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Copyright of Annals of Burns & Fire Disasters is the property of Euro-Mediterranean Council for Burns & Fire Disasters and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: To investigate the effects of anticancer therapy on dental development and caries formation in Italian childhood cancer survivors compared to healthy controls., Methods: A total of 52 children treated with chemotherapy and/or radiotherapy when younger than 10 years and in remission from at least 2 years, and 52 healthy age- and gender-matched children were consecutively enrolled in this cross-sectional study. All participants were examined for dental caries and enamel defects according to the decayed-missing-filled teeth (dmft/DMFT) index and the Aine rating scale. Panoramic radiographs were taken to estimate dental age and to assess dental abnormalities using the Höltta Defect Index., Conclusion: These children are at high risk for tooth developmental abnormalities and poor dental health and should be closely monitored by a specialist dentist.

Cell growth is driven by the acquisition and synthesis of both dry biomass and water mass. In this study, we examine the increase of water mass in T cell during cell growth. We found that T-cell growth is characterized by an initial phase of slow increase in cellular water, followed by a second phase of rapid increase in water content. To study the origin of the water gain, we developed a novel methodology we call cold aqua trap-isotope ratio mass spectrometry, which allows analysis of the isotope composition of intracellular water. Applying cold aqua trap-isotope ratio mass spectrometry, we discovered that glycolysis-coupled metabolism of water accounts on average for 11 fl out of the 20 fl of water gained per cell during the initial slow phase. In addition, we show that at the end of the rapid phase before initiation of cell division, a water influx occurs, increasing the cellular water mass by threefold. Thus, we conclude that activated T cells switch from metabolizing water to rapidly taking up water from the extracellular medium prior to cell division. Our work provides a method to analyze cell water content as well as insights into the ways cells regulate their water mass., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Backround and study aims  Duodenal cancer is the cancer most often seen in patients with familial adenomatous polyposis (FAP) who have undergone risk-reducing colonic surgery. Almost all patients with FAP eventually develop duodenal adenomas and risk for duodenal cancer is up to 12 % with poor prognosis. In addition, there is a rising concern regarding increased gastric cancer risk in patients with FAP. Our aim was to enhance polyp detection by using CE (CE) with the application of indigo carmine dye. Patient and methods  We conducted a prospective, blinded study of patients with FAP undergoing endoscopic examination of the upper gastrointestinal tract. First, a standard white-light examination (WLE) was done followed by an examination performed by an endoscopist who was blinded to the previous examination, using chromoendoscopy (CE) (0.4 % indigo carmine dye). Results  Fifty patients were included in the study. Using WLE, a median number of 13 adenomas (range 0-90) was detected compared to 23 adenomas/patient (range 0-150; P  < 0.0001) detected after staining, leading to a higher Spigelman stage in 16 patients (32 %; P  = 0.0003). CE detected significantly more larger adenomas (> 10 mm) than WLE (12 vs. 19; P  = 0.0391). In the gastric antral region, a median number of 0 adenomas (range 0-6) before and 0.5 adenomas (range 0-7) after staining ( P  = 0.0025) were detected. Conclusion  This prospective endoscopic trial, to our knowledge the largest in patients with FAP, showed a significant impact of CE on adenoma detection and therapeutic management in the upper gastrointestinal tract. This leads to more intensive surveillance intervals., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Recent studies reported elevated concentrations of ultrafine particles (UFP) near airports. Little is known about the health effects of UFP from aviation. Since UFP can deposit deep into the lungs and other organs, they may cause significant adverse health effects., Objective: We investigated health effects of controlled short-term human exposure to UFP near a major airport., Methods: In this study, 21 healthy non-smoking volunteers (age range: 18-35 years) were repeatedly (2-5 visits) exposed for 5 h to ambient air near Schiphol Airport, while performing intermittent moderate exercise (i.e. cycling). Pre- to post-exposure changes in cardiopulmonary outcomes (spirometry, forced exhaled nitric oxide, electrocardiography and blood pressure) were assessed and related to total- and size-specific particle number concentrations (PNC), using linear mixed effect models., Results: The PNC was on average 53,500 particles/cm 3 (range 10,500-173,200). A 5-95th percentile increase in exposure to UFP (i.e. 125,400 particles/cm 3 ) was associated with a decrease in FVC of -73.8 mL (95% CI -138.8 - -0.4) and a prolongation of the corrected QT (QTc) interval by 9.9 ms (95% CI 2.0 - 19.1). These effects were associated with particles < 20 nm (mainly UFP from aviation), but not with particles > 50 nm (mainly UFP from road traffic)., Discussion: Short-term exposures to aviation-related UFP near a major airport, was associated with decreased lung function (mainly FVC) and a prolonged QTc interval in healthy volunteers. The effects were relatively small, however, they appeared after single exposures of 5 h in young healthy adults. As this study cannot make any inferences about long-term health impacts, appropriate studies investigating potential health effects of long-term exposure to airport-related UFP, are urgently needed., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8 + and CD4 + T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8 + T cells from all patients demonstrated significantly reduced IFN-γ production. When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients., (© 2020 British Society for Immunology.)

Background: Resolution of inflammation is an active and dynamic process after surgery. Maresin 1 (MaR1) is one of a growing number of specialised pro-resolving lipids biosynthesised by macrophages that regulates acute inflammation. We investigated the effects of MaR1 on postoperative neuroinflammation, macrophage activity, and cognitive function in mice., Methods: Adult male C57BL/6 (n=111) and Ccr2 RFP/+ Cx3cr1 GFP/+ (n=54) mice were treated with MaR1 before undergoing anaesthesia and orthopaedic surgery. Systemic inflammatory changes, bone healing, neuroinflammation, and cognition were assessed at different time points. MaR1 protective effects were also evaluated using bone marrow derived macrophage cultures., Results: MaR1 exerted potent systemic anti-inflammatory effects without impairing fracture healing. Prophylaxis with MaR1 prevented surgery-induced glial activation and opening of the blood-brain barrier. In Ccr2 RFP/+ Cx3cr1 GFP/+ mice, fewer infiltrating macrophages were detected in the hippocampus after surgery with MaR1 prophylaxis, which resulted in improved memory function. MaR1 treatment also reduced expression of pro-inflammatory cell surface markers and cytokines by in vitro cultured macrophages. MaR1 was detectable in the cerebrospinal fluid of older adults before and after surgery., Conclusions: MaR1 exerts distinct anti-inflammatory and pro-resolving effects through regulation of macrophage infiltration, NF-κB signalling, and cytokine release after surgery. Future studies on the use of pro-resolving lipid mediators may inform novel approaches to treat neuroinflammation and postoperative neurocognitive disorders., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions.Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

Study Question: Can a discriminant threshold be determined for human sperm DNA oxidation?, Summary Answer: A discriminant threshold was found with 65.8% of 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive sperm cells and a mean intensity of fluorescence (MIF) of 552 arbitrary units., What Is Known Already: Oxidative stress is known to interfere with sperm quality and fertilizing capacity. However, current practice does not include the routine determination of oxidative DNA damage in spermatozoa; optimized consensus protocols are lacking and no thresholds of normality have been established., Study Design, Size, Duration: Intra- and inter-method comparisons between four protocols (I-IV) were conducted to determine the most relevant and efficient means of assessing human sperm 8-OHdG content. Tests of assay repeatability, specificity, sensitivity and stability were performed to validate an optimized methodology for routine diagnostic use., Participants/materials, Setting, Methods: This prospective study compared three immuno-detection methods including immunocytochemistry, fluorescence microscopy and flow cytometry. Sperm DNA oxidation for 80 patients was determined relative to semen parameters and clinical conditions, using the selected immuno-detection protocol in comparison with a commercial kit. These patients (age 35 ± 1 years: mean ± SEM) presented with normozoospermic (n = 40) or altered parameters (necro- or/and astheno- or/and teratozoospermia or/and leukocytospermia)., Main Results and the Role of Chance: Significant positive Pearson and Spearman correlations were determined for 8-OHdG values and sperm parameters using protocol III. A notable high and positive correlation was revealed for MIF with BMI and leukocyte concentration. Protocol III was the most discriminating method regarding assay repeatability, specificity, sensitivity, stability and reliability for sperm parameter alterations, in particular leukocytospermia according to parametric or non-parametric tests, effect-size determinations and factorial analysis such as principal component analysis and factor discriminant analysis. Of interest is that 39% of the subjects with 'pathological' sperm DNA oxidation values were normozoospermic., Limitations, Reasons for Caution: The oligozoospermic population was not evaluated in this study because insufficient material was available to carry out the comparisons. However, spermatozoa concentration was taken into account in the statistical analysis., Wider Implications of the Findings: Our study is the first validation of a protocol to determine a discriminant threshold for human sperm DNA oxidation. The protocol's detection accuracy for 8-OHdG human sperm DNA residues, stability over time, and relationship to human sperm quality were demonstrated. The assay should find application in the diagnosis of male factor infertility associated with oxidative stress., Study Funding/competing Interest(s): This work was funded by institutional grants from the CNRS, INSERM and Université Clermont Auvergne (to J.R.D.) and by Clermont-Ferrand Hospital-CECOS research funds (to L.J. and F.B.). P.G., A.M., R.J.A. and J.D. are, respectively, CEO, scientific director and scientific advisors of a US-based biotech company (Celloxess, Princeton, NJ, USA) involved in preventative medicine with a focus on the generation of antioxidant oral supplements.

Teaching nonhuman primates the complex cognitive behavioral tasks that are central to cognitive neuroscience research is an essential and challenging endeavor. It is crucial for the scientific success that the animals learn to interpret the often complex task rules and reliably and enduringly act accordingly. To achieve consistent behavior and comparable learning histories across animals, it is desirable to standardize training protocols. Automatizing the training can significantly reduce the time invested by the person training the animal. In addition, self-paced training schedules with individualized learning speeds based on automatic updating of task conditions could enhance the animals' motivation and welfare. We developed a training paradigm for across-task unsupervised training (AUT) of successively more complex cognitive tasks to be administered through a stand-alone housing-based system optimized for rhesus monkeys in neuroscience research settings (Calapai A, Berger M, Niessing M, Heisig K, Brockhausen R, Treue S, Gail A. Behav Res Methods 5: 1-11, 2016). The AUT revealed interindividual differences in long-term learning progress between animals, helping to characterize learning personalities, and commonalities, helping to identify easier and more difficult learning steps in the training protocol. Our results demonstrate that 1) rhesus monkeys stay engaged with the AUT over months despite access to water and food outside the experimental sessions but with lower numbers of interaction compared with conventional fluid-controlled training; 2) with unsupervised training across sessions and task levels, rhesus monkeys can learn tasks of sufficient complexity for state-of-the-art cognitive neuroscience in their housing environment; and 3) AUT learning progress is primarily determined by the number of interactions with the system rather than the mere exposure time. NEW & NOTEWORTHY We demonstrate that highly structured training of behavioral tasks, as used in neuroscience research, can be achieved in an unsupervised fashion over many sessions and task difficulties in a monkey housing environment. Employing a predefined training strategy allows for an observer-independent comparison of learning between animals and of training approaches. We believe that self-paced standardized training can be utilized for pretraining and animal selection and can contribute to animal welfare in a neuroscience research environment.

A high proportion of individuals deemed at elevated risk for psychosis will actually never progress to develop the illness. Pharmaceutical intervention may not be necessary in these cases, and may in fact be damaging depending on the invasiveness of the treatment strategy. This highlights the need for biomarkers that are better able to reliably differentiate between at-risk individuals who will subsequently transition to psychosis and those who will not. Low glutathione (GSH) levels have been observed in schizophrenia and in patients with first-episode psychosis. The aim of this study was to determine the predictive value of erythrocyte GSH levels on the transition to psychosis in individuals at risk of developing the illness. Erythrocyte GSH levels were measured in 36 at-risk individuals, 15 of whom had transitioned to psychosis at the 7-year follow-up. Univariate Cox regression analysis showed that transition to psychosis at the 7-year time point was significantly associated with low GSH levels at baseline. The area under the receiving operating characteristic curve was 0.819, indicating that GSH can be considered a good predictor of outcome. Although these results need to be replicated, adding the criterion 'low erythrocyte GSH' to the set of criteria used to identify individuals at risk of psychosis may be indicated.

Background: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion., Patients and Methods: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions., Results: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays., Conclusions: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Side and initial degradation products of the persistent organic pollutant hexachlorocyclohexane (HCH) were largely neglected in environmental analysis so far. However, these compounds can be indicative for biodegradation or emission sources. Thus, several samples from a contaminated riverine system in vicinity to a former HCH production site in Central Germany were analyzed. This area adjacent to the industrial megasite Bitterfeld-Wolfen is known for elevated concentrations of various organic industrial pollutants as legacy of decades of industrial activity and subsequent deposition of chemical waste and emission of waste effluents. In environmental compartments of this riverine system, several isomers of HCH related compounds were detected comprising the two lower chlorinated species tetrachlorocyclohexene (TeCCH) and pentachlorocyclohexene (PeCCH) and the higher chlorinated species heptachlorocyclohexane (HpCCH). Except for the uppermost soil of an analyzed riparian wetland, concentrations of these compounds were low. Detected isomers in sediment, water, and soil samples correlated and dominant isomers of PeCCH and HpCCH were observed in the alluvial deposits. Comparisons with industrial HCH waste revealed isomeric patterns similar to patterns found in soil samples. Therefore, the application of HpCCH as an indicator of industrial HCH pollution is suggested., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for the treatment of juvenile idiopathic arthritis (JIA). However, the effect of NSAIDs on blood pressure (BP) in children has not been rigorously examined., Methods: In this randomized, double-blind, multicenter, active-controlled, 6-week trial, the safety and efficacy of celecoxib (50 mg twice daily [bid] or 100 mg bid) or naproxen (7.5 mg/kg bid) was evaluated in patients aged 2-17 years with JIA., Results: The least squares (LS) mean difference (celecoxib - naproxen) in change from baseline to week 6/final visit in systolic BP was 1.10 (90% confidence interval, -0.56, 2.76). No significant LS mean differences in diastolic BP relative to baseline were reported. Treatment-emergent adverse events occurred in 48% of patients in each treatment group., Conclusion: Both celecoxib and naproxen had no impact on BP, and both treatments had comparable safety profiles. Celecoxib, or naproxen, could be seen as suitable treatment options for pediatric patients with JIA.

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality-of-life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion-centre administration, and the use of self- or health-professional-administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient's treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self-infusion regimens, however, require independence and self-reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self-administer or a lack of self-reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health-related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed., (© 2014 British Society for Immunology.)

The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment., (© 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.)

Background: Since the number of heart failure (HF) patients is still growing and long-term treatment of HF patients is necessary, it is important to initiate effective ways for structural involvement of primary care services in HF management programs. However, evidence on whether and when patients can be referred back to be managed in primary care is lacking., Aim: To determine whether long-term patient management in primary care, after initial optimisation of pharmacological and non-pharmacological treatment in a specialised HF clinic, is equally effective as long-term management in a specialised HF clinic in terms of guideline adherence and patient compliance., Method: The study is designed as a randomised, controlled, non-inferiority trial. Two-hundred patients will be randomly assigned to be managed and followed in primary care or in a HFclinic. Patients are eligible to participate if they are (1) clinically stable, (2) optimally up-titrated on medication (according to ESC guidelines) and, (3) have received optimal education and counselling on pre-specified issues regarding HF and its treatment. Furthermore, close cooperation between secondary and primary care in terms of back referral to or consultation of the HF clinic will be provided.The primary outcome will be prescriber adherence and patient compliance with medication after 12 months. Secondary outcomes measures will be readmission rate, mortality, quality of life and patient compliance with other lifestyle changes., Expected Results: The results of the study will add to the understanding of the role of primary care and HF clinics in the long-term follow-up of HF patients.

Background: Bone metastatic patients with osteosarcoma have a very poor prognosis. Targeted radiation therapy has been pursued as a valid alternative. The primary end point of this study was progression-free survival (PFS) at 4 months., Patients and Methods: Twenty-two osteosarcoma patients were treated with Samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP) at various dosages. Administered activities ranged from 150 (3 mCi/kg) to 1140 MBq/kg (30 mCi/kg). Autologous hematopoietic stem cell infusion was carried out on day 14 after the (153)Sm-EDTMP infusion., Results: The median PFS was 61 days (18-436 days) and the median overall survival (OS) was 189 days (31-1175 days). PFS and OS for the entire patient population were 32% [95% confidence interval (CI) 16-50] and 76% (95% CI 52-89) at 4 months, respectively. No statistical differences emerged according to 153Sm-EDTMP administered or 24-h retained activity. One-month pain palliation was only observed in a minority of subjects and in none at 4 months., Conclusions: Based on our series, the PFS is dramatically short even when higher activity of (153)Sm-EDTMP is administered. This would mean that, even at high level, 153Sm-EDTMP is itself ineffective against relapsed osteosarcoma or the residual activity is too low to be active on these particular subsets of patients.

Background: Although the vast majority of children with acute infections are managed at home, this is one of the most common problems encountered in children attending emergency departments (EDs) and primary care. Distinguishing children with serious infection from those with minor or self-limiting infection is difficult. This can result in misdiagnosis of children with serious infections, which results in a poorer health outcome, or a tendency to refer or admit children as a precaution; thus, inappropriately utilising secondary-care resources., Objectives: We systematically identified clinical features and laboratory tests which identify serious infection in children attending the ED and primary care. We also identified clinical prediction rules and validated those using existing data sets., Data Sources: We searched MEDLINE, Medion, EMBASE, Cumulative Index to Nursing and Allied Health Literature and Database of Abstracts of Reviews of Effects in October 2008, with an update in June 2009, using search terms that included terms related to five components: serious infections, children, clinical history and examination, laboratory tests and ambulatory care settings. We also searched references of included studies, clinical content experts, and relevant National Institute for Health and Clinical Excellence guidelines to identify relevant studies. There were no language restrictions. Studies were eligible for inclusion if they were based in ambulatory settings in economically developed countries., Review Methods: Literature searching, selection and data extraction were carried out by two reviewers. We assessed quality using the quality assessment of diagnostic accuracy studies (QUADAS) instrument, and used spectrum bias and validity of the reference standard as exclusion criteria. We calculated the positive likelihood ratio (LR+) and negative likelihood ratio (LR-) of each feature along with the pre- and post-test probabilities of the outcome. Meta-analysis was performed using the bivariate method when appropriate. We externally validated clinical prediction rules identified from the systematic review using existing data from children attending ED or primary care., Results: We identified 1939 articles, of which 35 were selected for inclusion in the review. There was only a single study from primary care; all others were performed in the ED. The quality of the included studies was modest. We also identified seven data sets (11,045 children) to use for external validation. The most useful clinical features for ruling in serious infection was parental or clinician overall concern that the illness was different from previous illnesses or that something was wrong. In low- or intermediate-prevalence settings, the presence of fever had some diagnostic value. Additional red flag features included cyanosis, poor peripheral circulation, rapid breathing, crackles on auscultation, diminished breath sounds, meningeal irritation, petechial rash, decreased consciousness and seizures. Procalcitonin (LR+ 1.75-2.96, LR- 0.08-0.35) and C-reactive protein (LR+ 2.53-3.79, LR- 0.25-0.61) were superior to white cell counts. The best performing clinical prediction rule was a five-stage decision tree rule, consisting of the physician's gut feeling, dyspnoea, temperature ≥ 40 °C, diarrhoea and age. It was able to decrease the likelihood of serious infections substantially, but on validation it provided good ruling out value only in low-to-intermediate-prevalence settings (LR- 0.11-0.28). We also identified and validated the Yale Observation Scale and prediction rules for pneumonia, meningitis and gastroenteritis., Limitations: Only a single study was identified from primary-care settings, therefore results may lack generalisability., Conclusions: Several clinical features are useful to increase or decrease the probability that a child has a serious infection. None is sufficient on its own to substantially raise or lower the risk of serious infection. Some are highly specific ('red flags'), so when present should prompt a more thorough or repeated assessment. C-reactive protein and procalcitonin demonstrate similar diagnostic characteristics and are both superior to white cell counts. However, even in children with a serious infection, red flags will occur infrequently, and their absence does not lower the risk. The diagnostic gap is currently filled by using clinical 'gut feeling' and diagnostic safety-netting, which are still not well defined. Although two prediction rules for serious infection and one for meningitis provided some diagnostic value, we do not recommend widespread implementation at this time. Future research is needed to identify predictors of serious infection in children in primary-care settings, to validate prediction rules more widely, and determine the added value of blood tests in primary-care settings., Funding: The National Institute for Health Research Health Technology Assessment programme.

Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.

Glycolaldehyde (GA) is a highly reactive aldehyde that can be generated during inflammation and hyperglycemia. It can react with arginine and lysine residues impairing protein function. As inflammation and diabetes present haemostatic dysfunction, we hypothesized that GA could participate in this process. The aim of this study was to investigate if plasma incubated in the presence of GA presents alteration in the coagulation process. We also aimed to evaluate the role of fibrinogen in GA-induced haemostatic dysfunction. For this purpose, plasma and fibrinogen were each incubated separately, either in the presence or absence of 1 mM GA for 8 and 4 h, respectively. After that, plasma coagulation and fibrin polymerization kinetics were recorded, as well as the kinetic of plasma clot digestion and fibrinolysis protein carbonylation was quantified. An SDS-PAGE was run to check the presence of cross-linking between fibrinogen chains. GA induced a delay in plasma coagulation and in fibrin polymerization. Maximum absorbance decreased after GA treatment, indicating the generation of thinner fibers. Fibrin generated after complete coagulation showed resistance to enzymatic digestion, which could be related to the generation of thinner fibers. Protein carbonylation also increased after GA treatment. All parameters could be reversed with AMG (a carbonyl trap) co-treatment. The data presented herein indicate that GA causes post-translational modification of lysine and arginine residues, which are central to many events involving fibrinogen to fibrin conversion, as well as to fibrinolysis. These modifications lead to the generation of persistent clots and may contribute to mortality seen in pathologies such diabetes and sepsis.

The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.

The purpose of this study was to identify genomic regions controlling seed protein content, kernel and hull weights, and seed density in water-stress conditions in sunflower (Helianthus annuus L.). The experiments consisted of a split-plot design (water treatment and recombinant inbred lines) with three blocks in two environments (greenhouse and field). High significant variation was observed between genotypes for all traits as well as for water treatment x genotype interaction. Several specific and nonspecific QTLs were detected for all traits under well-watered and water-stress conditions. Two SSR markers, ORS671&#95;2 and HA2714, linked to protein content were identified that have no interaction with water treatments in greenhouse conditions. We also detected the E35M60&#95;4 marker associated with kernel weight that had no interaction with water treatments. A specific QTL for protein content was detected with important phenotypic variance (17%) under water-stress conditions. Overlapping QTLs for protein content and seed density were identified in linkage group 15. This region probably has a peliotropic effect on protein content and seed density. QTLs for protein content colocated with grain weight traits were also identified.

The objectives of the present research were to determine the effects of water stress on seed-quality traits and to map QTLs controlling the studied traits under two different water treatments in a population of sunflower recombinant inbred lines (RILs). Two experiments were conducted in greenhouse and field conditions, each with well-watered and water-stressed treatments. The experiments consisted of a split-plot design (water treatment and RIL) with three blocks. Analyses of variance showed significant variation among genotypes, and a water treatment x genotype interaction was also observed for most of the traits. Two to 15 QTLs were found, depending on trait and growth conditions, and the percentage of phenotypic variance explained by the QTLs ranged from 5% to 31%. Several QTLs for oil content overlapped with QTLs for palmitic and stearic acid contents in all four conditions. An overlapping region on linkage group 3 (QTLs 2.OC.3.1 and 4.SA.3.1) was linked to an SSR marker (ORS657). A principal component analysis was performed on four fatty acid traits. Two principal components, P1 and P2, were used for QTL analysis. This method improved the ability to identify chromosomal regions affecting the fatty acids. We also detected the principal-component QTLs that did not overlap with the fatty acid QTLs. The results highlight genomic regions of interest in marker-based breeding programmes for increasing oil content in sunflower.

Fluorescence-enhanced diffuse optical tomography is expected to be useful to the collection of functional information from small animal models. This technique is currently limited by the extent of tissue heterogeneity and management of the shape of the animals. We propose an approach based on the reconstruction of object heterogeneity, which provides an original solution to the two problems. Three evaluation campaigns are described: the first two were performed on phantoms designed to test the reconstructions in highly heterogeneous media and noncontact geometries; the third was conducted on mice with lung tumors to test fluorescence yield reconstruction feasibility in vivo.

We describe a novel method for localizing a fluorescent inclusion in a homogeneous turbid medium through the use of time-resolved techniques. Based on the calculation of the mean time of the fluorescence curves, the method does not require a priori knowledge of either the fluorescence lifetime or the mean time of the instrument response function since it adopts a differential processing approach. Theoretical expressions were validated and experiments for assessing the accuracy of localization were carried out on liquid optical phantoms with a small fluorescent inclusion. The illumination and detection optical fibers were immersed in the medium to achieve infinite medium geometry as required by the model used. The experimental setup consisted of a time-correlated single-photon counting system. Submillimeter accuracy was achieved for the localization of the inclusion.

The akr1b7 gene encodes an aldose reductase-like protein that is responsible for detoxifying isocaproaldehyde generated by the conversion of cholesterol to pregnenolone. The regulation of gene expression by human chorionic gonadotropin (hCG) was first investigated in the MA-10 Leydig tumor cell line. The akr1b7 gene was constitutively expressed and accumulation of its mRNA was increased in a dose- and time-dependent manner by treatment with hCG. akr1b7 mRNA accumulation was sharply increased in the presence of 0.25 nM hCG and it reached a fivefold increase within 2 h. AKR1B7 protein accumulation was delayed compared with that of the corresponding mRNA. In agreement, hCG significantly increased the levels of mRNA and protein of akr1b7 in primary cultures of adult mouse Leydig cells, thus suggesting that LH potentially regulates akr1b7 gene expression in vivo. Expression of akr1b7 was developmentally regulated in the testis. Unexpectedly, levels of akr1b7 mRNA increased from embryonic day 15 to the day of birth and declined until adulthood while AKR1B7 protein levels followed an inverse pattern, suggesting an important role for translational mechanisms.

Diabetes education or self-management programmes are complex interventions. Their evaluation is difficult because of problems in identifying and separately assessing the effect of the various components of the intervention. A phased approach defining sequential stages of a continuum of increasing evidence has been proposed as a framework for the design and evaluation of such complex interventions. As an example we present the available evidence for diabetes treatment and teaching programmes implemented in Germany. Evidence is compiled for structured group treatment and teaching programmes for Type I diabetes, non-insulin dependent Type II diabetes, and hypertension according to the following sequential stages of increasing evidence: (i) preclinical or theoretical phase; (ii) modelling the components of the intervention; (iii) exploratory trials; (iv) randomized controlled trials; (v) phase of implementation including replication and transfer to different settings. Evidence for most of these phases has been generated for the three programmes, although individual studies do not fulfill all important quality criteria by today's standards. The time span for gathering the evidence from the theoretical phase to surveillance after implementation was about 20 years. It can only be speculated which parts of the programmes are the most active ones. The presentation of a continuum of increasing evidence for diabetes education or self-management programmes could provide useful information for the appraisal of such complex interventions. Since this evidence cannot be readily extracted from databases we suggest that other research groups present their data in a similar way.

Aims/hypothesis: To compare causes of death assessed by a clinical review committee, the information given on death certificates, and ICD-codes provided by the State Documentation Office in deceased persons with Type 1 (insulin-dependent) diabetes mellitus., Methods: A cohort of 3674 patients were monitored for 10+/-3 (mean +/- SD) years. Vital status and end-stage diabetic complications were documented for 97%; 251 patients had died. Causes of death were assessed by a clinical review committee and compared to the information provided by death certificates and ICD-9 codes., Results: The review committee defined a leading cause of death in 94% of cases, whereas death certificates were available for 73% and ICD-codes for 79% of patients; 10% of death certificates could not be evaluated due to insufficient information. Diabetes was mentioned on 71% of death certificates, and renal disease in 75% of cases with renal replacement therapy. There was acceptable agreement between the committee, death certificates and ICD-codes only for deaths due to neoplasma, and between the committee and death certificates for deaths due to acute myocardial infarction, cerebrovascular events and accidents. In only one out of four deaths due to hypoglycaemia and in four of seven deaths due to ketoacidosis was this diagnosis mentioned on the death certificate. No death due to hypoglycaemia or ketoacidosis and 41% due to suicide were identifiable by ICD-codes., Conclusion/interpretation: Reliance on death certificates or ICD-codes as the only sources of information on the cause of specific mortality does not provide data of sufficient reliability for evaluation of clinical outcome in Type I diabetes.

Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT--PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha') chains, however common gamma(c), a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo., (Copyright 2002 The Cancer Research Campaign)

During neutrophil activation, the properties of the cell are rapidly altered by increases in the surface expression of functionally important receptors and adherence molecules. At the same time, endocytic and phagocytic activities increase. These alterations require precise regulation of membrane and protein movement, which is achieved, at least in part, by bidirectional movement of small transport vesicles. GTP-binding proteins, including Rabs and ADP-ribosylation factors (ARFs), play critical roles in regulating vesicle trafficking in other types of cells. The ability to immunoisolate the "secretory" vesicle subpopulation in which complement receptor type 1 (CR1) is stored allowed us to determine which types of low-molecular-weight GTP-binding proteins interact with these vesicles and under what conditions. CR1-containing vesicles from resting human neutrophils constitutively copurify with Rabs 3a, 4, and 5a, and reversibly bind an ARF, likely ARF1. ARF binding is dependent on free Mg(2+) and is enhanced by GTPgammaS. Mg(2+) at 0.4 microM is necessary for half-maximal binding of ARFs to CR1 storage vesicles. Artificial phospholipid vesicles and primary and secondary granules from human neutrophils do not bind ARFs themselves and do not compete for recruitment of ARFs to CR1 vesicles, suggesting that specific membrane environments and/or proteins on these vesicles stabilize the ARF-GTP-Mg(2+) complex. Free Ca(2+) at 300 nM does not inhibit ARF binding to CR1 storage vesicles, but 10 mM Ca(2+) does reduce such binding. These findings suggest that ARF-GTP specifically and reversibly interacts with CR1 storage vesicles in human polymorphonuclear leukocytes and may play a role in regulating their transport.

The p53 protein is subject to Mdm2-mediated degradation by the ubiquitin-proteasome pathway. This degradation requires interaction between p53 and Mdm2 and the subsequent ubiquitination and nuclear export of p53. Exposure of cells to DNA damage results in the stabilization of the p53 protein in the nucleus. However, the underlying mechanism of this effect is poorly defined. Here we demonstrate a key role for c-Abl in the nuclear accumulation of endogenous p53 in cells exposed to DNA damage. This effect of c-Abl is achieved by preventing the ubiquitination and nuclear export of p53 by Mdm2, or by human papillomavirus E6. c-Abl null cells fail to accumulate p53 efficiently following DNA damage. Reconstitution of these cells with physiological levels of c-Abl is sufficient to promote the normal response of p53 to DNA damage via nuclear retention. Our results help to explain how p53 is accumulated in the nucleus in response to DNA damage.

Low-abundance gene products are of interest in proteomic studies, because they are probably involved in disease-related changes and their altered levels or modifications may carry significant biological information. Detection of low-abundance proteins of a proteome is one of the major limitations of proteomics and a scientific challenge. We investigated the changes in the levels of low-abundance rat brain cytosolic proteins after administration of kainic acid, a potent neurotoxin and excitatory amino acid. The cytosolic proteins from controls and animals treated with kainic acid were fractionated on an ion-exchange column. The fractions collected were analyzed by 2D electrophoresis, and the proteins with altered levels were identified by matrix-assisted laser desorption ionization or ion-spray MS. We found a manifold decrease in annexin VII, heat-shock cofactor HOP/p60 and SP-22 and a manifold increase in heparin-binding protein p30. The results suggest, respectively, the involvement of an apoptotic pathway, recruitment of the heat-shock protein machinery, generation of an antioxidant response, and, probably, induction of repair mechanisms. Three of the four proteins with altered levels had not been previously detected in the cytosolic fraction, and detection of the altered levels was possible only after the protein-enriching step.

Objective: A reduction of diabetes-related amputations by at least one-half within 5 years was declared a primary objective for Europe (St. Vincent Declaration, 1989). We collected data about incidence rates of amputations in one German city (Leverkusen, with a population of approximately 160,000 inhabitants) between 1990 and 1998 to ascertain a potential change in rates of incidence., Research Design and Methods: From all three hospitals in Leverkusen, we obtained complete lists of lower-limb amputations. From each patient record, diabetic status was determined. Only the first observed amputation was counted for the analysis. We estimated incidence rates of amputations in the entire population, the diabetic population, and the nondiabetic population. To test for time trend, we fitted Poisson regression models, adjusting for age and sex., Results: During, the defined period (the years 1990, 1991, and 1994-1998), 339 patients (all residents of Leverkusen) without previous amputations had nontraumatic lower-limb amputations. Of all subjects. 46% were female. Moreover, 76% of the subjects were known to have diabetes. Mean age was 71.3 years. Incidence rates in the diabetic population (standardized to the estimated German diabetic population, per 100,000 person-years) were as follows: 1990, 549; 1991, 356; 1994, 544; 1995, 386; 1996, 426; 1997, 433; and 1998, 463. The Poisson models showed no significant change of incident amputations over time in the diabetic population or in the nondiabetic population., Conclusions: Beyond random variation, no change of incidence rates could be observed over the past 9 years. More specific interventions are needed to achieve a substantial reduction of diabetes-related amputations.

Ependymoma occurs most frequently within the central nervous system of children and young adults. We determined relative chromosomal copy-number aberrations in 44 ependymomas using comparative genomic hybridization. The study included 24 intracranial and 20 spinal cord tumors from pediatric and adult patients. Frequent chromosomal aberrations in intracranial tumors were gain of 1q and losses on 6q, 9, and 13. Gain of 1q and loss on 9 were preferentially associated with histological grade 3 tumors. On the other hand, gain on chromosome 7 was recognized almost exclusively in spinal cord tumors, and was associated with various other chromosomal aberrations including frequent loss of 22q. We conclude that cytogenetic analysis of ependymomas may help to classify these tumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed.