overall environmental impact of UV filters in combination with its efficacy (Sun Protection Factor, SPF and UVA Protection Factor, UVA-PF)., Methods: For that purpose, at first 24 of the EU-approved UV filters for sunscreen applications were evaluated for their environmental hazard profiles. Nine example UV filter compositions representing both SPF 30 and 50 were evaluated for ecofriendliness using the ESP tool., Results: The results revealed that two out of four SPF 30 compositions are considered as ecofriendly. Likewise, from the SPF 50 two out of five did meet the criteria for ecofriendliness. Furthermore, the results showed that most ecofriendly example formulations have also the lowest overall UV filter content in the product, based on the use of highly innovative and least hazardous UV filters., Conclusion: These results demonstrate that the tool is applicable to various formulations being present on the market and thus allows for a selection of most ecofriendly and efficient UV filters to be used in sunscreens., (© 2020 The Authors. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

Background: Haemophilic arthropathy is a chronic and debilitating joint disease caused by recurrent spontaneous joint bleeds in patients with haemophilia. Understanding how characteristics of individual joint bleeds relate to the subsequent development of arthropathy could improve management and prevention of this joint disease. Here, we aimed to explore relations between joint bleed characteristics and development of bone pathology in a mouse model of haemophilic arthropathy by using novel in vivo imaging methodology., Methods: We characterised induced knee bleeds in a murine model of haemophilic arthropathy by quantitative in vivo fluorescence molecular tomography (FMT) and by measurements of changes in the diameter of the injured knee. Wild-type mice and non-injured haemophilic mice acted as controls. Development of arthropathy was characterised by post mortem evaluation of bone pathology by micro-CT 14 days after bleed-induction. In an in vitro study, we assessed the effect of blood on the quantification of fluorescent signal with FMT., Results: In most injured haemophilic mice, we observed significant loss of trabecular bone, and half of the mice developed pathological bone remodelling. Development of pathological bone remodelling was associated with significantly increased fluorescent signal and diameter of the injured knee just 1 day after induction of the bleed. Further, a correlation between the fluorescent signal 1 day after induction of the bleed and loss of trabecular bone reached borderline significance. In the in vitro study, we found that high concentrations of blood significantly decreased the fluorescent signal., Conclusion: Our results add novel insights on the pathogenesis of haemophilic arthropathy and underline the importance of the acute phase of joint bleeds for the subsequent development of arthropathy.

Introduction: Alzheimer disease (AD) is a neurodegenerative disease characterised by progressive dementia associated with global cognitive dysfunction., Methods: We conducted a systematic review and meta-analysis of clinical trials evaluating omega-3 supplementation in patients with AD., Objective: To determine if there is scientific evidence of the effectiveness of omega-3 supplementation in improving cognitive function in patients with AD., Search Strategy: We included only randomised controlled trials (RCTs) from the following databases: Medline, Cochrane Central, Cinahl, and LILACS. An electronic search was also conducted using Google Scholar., Study Selection: Six articles met the eligibility criteria. The risk of bias was assessed following the Cochrane method., Conclusion: There is no consistent evidence to support the effectiveness of omega-3 supplementation in improving cognitive function in AD patients in the short and medium term., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Survival predictions before surgery for metastatic bone disease in the extremities (based on statistical models and data of previous patients) are important for choosing an implant that will function for the remainder of the patient's life. The 2008-SPRING model, presented in 2016, enables the clinician to predict expected survival before surgery for metastatic bone disease in the extremities. However, to maximize the model's accuracy, it is necessary to maintain and update the patient database to refit the prediction models achieving more accurate calibration., Questions/purposes: The purposes of this study were (1) to refit the 2008-SPRING model for prediction of survival before surgery for metastatic bone disease in the extremities with a more modern cohort; and (2) to evaluate the performance of the refitted SPRING model in a population-based cohort of patients having surgery for metastatic bone disease in the extremities., Methods: We produced the 2013-SPRING model by adding to the 2008-SPRING model (n = 130) a cohort of patients from a consecutive institutional database of patients who underwent surgery for bone metastases in the extremities with bone resection and reconstruction between 2009 and 2013 at a highly specialized surgical center in Denmark (n = 140). Currently the model is only available as the nomogram fully available in the current article, which is sufficient to use in daily clinical work, but we are working on making the tool available online. As such, the 2013-SPRING model was produced using a consecutive cohort of patients (n = 270) treated during an 11-year period (2003-2013) called the training cohort, all treated with bone resection and reconstruction. We externally validated the 2008-SPRING and the 2013-SPRING models in a prospective cohort (n = 164) of patients who underwent surgery for metastatic bone disease in the extremities from May 2014 to May 2016, called the validation cohort. The validation cohort was identified from a cross-section of the Danish population who were treated for metastatic lesions (using endoprostheses and internal fixation) in the extremities at five secondary surgical centers and one highly specialized surgical center. This cross-section is representative of the Danish population and no patients were treated outside the included centers as a result of public healthcare settings. The indications for surgery for training and the validation cohort were pathologic fracture, impending fracture, or intractable pain despite radiation. Exact date of death was known for all patients as a result of the Danish Civil Registration System and no loss to followup existed. In the training cohort, 150 patients (out of 270 [56%]) and in the validation cohort 97 patients (out of 164 [59%]) died of disease within 1 year postoperatively. The 2013 model did not differ from the 2008 model and included hemoglobin, complete fracture/impending fracture, visceral and multiple bone metastases, Karnofsky Performance Status, and the American Society of Anesthesiologists score and primary cancer. The models were evaluated by area under the receiver operating characteristic curve (AUC ROC) and Brier score (the lower the better)., Results: The 2013-SPRING model was successfully refitted with a cohort using more patients than the 2008-SPRING model. Comparison of performance in external validation between the 2008 and 2013-SPRING models showed the AUC ROC was increased by 3% (95% confidence interval [CI], 0%-5%; p = 0.027) and 2% (95% CI, 0%-4%; p = 0.013) at 3-month and 6-month survival predictions, respectively, but not at 12 months at 1% (95% CI, 0%-3%; p = 0.112). Brier score was improved by -0.018 (95% CI, -0.032 to -0.004; p = 0.011) for 3-month, -0.028 (95% CI, -0.043 to -0.0123; p < 0.001) for 6-month, and -0.014 (95% CI, -0.025 to -0.002; p = 0.017) for 12-month survival prediction., Conclusions: We improved the SPRING model's ability to predict survival after surgery for metastatic bone disease in the extremities. As such, the refitted 2013-SPRING model gives the surgeon a tool to assist in the decision-making of a surgical implant that will serve the patient for the remainder of their life. The 2013-SPRING model may provide increased quality of life for patients with bone metastasis because potential implant failures can be minimized by precise survival prediction preoperatively and the model is freely available and ready to use from the current article., Level of Evidence: Level I, diagnostic study.

Essentials N8-GP is an extended half-life recombinant factor VIII (FVIII) for the treatment of hemophilia A. Subcutaneous (SC) FVIII dosing might reduce the treatment burden of prophylaxis. SC N8-GP has a favorable PK profile in animal models and disappears from skin injection sites. Combined animal (SC) and clinical (IV) data suggest that daily SC dosing may provide prophylaxis., Summary: Background N8-GP is an extended half-life recombinant factor VIII (FVIII) for the treatment of hemophilia A. Subcutaneous administration of FVIII may reduce the treatment burden of prophylaxis; however, standard FVIII products have low bioavailability after subcutaneous dosing in animals. Objective To evaluate the pharmacokinetics, effectiveness and local distribution of subcutaneously administered N8-GP in preclinical models and predict the human pharmacokinetic (PK) profile. Methods The pharmacokinetics of subcutaneously administered N8-GP were evaluated in FVIII knockout (F8-KO) mice and cynomolgus monkeys; a human PK prediction model in hemophilia A patients was developed. The hemostatic effect was evaluated in a tail vein bleeding model in F8-KO mice. The injection-site distribution and absorption of subcutaneously administered N8-GP were assessed in F8-KO mice by the use of temporal fluorescence imaging and immunohistochemistry. Results Subcutaneously administered N8-GP had a bioavailability, a first-order absorption rate and a half-life, respectively, of 24%, 0.094 h -1 and 14 h in F8-KO mice, and 26%, 0.33 h -1 and 15 h in cynomolgus monkeys. A dose-dependent effect of subcutaneously administered N8-GP on blood loss was observed in mice. A minimal amount of N8-GP was detected at the injection site 48-72 h after single or multiple dose(s) in F8-KO mice. Subcutaneously administered N8-GP was localized to the skin around the injection site, with time-dependent disappearance from the depot. PK modeling predicted that subcutaneously administered N8-GP at a daily dose of 12.5 IU kg -1 will provide FVIII trough levels of 2.5-10% in 95% of patients with severe hemophilia A. Conclusions Subcutaneously administered N8-GP may provide effective hemophilia A prophylaxis. A phase I clinical trial is underway to investigate this possibility., (© 2018 Novo Nordisk A/S. Journal of Thombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society of Thombosis and Haemostasis.)

Bretschneider (histidine-tryptophan-ketoglutarate) solution with its high histidine concentration (198 mM) is one of many cardioplegic solutions, which are routinely used for cardiac arrest. The aim of this study was to evaluate the physiological biochemical degradation of administered histidine to histamine and its major urinary metabolite N-methylimidazole acetic acid. A total number of thirteen consecutive patients scheduled for elective isolated coronary artery bypass grafting with cardiopulmonary bypass were enrolled in the prospective observational designed study at the Department of Thoracic and Cardiovascular Surgery between 04/2016 and 06/2016. Patients received 1.7 l Bretschneider solution on average. Before and at the end of operation as well as in the postoperative course, urine samples gathered from the urinary catheter bag were analyzed. During the operative period, urinary histidine concentration significantly increased from 29 micromol/mmol creatinine to 9,609 micromol/mmol creatinine. Postoperatively, histidine excretion reduced while histamine as well as N-methylimidazole acetic acid excretion rose significantly. Patients showed elevated levels of histidine, histamine as well as N-methylimidazole acetic acid in urine, but no unmanageable hemodynamic instability possibly arising from the histamine's biological properties. Chemically modified histidine might reduce uptake and metabolization while maintaining the advantages of buffer capacity.

Background: Persistent or increased long-term opioid consumption has previously been described following total hip- (THA) and knee arthroplasty (TKA). However, detailed information on postoperative analgesic consumption trajectories and risk factors associated with continued need of analgesics in fast-track THA and TKA is sparse., Methods: This is a descriptive multicentre study in primary unilateral fast-track THA or TKA with prospective data on patient characteristics and information on reimbursement entitled dispensed prescriptions of paracetamol, non-steroidal anti-inflammatory drugs, opioids, anticonvulsants and antidepressants 1 month preoperatively and 1 year postoperatively. Patients were stratified according to preoperative opioid use. Postoperative analgesic consumption trajectories were stratified as increased, decreased or no use compared to the preoperative period., Results: Of 8975 patients (4849 THA/4126 TKA), 33.9% had relevant reimbursed prescriptions 9-12 months postoperatively. Of 2136 (23.8%) patients with preoperative opioid use, 3.4% had unchanged opioid consumption at 9-12 months postoperatively. However, increased opioid consumption after 9-12 months occurred in 17.6 (TKA) and 10.2% (THA) compared to 9.9 and 6.3% in opioid-naive TKA and THA patients, respectively. Increased NSAID and paracetamol use was seen in 11.5 and 12.4% of all patients. Preoperative analgesic use (any), TKA, psychiatric disorder, tobacco abuse, cardiac disease and use of walking aids were associated with increased opioid consumption., Conclusion: Continued and increased opioid and other analgesic use occur in a clinically significant proportion of fast-track TKA and THA patients 9-12 months postoperatively, suggesting treatment failure and need for early intervention. Preoperative risk assessment may allow identification of patients in risk of increased postoperative opioid consumption., Significance: We found a considerable fraction of patients with continued or increased opioid consumption 9-12 months after fast-track THA and TKA. Increase in opioid consumption was more frequent in preoperative opioid users than opioid-naive patients, but a pattern of increased analgesic consumption was present across all analgesics. Our data demonstrate a need for increased focus on long-term analgesic strategies and postoperative follow-up after THA and TKA, especially in preoperative opioid users., (© 2018 European Pain Federation - EFIC®.)

Introduction: A major complication of haemophilia is haemophilic arthropathy (HA), a debilitating disorder with an incompletely defined pathobiology. High-resolution imaging may provide new knowledge about onset and progression of HA, and thereby support identification of new treatment opportunities. Recently, a F8 -/- rat model of HA was developed. The size of the rat allows for convenient and high resolution imaging of the joints, which could enable in vivo studies of HA development., Aim: To determine whether HA in the F8 -/- rat can be visualized using ultrasonography (US) and micro-computed tomography (μCT)., Methods: Sixty F8 -/- and 20 wild-type rats were subjected to a single or two induced knee bleeds. F8 -/- rats were treated with either recombinant human FVIII (rhFVIII) or vehicle before the induction of knee bleeds. Haemophilic arthropathy was visualized using in vivo US and ex vivo μCT, and the observations correlated with histological evaluation., Results: US and μCT detected pathologies in the knee related to HA. There was a strong correlation between disease severity determined by μCT and histopathology. rhFVIII treatment reduced the pathology identified with both imaging techniques., Conclusion: US and μCT are suitable imaging techniques for detection of blood-induced joint disease in F8 -/- rats and may be used for longitudinal studies of disease progression., (© 2016 John Wiley & Sons Ltd.)

Background: With the recognition of the need for research capacity strengthening for advancing health and development, this research capacity article explores the use of technology enhanced learning in the delivery of a collaborative postgraduate blended Master's degree in Malawi. Two research questions are addressed: (i) Can technology enhanced learning be used to develop health research capacity?, and: (ii) How can learning content be designed that is transferrable across different contexts?, Methods: An explanatory sequential mixed methods design was adopted for the evaluation of technology enhanced learning in the Masters programme. A number of online surveys were administered, student participation in online activities monitored and an independent evaluation of the programme conducted., Results: Remote collaboration and engagement are paramount in the design of a blended learning programme and support was needed for selecting the most appropriate technical tools. Internet access proved problematic despite developing the content around low bandwidth availability and training was required for students and teachers/trainers on the tools used. Varying degrees of engagement with the tools used was recorded, and the support of a learning technologist was needed to navigate through challenges faced., Conclusion: Capacity can be built in health research through blended learning programmes. In relation to transferability, the support required institutionally for technology enhanced learning needs to be conceptualised differently from support for face-to-face teaching. Additionally, differences in pedagogical approaches and styles between institutions, as well as existing social norms and values around communication, need to be embedded in the content development if the material is to be used beyond the pilot resource-intensive phase of a project.

Adolescent patients with inflammatory bowel disease (IBD) show an increased risk for behavioral and emotional dysfunction. Health-related quality of life (HRQoL) is influenced by medical illnesses, as well as by psychiatric disorders, but for adolescents with IBD, the extent to which HRQoL is influenced by these two factors is unclear. For 47 adolescent IBD patients, we analyzed disease activity, HRQoL and whether or not a psychiatric disorder was present. Disease activity was estimated using pediatric Ulcerative Colitis Activity Index and pediatric Crohn's Disease Activity Index. The IMPACT-III and the EQ-5D were used to measure HRQoL and QoL, respectively. In addition, patient and parent diagnostic interviews were performed. 55.3 % patients fulfilled DSM-IV criteria for one or more psychiatric disorders. In all patients, psychiatric comorbidity together with disease activity contributed to a reduction in quality of life. Adolescents with IBD are at a high risk for clinically relevant emotional or behavioral problems resulting in significantly lower HRQoL. We conclude that accessible, optimally structured psychotherapeutic and/or psychiatric help is needed in adolescent patients with IBD.

The antibiotic trimethoprim acts as a folate antagonist. Since trophoblasts are very sensitive to drugs that interfere with the folic acid cycle and thereby inhibit DNA synthesis, use of trimethoprim during the first trimester could be associated with miscarriage. A nationwide cohort study including all women in Denmark with a registered pregnancy between 1997 and 2005 was conducted. We used nationwide registers to identify all women giving birth, having a record of miscarriage or induced abortion. Data on exposure to trimethoprim were obtained from the National Prescription Register. Cox proportional hazard regression analysis with exposure to trimethoprim as a time-dependent variable was used to estimate the risk of miscarriage. The adjusted hazard ratio of having a miscarriage after exposure to trimethoprim in the first trimester compared to non-exposure was 2∙04 (95% confidence interval 1∙43-2∙91). Our results indicate that trimethoprim exposure in the first trimester is associated with a doubling of the hazard of miscarriage.

We present three consecutive cases of skeletal dysplasias of a non-consanguineous couple with five pregnancies. The diagnosis of short-rib polydactyly syndrome (SRPS) was feasible by ultrasound during the 1st trimester of pregnancy. SRPS represents a heterogeneous group of lethal skeletal dysplasias. It is characterised by short limb dwarfism complicated by thoracic hypoplasia, polydactyly and different anomalies of major organs such as congenital heart defects and renal dysplasia. Four major types of the SRPS have been described: type I (Saldino-Noonan); type II (Majewski); type III (Verma-Naumoff) and type IV (Beemar-Langer). However, there is phenotypic overlapping between four types and with those of non-lethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). Our cases show the importance of the nuchal translucency (NT) scan that offers the opportunity to examine fetal anatomy in the 1st trimester and diagnose rare skeletal abnormalities early in pregnancy.

Purpose: The aim of this study was to show the different origins and courses of the extracranial VA on CTA with special emphasis on embryological considerations. The duplicated VA is an anomaly that has been assumed to predispose for dissection and to be associated with aneurysms. We report its frequency and clinical significance., Methods: We retrospectively reviewed CTA of 539 patients by using a contrast-enhanced CTA protocol of the VA on CT., Results: Ninety-four-point-two percent of left VA originated from left subclavian artery and entered the transverse foramen at C6 in nearly all cases. Six-point-three-percent of left VA (m = 4 %, f  = 10 %) originated from the aortic arch and entered the transverse foramen either at C4, C5 or C7 but never at C6. One case of an aberrant retroesophageal right VA originated from the aortic arch distal to the left subclavian artery and entered at C7 (0.19 %). All other right VA originated from the right subclavian artery (99.8 %) and entered between C4 and C6. We diagnosed four cases of duplicated VA (0.74 %) with a female predominance (1.9 %) without any signs of dissection on CTA. Two cases with VA duplication had intracranial arterial aneurysms., Conclusions: The VA is a longitudinal anastomosis of segmental metameric arteries. The level of entrance into the transverse foramen indicates which metameric artery or arteries persist. Duplication corresponds to persistence of two segmental arteries and is a rare phenomenon. VA duplication might be associated with vascular lesions.

Background: GB virus C (GBV-C) infection is transmitted by blood exposure and associated with lower human immunodeficiency virus (HIV) load and slower HIV disease progression. Few studies describe predictors of acute GBV-C infection following transfusion in HIV-infected patients., Methods: We used a limited-access database from the National Heart Lung and Blood Institute's Viral Activation Transfusion Study, a randomized controlled trial of leukoreduced versus nonleukoreduced transfusions received by HIV-infected, transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers in pretransfusion and posttransfusion samples. We estimated the risk of acquiring GBV-C RNA and predictors of GBV-C acquisition, using pooled logistic regression., Results: GBV-C RNA was detected ≤120 days following the first transfusion in 22 (7.5%) of 294 subjects who were GBV-C negative before transfusion. The risk of GBV-C RNA acquisition increased with each unit transfused (odds ratio, 1.09; 95% confidence interval, 1.06-1.11). Lower baseline HIV load and use of antiretroviral therapy were associated with subsequent GBV-C RNA acquisition, after control for units of blood transfused. Leukoreduced status of transfused units was not associated with GBV-C transmission., Conclusions: Blood transfusion is associated with a significant risk of GBV-C acquisition among HIV-infected patients. Transmission of GBV-C by blood transfusion was inversely related to HIV load.

Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelial-to-mesenchymal transition by factors like transforming growth factor-β (TGFβ) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFβ, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH(hi)/CD44(hi)/CD24(-/low)) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFβ-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH(hi)/CD44(hi)/CD24(-/low) CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFβ antagonist with anti-metastatic potency.

Ancient autophagy pathways are emerging as key defense modules in host eukaryotic cells against microbial pathogens. Apart from actively eliminating intracellular intruders, autophagy is also responsible for cell survival, for example by reducing the deleterious effects of endoplasmic reticulum stress. At the same time, autophagy can contribute to cellular suicide. The concurrent engagement of autophagy in these processes during infection may sometimes mask its contribution to differing pro-survival and pro-death decisions. The importance of autophagy in innate immunity in mammals is well documented, but how autophagy contributes to plant innate immunity and cell death is not that clear. A few research reports have appeared recently to shed light on the roles of autophagy in plant-pathogen interactions and in disease-associated host cell death. We present a first attempt to reconcile the results of this research.

Programmed cell death (PCD) is an integral part of plant development and of responses to abiotic stress or pathogens. Although the morphology of plant PCD is, in some cases, well characterised and molecular mechanisms controlling plant PCD are beginning to emerge, there is still confusion about the classification of PCD in plants. Here we suggest a classification based on morphological criteria. According to this classification, the use of the term 'apoptosis' is not justified in plants, but at least two classes of PCD can be distinguished: vacuolar cell death and necrosis. During vacuolar cell death, the cell contents are removed by a combination of autophagy-like process and release of hydrolases from collapsed lytic vacuoles. Necrosis is characterised by early rupture of the plasma membrane, shrinkage of the protoplast and absence of vacuolar cell death features. Vacuolar cell death is common during tissue and organ formation and elimination, whereas necrosis is typically found under abiotic stress. Some examples of plant PCD cannot be ascribed to either major class and are therefore classified as separate modalities. These are PCD associated with the hypersensitive response to biotrophic pathogens, which can express features of both necrosis and vacuolar cell death, PCD in starchy cereal endosperm and during self-incompatibility. The present classification is not static, but will be subject to further revision, especially when specific biochemical pathways are better defined.

Aim: We studied the accuracy of bioelectrical impedance analysis (BIA) to assess changes in body composition during moderate weight loss in obese subjects., Methods: Estimates of changes in fat mass (FM) and fat-free mass (FFM) by BIA were compared with those by dual-energy X-ray absorptiometry (DXA) as the reference method during a 10-week standardized weight-loss intervention. In obese women (age: 20-50 years, mean BMI: 33.8 kg/m(2)) participating in a European multicentre trial (nutrient-gene interactions in human obesity [NUGENOB]), body composition was assessed by BIA (Bodystat QuadScan 4000) and DXA (Lunar DPX-IQ at two centres, Hologic QDR 2000 at another centre) at baseline (n=131) and at week 10 (n=105) after a mean weight loss of -5.7 kg., Results: At baseline, BIA significantly overestimated FFM and underestimated FM (by 1-3 kg on average) compared with DXA, and the limits of agreement were wide (mean ± 7-8.5 kg). For body-composition changes, although biases were generally non-significant, the limits of agreement were also wide (mean ± 3.7-4.6 kg). An FFM prediction equation for BIA data was developed in subjects scanned with Lunar instruments and cross-validated in an independent sample of 31 obese women undergoing similar weight loss. However, no major improvement in limits of agreement was found., Conclusion: During moderate diet-induced weight loss, the use of BIA leads to estimates of changes in body composition at the individual level that can differ substantially from those assessed by DXA, indicating that BIA and DXA cannot be used interchangeably. However, BIA in this context may be used for assessing changes in body composition at group level., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Transforming growth factor (TGF)-beta can suppress and promote breast cancer progression. How TGF-beta elicits these dichotomous functions and which roles the principle intracellular effector proteins Smad2 and Smad3 have therein, is unclear. Here, we investigated the specific functions of Smad2 and Smad3 in TGF-beta-induced responses in breast cancer cells in vitro and in a mouse model for breast cancer metastasis. We stably knocked down Smad2 or Smad3 expression in MDA-MB-231 breast cancer cells. The TGF-beta-induced Smad3-mediated transcriptional response was mitigated and enhanced by Smad3 and Smad2 knockdown, respectively. This response was also seen for TGF-beta-induced vascular endothelial growth factor (VEGF) expression. TGF-beta induction of key target genes involved in bone metastasis, were found to be dependent on Smad3 but not Smad2. Strikingly, whereas knockdown of Smad3 in MDA-MB-231 resulted in prolonged latency and delayed growth of bone metastasis, Smad2 knockdown resulted in a more aggressive phenotype compared with control MDA-MB-231 cells. Consistent with differential effects of Smad knockdown on TGF-beta-induced VEGF expression, these opposing effects of Smad2 versus Smad3 could be directly correlated with divergence in the regulation of tumor angiogenesis in vivo. Thus, Smad2 and Smad3 differentially affect breast cancer bone metastasis formation in vivo.

Cystic tumor lesions of the pancreas are relatively uncommon. Advances in imaging and pathohistology, including immunohistochemistry, have led to the detection and classification of novel tumor entities. A promoting aspect is the extended indication profile in pancreatic surgery, in particular, because of lower perioperative morbidity and mortality. One of these classified cystic neoplasms of the pancreas is serous oligocystic adenoma (SOIA), a rare and benign tumor lesion. We report on a 41-year-old man with a cystic lesion within the pancreatic head. Therefore, he underwent pylorus-preserving cephal duodenopancreatectomy. Pathohistologic investigation revealed a SOIA. He had a medical history significant for subtotal colectomy because of a synchronous double colonic carcinoma. Both tumor tissue specimens had been characterized for a high level of microsatellite instability (MSI) and loss of hMLH1, as well as for a corresponding germ line mutation in hMLH1 gene, leading to the diagnosis of hereditary non-polyposis associated colon cancer (HNPCC). The case is remarkable since the SOIA revealed MSI and loss of hMLH1 protein in the tumor cells that has never been reported for this tumor type. In addition, there is a rare and extraordinary association between SOIA and HNPCC, which has never been published before, since SOIA, in this case, could have been developed in the setting of HNPCC syndrome.

We report direct laser spectroscopy of the 1S0-3P0 transition at 265.6 nm in fermionic isotopes of neutral mercury in a magneto-optical trap. Measurements of the frequency against the LNE-SYRTE primary reference using an optical frequency comb yield 1 128 575 290 808.4+/-5.6 kHz in 199Hg and 1 128 569 561 139.6+/-5.3 kHz in 201Hg. The uncertainty, allowed by the observation of the Doppler-free recoil doublet, is 4 orders of magnitude lower than previous indirect determinations. Mercury is a promising candidate for future optical lattice clocks due to its low sensitivity to blackbody radiation.

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE) deficiency and resulting in the storage of abnormal glycogen (polyglucosan). Prenatal diagnosis is based on biochemical assay of GBE activity or on mutation analysis, but polyglucosan can also be identified histologically in fetal tissues. We document placental involvement at 25 and 35 weeks of gestation in two cases with genetically confirmed GSD IV. Intracellular inclusions were seen mainly in the extravillous trophoblast. Our findings suggest the possibility of prenatal diagnosis by histological evaluation of placental biopsies.

Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. Using db/db mice, which develop diabetic nephropathy, we found that GW788388 given orally for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys. Our study shows that GW788388 is a potent and selective inhibitor of TGF-beta signalling in vitro and renal fibrosis in vivo.

A full line-shape analysis of the VT 31P NMR spectra was carried out for the monomer-dimer equilibrium of neutral ZDDP. The energy surface and the energetics of the monomer-dimer equilibrium (DeltaH degrees , DeltaG degrees , Ea, DeltaH(not equal), and DeltaG(not equal)) are reported for three variants wherein the alkyl groups in the ZDDP are 2-ethylhexyl, isopropyl, and isobutyl. We explored a reaction pathway between the monomer and dimer form by means of density functional theory (DFT). The linear combination of atomic orbitals (LCAO) code DMol3 was used together with a synchronous transient method to effectively locate transition states. Vibrational eigenmodes of all intermediates were computed to capture finite temperature effects. Methyl and ethyl were considered as alkyl groups. Two novel intermediates were located-a four-membered ring and a six-membered ring intermediate along the reaction coordinate. Comparison of the experimentally derived and computed energy surfaces was carried out., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Objective: Low density lipoprotein cholesterol (LDL-C) is an independent and modifiable risk factor for development of cardiovascular disease (CVD). Postprandial lipid metabolism has been linked to CVD, but little is known about the postprandial LDL-C profile in patients with type-2 diabetes (T2DM). We aimed to study the postprandial levels of LDL-C in T2DM patients., Material and Methods: After an overnight fast, 74 T2DM patients, mean age approximately 60 years, were served a standard fat-rich meal of 3515 kJ containing 54% fat, 13 % protein and 33 % carbohydrates. Only drinking water was allowed postprandially. Blood samples were drawn at times 0 (fasting), 1.5, 3.0, 4.5 and 6.0 h (postprandial). In all samples, LDL-C was measured with modified beta quantification (separation by ultracentrifugation followed by measurement of infranate high density lipoprotein cholesterol (HLD-C) using a homogeneous assay)., Results: At all postprandial times, levels of LDL-C showed highly significant (p < 0.005) decreases compared to time 0 (mean [95% CI] maximum change in LDL-C levels at 3.0 h: -0.16 mmol/L [-0.12; -0.20]; p < 0.001). Independently of fasting LDL-C levels and ongoing statin therapy, LDL-C decreased significantly more in female compared to male patients postprandially (mean [95% CI] maximum unadjusted change versus time 0 in LDL-C for men [n=56] at 3.0 h: -0.14 mmol/L [-0.19; -0.10], p < 0.001; for women [n=18] at 4.5 h: -0.26 mmol/L [-0.35; -0.18], p < 0.001; -0.14 mmol/L [-0.24; -0.05], p = 0.005 between genders for the mean [95% CI] fasting adjusted difference at 4.5 h in the change versus time 0 in LDL-C; gender by time interaction: p = 0.007 (repeated measures mixed model))., Conclusions: In T2DM patients served a fat-rich meal, levels of LDL-C decreased significantly more in women compared to men postprandially, irrespective of fasting levels or ongoing statin therapy. This might have implications in the atherosclerotic process and on any difference in the risk of CVD between genders.

The Postgraduate Hospital Educational Environment Measure (PHEEM) has been translated into Danish and then validated with good internal consistency by 342 Danish junior and senior hospital doctors. Four of the 40 items are culturally dependent in the Danish hospital setting. Factor analysis demonstrated that seven items are interconnected. This information can be used to shorten the instrument by perhaps another three items.

1-Bromopropane (1-BP) has been marketed as an alternative for ozone depleting solvents and suspect carcinogens and is in aerosol products, adhesives and solvents used for metal, precision and electronics cleaning. Toxicity of 1-BP is poorly understood, but it may be a neurologic, reproductive and hematologic toxin. Sparse exposure information prompted this exposure assessment study using air sampling, and measurement of urinary metabolites. Mercapturic acid conjugates are excreted in urine from 1-BP metabolism involving removal of bromide (Br) from the propyl group. One research objective was to evaluate the utility of urinary Br analysis for assessing 1-BP exposure using a relatively inexpensive, commercially available method. Complete 48 h urine specimens were obtained from 30 workers on two consecutive days at two facilities using 1-BP adhesives to construct polyurethane foam seat cushions and from seven unexposed control subjects. All of the workers' urine was collected into composite samples representing three daily time intervals (at work; after work but before bedtime; and upon wake-up) and analyzed for Br ion by inductively coupled plasma-mass spectrometry. Full-shift breathing zone samples were collected for 1-BP on Anasorb carbon molecular sieve sorbent tubes and analyzed by gas chromatography-flame ionization detection via NIOSH method 1025. Geometric mean (GM) breathing zone concentrations of 1-BP were 92 parts per million (p.p.m.) for adhesive sprayers and 11 p.p.m. for other jobs. For sprayers, urinary Br concentrations ranged from 77 to 542 milligrams per gram of creatinine [mg (g-cr)(-1)] at work; from 58 to 308 mg (g-cr)(-1) after work; and from 46 to 672 mg (g-cr)(-1) in wake-up samples. Pre-week urinary Br concentrations for sprayers were substantially higher than for the non-sprayers and controls, with GMs of 102, 31 and 3.8 mg (g-cr)(-1), respectively. An association of 48 h urinary Br concentration with 1-BP exposure was statistically significant (r(2) = 0.89) for all jobs combined. This study demonstrates that urinary elimination is an important excretion pathway for 1-BP metabolism, and Br may be a useful biomarker of exposure.

Objective: To investigate whether a hypo-energetic low-fat diet is superior to a hypo-energetic high-fat diet for the treatment of obesity., Design: Open-label, 10-week dietary intervention comparing two hypo-energetic (-600 kcal/day) diets with a fat energy percent of 20-25 or 40-45., Subjects: Obese (BMI >or=30 kg/m(2)) adult subjects (n = 771), from eight European centers., Measurements: Body weight loss, dropout rates, proportion of subjects who lost more than 10% of initial body weight, blood lipid profile, insulin and glucose., Results: The dietary fat energy percent was 25% in the low-fat group and 40% in the high-fat group (mean difference: 16 (95% confidence interval (CI) 15-17)%). Average weight loss was 6.9 kg in the low-fat group and 6.6 kg in the high-fat group (mean difference: 0.3 (95% CI -0.2 to 0.8) kg). Dropout was 13.6% (n = 53) in the low-fat group and 18.3% (n = 70) in the high-fat group (P=0.001). Among completers, more subjects lost >10% in the low-fat group than in the high-fat group ((20.8%, n = 70) versus (14.7%, n = 46), P = 0.02). Fasting plasma total, low-density lipoprotein- and high-density lipoprotein-cholesterol decreased in both groups, but more so in the low-fat group than in the high-fat group. Fasting plasma insulin and glucose were lowered equally by both diets., Conclusions: The low-fat diet produced similar mean weight loss as the high-fat diet, but resulted in more subjects losing >10% of initial body weight and fewer dropouts. Both diets produced favorable changes in fasting blood lipids, insulin and glucose.

Introduction: The aim of the study is to establish a complete comprehension of the pathogenesis of Biliary Atresia, and to explain both the variable and redundant pathomorphological, as well as, histological findings., Materials and Methods: The pathomorphological and histological findings in 223 patients with histologically evident EHBA were recorded retrospectively (72 patients) or prospectively (151 patients), according to a projected ascending study. These findings were compared with histological findings in human and rat embryos., Results: 1) The pathomorphological findings recorded in patients with EHBA were also found in stages of normal embryogenesis of the bile duct system in human and rat embryos. 2) Each histological finding in Biliary Atresia corresponds to a finding in an interrupted stage of the normal development in human and rat embryos. 3) The findings in patients and embryos can be explained completely by a disturbed intrinsic epithelium/mesoderm interaction. 4) Some findings in Biliary Atresia cannot be explained easily by the assumption of an extrinsic factor., Conclusion: There is no finding in Biliary Atresia which cannot be completely explained as the result of an intrinsic developmental error, probably due to disturbances or interruption of epithelium/mesoderm interaction during embryogenesis.

Background: The aim of this study is to show that five distinct types of tracheal anomalies should be differentiated with respect to therapy and prognosis., Methods: The records of 12 infants and children seen over a period of 20 years for different tracheal anomalies such as laryngotracheal stenosis (n = 3), long or short-segment stenosis of the upper (n = 2), middle (n = 6), and lower (n = 1) trachea were reviewed. In addition to these 12 patients with congenital stenosis, 3 other patients needed tracheal resections because of oncologic or traumatic disease: in 2, the trachea was infiltrated by a papillary carcinoma of the thyroid gland and in one, the upper part of the trachea was injured by an oral explosion accident. 25 patients presenting during the same period for other tracheal pathologies including esophagotracheal cleft syndrome (n = 7), tracheomalacia (n = 4), total tracheal agenesis (n = 3), or for placement of a tracheostomy (n = 11) due to other diseases were excluded from this study., Results: There was 1 early death after repair of a laryngotracheal stenosis by cricoid-split and cricoid-splint due to both cerebral hemorrhage and cardiac insufficiency secondary to Fallot's tetralogy. Another child died four weeks after slide tracheoplasty as a result of hypoxic cerebral lesions induced by severe central catheter-related septicemia. One child with therapy-resistant obstructing granulation tissue which developed after a slide tracheoplasty required a tracheostomy. The patient with the tracheal injury died after another accident one year after discharge. All other patients (n = 11) are doing well., Conclusions: With respect to therapy of congenital and post-intubation tracheal stenosis, four types should be distinguished. Each of these types requires an adequate surgical procedure. The most important postoperative problem in tracheal surgery is the development of granulation tissue. However, the pathogenesis of granulation is still unknown.

Objective: Fish oil supplement has been proposed as a non-pharmacological strategy to correct the atherogenic lipid profile associated with type 2 diabetes mellitus. However, fish oil may have deleterious effects on lipid peroxidation and glycemic control., Design: In this study, 44 type 2 diabetic patients were randomized to vitamin E standardized (53.6 mg/day) supplementation (capsules) with 4 g daily of either fish oil (n=23) or corn oil (n=21) for 8 weeks preceded by a 4 week run-in period of corn oil supplementation. LDL was isolated by density gradient ultracentrifugation and oxidized in vitro with Cu(2+). As a marker of in vivo oxidation malondialdehyde concentration in LDL (LDL-MDA) was measured., Results: Fish oil reduced both mean lag time (before, 57.8; after, 48.8 min, P<0.001) and mean propagation rate (before, 0.018 DeltaOD/min; after, 0.015 DeltaOD/min, P<0.001), whereas corn oil had no influence on lag time and propagation rate. The changes in lag time and propagation rate differed significantly between fish oil and corn oil treatment. LDL-MDA changes differed borderline significantly between groups (FO, 110.4 pmol/mg protein; CO, 6.7 pmol/mg protein; P=0.057). Fish oil supplementation had no influence on glycemic control as assessed from HbA(1c) and fasting blood glucose., Conclusion: According to our findings, fish oil supplementation leads to increased in vivo oxidation and increased in vitro oxidation susceptibility of LDL particles. More studies are needed to clarify the clinical importance of this finding.

Introduction: The pathogenetic model for biliary atresia presently most favored is that EHBA is the result of a peri- or postnatal bile duct lesion. Several authors demonstrated inflammatory infiltrations in the mesenchymal areas of the liver and thus concluded an infectious genesis. An association of rota-, reo- (and CMV) virus infection with EHBA was suspected, but the presence of these viruses in EHBA could not be reproduced. In view of this controversial debate we found it to be indicated to investigate tissue blocks from the porta hepatis and liver biopsies in children with EHBA by histo- and immunohistochemistry for the quality and quantity of leukocyte infiltrations., Methods: 31 tissue excidates of the porta hepatis were gained on the occasion of hepatoportoenterostomy, fixed in 4 % buffered formalin and embedded in paraffin. The presence of leukocyte infiltrations and their subpopulations was demonstrated by histochemical reactions and immunohistochemical staining methods using specific antibodies against surface markers. The number of leukocytes and their subpopulations was counted in three different regions of the porta hepatis, the obliterated extrahepatic bile duct, the fibrous mass of the porta hepatis and the transition zone between the fibrous mass and liver parenchyma. A statistical analysis was done., Results: In EHBA, leukocyte infiltrations consist mainly of macrophages. Antigen-presenting cells and lymphatic cells play a minor role. Lymphatic cells could only be detected in 6 out of 31 tissue preparations. Antigen-presenting cells could only be detected via anti-F13a antibody which shows cross-reactivities, i.e. against macrophages and embryonal tissue. Evaluating the density of leukocyte infiltrations with regard to the different anatomical regions of the porta hepatis we could demonstrate that leukocyte infiltrations are scarce around the rudiment of the bile duct whereas the highest leukocyte density could be found in the fibrous mass of the porta hepatis and the intrahepatic fibrous septs interconnecting the fibrous mass of the porta hepatis with liver parenchyma. Liver parenchyma was mainly free of leukocyte infiltrations with the exception of neutrophilic granulocytes. Regardless of the subpopulations, leukocytes were mainly arranged around the bile ducts of the fibrotic septa., Conclusions: Most tissue preparations from children operated on during the 4th-8th week of life show only small leukocyte infiltrations and in the majority of cases no immunocompetent lymphocytes. This leads to the conclusion that a virus infection as an underlying cause for EHBA is very unlikely. Most probably, the observed leukocyte infiltrations are due to an unspecific phagocytotic activity. Comparing our results to reports from Hadchouel et al (9) and Landing et al (12) led us to believe that a pathologic immunoreaction with a possible defective antigen elimination could also be considered as a reason for EHBA.

In mammals, the cloned low-threshold heat receptor, vanilloid receptor subtype 1 (VR1), is involved in the genesis of thermal hyperalgesia after inflammation. However, there is evidence that VR1 is not involved in the thermal hyperalgesia that occurs after nerve injury. In search for other heat receptors which might be involved in this phenomenon, we previously demonstrated that chick dorsal root ganglion neurons, which are insensitive to capsaicin, respond to low-threshold heat. Here, we investigated whether expression of the low-threshold noxious heat receptor in chicks is regulated by nerve growth factor (NGF), as VR1 is in mammals. Heat (44 degrees C) responsiveness of isolated dorsal root ganglion neurons of chicks was investigated (i) under culture conditions for up to 4 days with and without NGF and (ii) after a tight ligation of the sciatic nerve for up to 6 days, using cobalt-uptake method. In every case, a significant upregulation in the proportion of heat-responsive neurons was observed. On the molecular level, there was an increase of chick VR1 mRNA level in dorsal root ganglion cells cultured for 3 days in medium lacking NGF. In rat dorsal root ganglion neurons cultured for 1-4 days without NGF, patch-clamp experiments revealed that after 1 day almost all neurons responding to heat also responded to capsaicin, whereas after 3-4 days, more than one-half of the heat-responsive neurons did not respond to capsaicin. These data suggest the existence of low-threshold heat receptors in chick dorsal root ganglion neurons, the expression of which is regulated independently of NGF., (Copyright 2003 IBRO)

Presently only those forms of Extrahepatic Biliary Atresia (EHBA) with minimal or no intrahepatic manifestations can be treated successfully by extensive hepatoportoenterostomy. Intraoperative macro- and microscopic observations show that the typical pathogenetic manifestations in EHBA are most prominent at the porta hepatis. We therefore postulate that EHBA is the result of a defective embryonic development of the porta hepatis. In rat embryos hepatic bile duct formation is initiated at the porta hepatis and in this context mesenchyme from the periportal region seems to play a major inductive role. In order to demonstrate the role of invading periportal mesenchyme for the process of bile duct rudiment formation we established an organ culture model of the embryonic porta hepatis by recombining periportal mesenchyme with peripheral liver fragments from 15 days old rat embryos (Carnegie Stage 21). The degree of mesenchyme invasion as well as the formation of mesenchyme-surrounded liver cell clusters, rosettes or vesicles (bile duct rudiments) were assessed. Mesenchyme from the porta hepatis invaded the peripheral liver fragments and induced the formation of mesenchyme-surrounded liver cell clusters and rosettes with the beginning of lumen formation. Kidney mesenchyme recombined with liver fragments as a mesenchymal alternative showed almost the same effect, lung mesenchyme showed only a very weak inductive effect. To assess the effect of a diffusible factor versus direct cell contact, a millipore filter with and without paraffin coating was interposed between mesenchyme containing tissue and peripheral liver tissue fragments. Without direct cell contact to mesenchyme no hepatoblast cluster or rosette formation could be observed. Comparing this result to the normal development of the liver in rats our investigations suggest that the embryogenesis of the porta hepatis is probably defined by the following two developmental steps: First, differentiation of the intrahepatic bile duct system which is induced by invading mesenchyme originating from the extrahepatic periportal region and realized by epithelium mesenchyme interaction. Second, fusion of extra- and intrahepatic bile duct systems at the level of the later porta hepatis. Disturbances of this complex process can possibly lead to biliary atresia. Further investigations regarding details of the role of the mesenchyme, its inductive factors and the kidney mesenchyme's inductive potential in liver development may provide a new perspective for future treatment of biliary atresia.

Cell-suspension cultures of Linum flavum L. (Linaceae) synthesize and accumulate aryltetrahydronaphthalene lignans with 6-methoxypodophyllotoxin as the main component. The experimental data indicate that the biosynthesis of 6-methoxypodophyllotoxin occurs via deoxypodophyllotoxin, beta-peltatin, and beta-peltatin-A methyl ether. The enzyme catalyzing the introduction of the hydroxyl group in position 6 is deoxypodophyllotoxin 6-hydroxylase (DOP6H). The enzyme was shown to be a cytochrome P450-dependent monooxygenase by blue-light reversion of carbon monoxide inhibition and inhibition by cytochrome c. DOP6H is a membrane-bound microsomal enzyme with a pH optimum of 7.6 and a temperature optimum of 26 degrees C. Deoxypodophyllotoxin is specifically accepted with an apparent Km of 20 microM and a saturation concentration of 200 microM; 4'-demethyldeoxypodophyllotoxin is the only other tested substrate accepted for hydroxylation. DOP6H predominantly accepts NADPH as electron donor; NADH can only sustain low hydroxylation activities. A synergistic effect of NADPH and NADH is not observed. The enzyme is saturated around 250 microM NADPH; the apparent Km for this substrate is 36 microM.

We generalize the level set approach to model epitaxial growth to include thermal detachment of atoms from island edges. This means that islands do not always grow and island dissociation can occur. We make no assumptions about a critical nucleus. Excellent quantitative agreement is obtained with kinetic Monte Carlo simulations for island densities and island size distributions in the submonolayer regime.

Bradykinin receptors are believed to contribute to hyperalgesia under conditions of neuropathic pain. Using calcium imaging we investigated responses to B1 and B2 agonists on isolated rat dorsal root ganglion neurons. No response to the B1 agonist was detected, whereas 12% of neurons responded to the B2 agonist. Northern blot analysis confirmed the lack of B1 receptor expression in dorsal root ganglia, as B1 mRNA was neither detected under normal conditions nor after nerve injury. In the calcium imaging experiments, agonists were applied with an elevated superfusion flow rate to avoid tachyphylaxis to the drug. Normal external solution applied at this flow rate constituted a mechanical stimulus causing a response in some neurons. Thus, in comparable set-ups mechanosensitivity has first to be tested to avoid masking effects.