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Aim: Invasive mold diseases (IMDs) are associated with significant morbidity and mortality. Approved treatments include voriconazole (VORI), liposomal amphotericin B (L-AMB), posaconazole (POSA) and isavuconazole (ISAV). A UK-based economic model was developed to explore the cost of treating IMDs with ISAV versus L-AMB followed by POSA. Materials & methods: As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration & monitoring, and hospitalization costs were evaluated from the healthcare system perspective. Results: Per-patient costs were UK£14,842 with ISAV versus UK£18,612 with L-AMB followed by POSA. Savings were driven by drug acquisition, and administration & monitoring costs. Conclusion: ISAV has the potential to reduce IMD treatment costs relative to L-AMB followed by POSA.

Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA. Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model. Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3–5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (−1.39 [−2.21, −0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [−1.17, 1.53], 0.50 [−1.11, 2.13] and 0.32 [−0.19, 0.84], respectively) or overall response (−0.99 [−2.21, 0.29], −0.89 [−2.41, 0.65] and 0.06 [−0.43, 0.57], respectively). Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.

Aim: Mucormycosis is a fungal infection associated with high mortality. Until recently, the only licensed treatments were amphotericin B (AMB) formulations. Isavuconazole (ISAV) is a new mucormycosis treatment. A UK-based economic model explored treatment costs with ISAV versus liposomal AMB followed by posaconazole. Materials & methods: As a matched case–control analysis showed similar efficacy for ISAV and AMB, a cost-minimization approach was taken. Direct costs – drug acquisition, monitoring and administration, and hospitalization costs – were estimated from the National Health Service perspective. Results: Per-patient costs for ISAV and liposomal AMB + posaconazole were UK£26,810 and UK£41,855, respectively, with savings primarily driven by drug acquisition and hospitalization costs. Conclusion: ISAV may reduce costs compared with standard mucormycosis therapy.

Research shows that juvenile female offenders have a higher prevalence rate of sexual risk behaviors than girls from the general population and that similar factors underlie both SRBs and delinquent behavior. Contributing to findings derived from young female delinquent samples, this study examines the impact of risk factors on delinquent behaviors and sexual risk behaviors in 146 delinquent girls (12 to 18 years) in outpatient forensic treatment. While controlling for ethnicity, results from structural equation modeling through bootstrapping showed that sexual risk behaviors (explained variance 26%) were predicted by the number of negative life events, peer rejection, and substance use, whereas the number of previous convictions and treatment dropout were predictive of delinquent behavior (explained variance 14.1%). Affiliation with deviant peers, parental monitoring, and conduct problems did not contribute to the explained variance in both outcome measures. These findings will be elaborated on in the discussion.

Background Voriconazole is well established as standard treatment for invasive aspergillosis (IA). In 2017, isavuconazole, a new antifungal from the azole class, with a broader pathogen spectrum, was introduced in Sweden. A model has therefore been developed to compare the cost-effectiveness of isavuconazole and voriconazole in the treatment of possible IA in adults in Sweden. Methods The cost-effectiveness of isavuconazole versus voriconazole was evaluated using a decision-tree model. Patients with possible IA entered the model, with 6% assumed to actually have mucormycosis. It was also assumed that pathogen information would become available during the course of treatment for only 50% of patients, with differential diagnosis unavailable for the remainder. Patients who were considered unresponsive to first-line treatment were switched to second-line treatment with liposomal amphotericin-B. Data and clinical definitions included in the model were taken from the published randomised clinical trial comparing isavuconazole with voriconazole for the treatment of IA and other filamentous fungi (SECURE) and the single-arm, open-label trial and case-control analysis of isavuconazole for the treatment of mucormycosis (VITAL). A probabilistic sensitivity analysis was used to estimate the combined parameter uncertainty, and a deterministic sensitivity analysis and a scenario analysis were performed to test the robustness of the model assumptions. The model followed a Swedish healthcare payer perspective, therefore only considering direct medical costs. Results The base case analysis showed that isavuconazole resulted in an incremental cost-effectiveness ratio (ICER) of 174,890 Swedish krona (SEK) per additional quality adjusted life-year (QALY) gained. This was mainly due to the efficacy of isavuconazole against IA and mucormycosis, as opposed to voriconazole, which is only effective against IA. Sensitivity and scenario analyses of the data showed that the average ICER consistently fell below the willingness to pay (WTP) threshold of 1,000,000 SEK. The probability of isavuconazole being cost-effective at a WTP of 170,000 SEK per QALY gained was 50% and at a WTP of 500,000 SEK per QALY gained was 100%. Conclusions This model suggests that the treatment of possible IA with isavuconazole is cost-effective compared with treatment with voriconazole from a Swedish healthcare payer perspective. Electronic supplementary material The online version of this article (10.1186/s12879-019-3683-2) contains supplementary material, which is available to authorized users.

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR. Electronic supplementary material The online version of this article (10.1007/s10875-017-0454-y) contains supplementary material, which is available to authorized users.

Chronic hand eczema places a heavy burden on patients, often affecting their ability to work. This paper compares the cost-of-illness and treatment approaches for patients with refractory chronic hand eczema, in relation to whether the disease was occupational or unrelated to work factors. Data from 2 surveys, comprising 310 patients with chronic hand eczema insured by German statutory health insurance (SHI) (including work-impaired patients, work-unaffected patients and non-working patients) and known work-related chronic hand eczema insured by occupational health insurance (OHI). Annual healthcare costs of managing work-impaired patients (SHI) and patients with work-related chronic hand eczema (OHI) were €3,164 and €3,309, respectively, approximately double the costs of managing non-working and work-unaffected (SHI) patients. This analysis shows that the costs associated with chronic hand eczema are affected by the correlation of chronic hand eczema with work, with costs being higher for occupational patients with chronic hand eczema.

Evaluation of the tympanic bulla (TB) in cases of otitis media in the rabbit can be a diagnostic challenge, although a feature often associated with the condition is the accumulation of fluid or material within the TB. Randomly selected TB from 40 rabbit cadavers were filled with a water-based, water-soluble jelly lubricant. A dorsoventral radiograph and single computed tomography (CT) slice were taken followed by an ultrasound (US) examination. Image interpretation was performed by blinded operators. The content of each TB was determined (fluid or gas) using each technique and the cadavers were frozen and sectioned for confirmation. CT was the most accurate diagnostic method, but US produced better results than radiography. Given the advantages of US over the other imaging techniques, the results suggest that further work is warranted to determine US applications in the evaluation of the rabbit TB and clinical cases of otitis media in this species.

Adipose regeneration strategies have been hampered by the inability to supply an adequate vascular supply following implantation. Vascularization in vitro, also called prevascularization, is a promising method that could promote the vascularization of engineered adipose tissue constructs upon implantation. In this study we compared the ability of prevascularized-to-non-prevascularized fibrin-based human adipose tissue to promote vascularization. Human adipose tissue-derived stromal cells (ASCs) and different mixtures (1:1, 1:2 and 1:5) of ASCs with human umbilical vein endothelial cells (HUVECs) were cultured in fibrin at two different densities (1.0 x 106 and 10 x 106 cells/ml) for 7 days. Histological analysis revealed that prevascular structures formed in 1:5 ASC/HUVEC fibrin-based constructs seeded with a total of 10 x 106 cells/ml. These constructs and ASC-only constructs were implanted subcutaneously in athymic mice for 7 days and generated lipid-containing grafts. The numbers and densities of blood vessels within the ASC/HUVEC constructs were similar to those of ASC-only constructs. Furthermore, immunostaining studies demonstrated human-derived vasculature within a few of the ASC/HUVEC and ASC-only constructs. A subset of this human-derived vasculature contained erythrocytes, indicating integration with the host vasculature. In conclusion, our study indicated no difference in the rate of vascularization of prevascularized ASC/HUVEC and non-prevascularized ASC-only fibrin-based constructs, suggesting that prevascularization of these fibrin-based constructs does not promote vascularization. Our results further indicated that not only endothelial cells, but also ASCs may contribute to the formation of vascular lumina upon implantation. This finding is interesting, since it demonstrates the possibility of vascularized adipose tissue engineering from a single cell source. Copyright (c) 2011 John Wiley & Sons, Ltd.

Background Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality. Design and Methods A detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses. Results The cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3- and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status. Conclusions These results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.

Vascularization is still one of the most important limitations for the survival of engineered tissues after implantation. In this study, we aim to improve the in vivo vascularization of engineered adipose tissue by preforming vascular structures within in vitro-engineered adipose tissue constructs that can integrate with the host vascular system upon implantation. Different cell culture media were tested and different amounts of human adipose tissue-derived mesenchymal stromal cells (ASC) and human umbilical vein endothelial cells (HUVEC) were combined in spheroid cocultures to obtain optimal conditions for the generation of prevascularized adipose tissue constructs. Immunohistochemistry revealed that prevascular structures were formed in the constructs only when 20% ASC and 80% HUVEC were combined and cultured in a 1:1 mixture of endothelial cell medium and adipogenic medium. Moreover, the ASC in these constructs accumulated lipid and expressed the adipocyte-specific gene fatty acid binding protein-4. Implantation of prevascularized ASC/HUVEC constructs in nude mice resulted in a significantly higher amount of vessels (37 ± 17 vessels/mm2) within the constructs compared to non-prevascularized constructs composed only of ASC (3 ± 4 vessels/mm2). Moreover, a subset of the preformed human vascular structures (3.6 ± 4.2 structures/mm2) anastomosed with the mouse vasculature as indicated by the presence of intravascular red blood cells. Our results indicate that preformed vascular structures within in vitro-engineered adipose tissue constructs can integrate with the host vascular system and improve the vascularization upon implantation.

Inadequate vascularization of in vitro-engineered tissue constructs after implantation is a major problem in most tissue-engineering applications. In this study we evaluated whether adipose tissue-derived stromal cells (ASCs), similar to bone marrow-derived stromal cells (BMSCs), can support the organization of endothelial cells into prevascular-like structures using an in vitro model. In addition, we investigated the mechanisms leading to the support of endothelial organization by these cells. We cultured human umbilical vein endothelial cells (HUVECs), ASCs, and BMSCs either alone or in combination in fibrin-embedded spheroids for 14 days. We found that BMSCs and ASCs formed cellular networks that expressed alpha smooth muscle actin and, in the case of ASCs, also CD34. Further, BMSCs and ASCs secreted hepatocyte growth factor and tissue inhibitor of metalloproteinase 1 and 2. In addition, ASC-conditioned medium induced HUVEC outgrowth, whereas BMSC-conditioned medium and hepatocyte growth factor-supplemented medium did not. Finally, both BMSCs and ASCs supported HUVEC organization into prevascular-like structures when cocultured. Our results suggest that both BMSCs and ASCs can support the formation of prevascular-like structures in vitro. Further, our findings indicate that cell-cell contacts and reciprocal signaling play an important role in the formation of these prevascular structures.

Background: Improving vascularization of engineered adipose tissue constructs is a major challenge in the field of plastic surgery. Although human adipose-derived stromal cells (hASCs) are known to release factors that stimulate new blood vessel formation, detailed information about the effects of adipogenic differentiation on the angiogenic potential of hASCs remains largely unknown. In the present study, we studied the expression and secretion of a large panel of angiogenic factors during hASC differentiation and evaluated the effects of hASC-conditioned medium (hASC-CM) on endothelial cells. Methods: hASCs were cultured on adipogenic medium or basal medium. Conditioned medium was collected, and cells were harvested following 0, 3, 7, 14, and 22 days of culture. The stage of adipogenic differentiation of hASC was assessed using Oil Red O staining, fatty acid binding protein-4 gene expression, and glycerol-3-phosphate dehydrogenase activity. Results: Gene expression of vascular endothelial growth factor ( VEGF), placental growth factor, angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), and protein secretion of VEGF significantly increased during short-term adipogenic differentiation of hASCs. Moreover, conditioned medium from differentiated hASCs strongly enhanced endothelial cell numbers compared to conditioned medium from undifferentiated hASCs. Conclusion: In vitro adipogenic differentiation of hASCs improves their ability to support endothelial viable cell numbers and suggests that hASCs differentiated for a short period potentially improve angiogenic responses for in vivo implantation.

Rats allowed extended daily access (6 h) to cocaine, consume high doses of the drug and escalate their cocaine intake over days, resembling the pattern of cocaine use seen in human addicts. The current study was designed to test whether such animals would also demonstrate the heightened motivation to seek cocaine seen in human addicts. Rats were trained to lever press for i.v. cocaine (0.25 mg/infusion) over a 5-day period of 1 h sessions. Subjects were then assigned to either a brief-access (1 h/day) or an extended-access condition for an additional 10 days. Control rats lever pressed for i.v. saline. Following the final self-administration session animals were tested for their motivation to receive cocaine in an operant runway apparatus. Extended-access animals exhibited significantly higher motivation for cocaine in the runway (where they received 1.0 mg/kg cocaine i.v. upon goal-box entry) as was evident by faster run times and less ambivalence about entering the goal box (i.e. retreat behavior) than either brief-access or control subjects. Brief and extended-access animals, tested in the Elevated Plus Maze, exhibited comparable and significant increases in anxiety following a single 1.0 mg/kg i.v. injection of cocaine, as compared to saline control animals that were challenged with i.v. saline infusion. Together, these data suggest that extended access to cocaine results in an especially high motivation for the drug that is not accounted for by reductions in the anxiogenic properties of cocaine.

Interleukin-7 (IL-7) has been shown to enhance thymic output of newly developed T cells following bone marrow transplantation (BMT) in mice. In addition, IL-7 may affect peripheral expansion of T cells. In order to study the relative contribution of thymopoiesis versus peripheral T-cell expansion in the setting of compromised thymopoiesis, we have applied IL-7 in an experimental stem cell transplantation model using T cell–deficient RAG-1–/– mice. C57BL/6 RAG-1–/– mice received transplants of syngeneic T-cell–depleted (TCD) bone marrow (Ly5.1) with or without supplemented T cells (Ly5.2). IL-7 was administered until day 63 after BMT. Peripheral blood T- and B-cell recovery was quantified by flow cytometry and thymopoiesis was studied by quantification of T-cell receptor rearrangement excision circles (TRECs). In mice receiving a T-cell–replete BMT, IL-7 selectively expanded mature CD45.2+ T cells without affecting the recovery of new bone marrow–derived CD45.1+ T cells. In contrast, IL-7 significantly enhanced the recovery of bone marrow–derived T cells after TCD BMT. Quantification of TRECs in mice receiving a TCD BMT revealed that enhanced T-cell recovery following IL-7 treatment resulted from a strong expansion of newly developed naive T cells. These results suggest that peripheral expansion of recent thymic emigrants or mature T cells may be a preferential mechanism by which IL-7 enhances T-cell recovery after BMT.

Objective Thymic output of newly developed ab T cells in humans can be measured via signal joint T-cell receptor rearrangement excision circles (sjTRECs). Deletion of the TCRD locus via dRec to ψJa recombination during TCRA rearrangement results in the production of such sjTRECs. The deleting elements dRec and ψJa are highly conserved between humans and mice and used in a comparable manner. We developed and evaluated a real-time quantitative PCR (RQ-PCR) to detect and quantify dRec-ψJa sjTRECs in murine peripheral blood leukocytes for estimation of thymic output of newly developed ab T cells in mice. Methods The threshold cycle (Ct) of the sjTREC RQ-PCR was related to the Ct value of an endogenous reference gene. The difference in Ct value (DCt) was correlated to the absolute numbers of CD45 + and CD3 + cells per mL of blood, as obtained by a single platform flow cytometric assay, resulting in the frequency of sjTRECs in CD45 + and CD3 + cells. Results The RQ-PCR proved to be sensitive with a detection level of approximately one sjTREC copy in 100 ng of DNA. SjTRECs could not be detected in peripheral blood leukocytes of RAG-1 −/− mice, demonstrating the specificity of the assay. As in humans and primates, sjTREC levels declined in aging and thymectomized mice. Remarkably, significant mouse strain–dependent differences in sjTREC levels were observed. 129Sv and C57BL/6 mice had significantly lower sjTREC levels in blood than Balb/c and DBA2 mice. Conclusion Quantification of murine sjTRECs by RQ-PCR may allow for accurate assessment of thymic output in mice.

The alpha(2) adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I(1)/alpha(2) (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala-NMe-Phe-Gly(ol)) to inhibit substance P-elicited nociceptive behavior in Institute of Cancer Research mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED(50)) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED(50) values of the combinations were statistically compared against their respective calculated theoretical additive ED(50) values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose-response curves compared to those of each agonist administered separately. The ED(50) values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED(50) values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine-opioid combinations may prove an effective therapeutic strategy to manage pain.

Contains fulltext : 125560.pdf (Publisher’s version ) (Open Access) Patients with hypogammaglobulinemia who do not fulfill all the classical diagnostic criteria for common variable immunodeficiency (reduction of two immunoglobulin isotypes and a reduced response to vaccination) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients with idiopathic primary hypogammaglobulinemia is not available. In 44 common variable immunodeficiency and 21 idiopathic primary hypogammaglobulinemia patients we determined the clinical phenotypes and performed flow cytometric immunophenotyping to assess the pathophysiological B-cell patterns and memory B-cell subset counts. Age-matched B-cell subset reference values of 130 healthy donors were generated. Severe pneumonia and bronchiectasis occurred at similar frequencies in idiopathic primary hypogammaglobulinemia and common variable immunodeficiency. Although IgG levels were only moderately reduced compared to common variable immunodeficiency, 12 of 21 idiopathic primary hypogammaglobulinemia patients required immunoglobulin replacement. Non-infectious disease-related clinical phenotypes (autoimmune cytopenia, polyclonal lymphocytic proliferation and persistent unexplained enteropathy) were exclusively observed in common variable immunodeficiency and were associated with early peripheral B-cell maturation defects or B-cell survival defects. T-cell dependent memory B-cell formation was more severely affected in common variable immunodeficiency. Furthermore, 14 of 21 idiopathic primary hypogammaglobulinemia patients showed normal peripheral B-cell subset counts, suggestive for a plasma cell defect. In conclusion, idiopathic primary hypogammaglobulinemia patients who do not fulfill all diagnostic criteria of common variable immunodeficiency have moderately decreased immunoglobulin levels and often a normal peripheral B-cell subset distribution, but still suffer from serious infectious complications. 01 oktober 2013

Success of adipose tissue engineering for soft tissue repair has been limited by insufficient adipogenic differentiation, an unfavorable host response, and insufficient vascularization. In this study, we examined how scaffold-free spheroid and fibrin-based environments impact these parameters in human adipose-derived stromal cell (ASC)-based adipose constructs. ASCs were differentiated in spheroids or fibrin-based constructs. After 7 days, conditioned medium was collected and spheroids/fibrin-based constructs were either harvested or implanted subcutaneously in athymic mice. Following 7 days of implantation, the number of blood vessels in fibrin-based constructs was significantly higher than in spheroids (93 ± 45 vs. 23 ± 11 vessels/mm2) and the inflammatory response to fibrin-based constructs was less severe. The reasons for these results were investigated further in vitro. We found that ASCs in fibrin-based constructs secreted significantly higher levels of the angiogenic factors VEGF and HGF and lower levels of the inflammatory cytokine IL-8. Furthermore, ASCs in fibrin-based constructs secreted significantly higher levels of leptin and showed a 2.5-fold upregulation of the adipogenic transcription factor PPARG and a fourfold to fivefold upregulation of the adipocyte-specific markers FABP4, perilipin, and leptin. These results indicate that fibrin-based ASC constructs are potentially more suitable for ASC-based adipose tissue reconstruction than scaffold-free spheroids.

Summary Background It is broadly assumed that costs caused by chronic hand eczema (CHE) are significant. However, there is a lack of cost-of-illness studies on CHE. Objectives To determine the direct and indirect costs of CHE under routine conditions in Germany from the societal perspective. Methods A cross-sectional survey was conducted in 24 outpatient practices and clinics across Germany. Patients with CHE refractory to potent topical steroids and insured by statutory health insurance were eligible. Clinical and cost data were collected using standardized questionnaires. Severity classes were defined according to a photographic guide and physician global assessment (PGA). Four treatment stages were defined based on the German CHE guidelines: topical treatments only (stage I), additionally ultraviolet (UV) radiation therapy (II), systemic therapy (III) and inpatient treatment (IV). Bivariate associations between costs and severity as well as treatment stage were assessed. Results Two hundred and twenty-three patients with CHE (mean age 45·7 years, 56% women) enrolled in the study, of whom 63·2% were treated only with topical treatments, 15·7% additionally with UV radiation and 11·7% with systemic treatments. Of all patients, 9·4% had been admitted to hospital. Total costs per year and patient were €2128, including €1742 direct costs and €386 indirect costs. The total costs increased with treatment stages I–IV (P

A processing method is presented to attenuate the surface ghost using marine twin streamer data. It is an extension to the dephase and sum method which corrects for the phase of the ghost in both streamer outputs and then adds them in an attempt to fill the notches in the amplitude spectrum. The method presented corrects both the phase and the amplitude effect of the surface ghost by combining both signals as a weighted sum. This method is applicable to all types of twin streamer data, ranging from deep exploration data to very shallow high-resolution surveys. Both the synthetic and real data examples shown are of the high-resolution type, using frequencies above 2 kHz and short streamers (active sections of the order of one metre). Both the dephase and sum method and the weighted sum method are applied to synthetic high-resolution data and the results are compared. This has been done for noise-free data, data with a high noise level and data with strong geometrical spreading on the ghost reflections. From these test results it can be concluded that in general the weighted sum method gives better results. The improvement in the signal-to-noise ratio appears to be the same, due to the additive character of both methods. In the case of high-resolution twin streamer data recorded in shallow water, the delay time of the ghost reflection can be of the same order of magnitude as the traveltime of the primary. For this situation, geometrical spreading can have a considerable effect on the amplitude of the ghost reflection. If no correction can be made for the spreading function, it might be better to use the dephase and sum method. Both methods are also applied to a real data set recorded in a high-resolution survey. Because the ghost delay is of the same order of magnitude as the arrival time of the primary, the ghost reflection is strongly affected by geometrical spreading. Since the spreading function of the source is unknown, it cannot be corrected for. This causes the result of the weighted sum method to be less reliable compared to the case where no spreading is involved.

More than 400 km of high-resolution, partially digitally acquired seismic data were collected in a 30 × 60 km area offshore from the Dutch mesotidal barrier island shoreline, in order to analyze the Holocene transgressive sequence. The investigated area was subaerially exposed during the most recent (Weichselian) Pleistocene lowstand and glaciated during the previous (Saale/Illinoian) glacial period. Sea level was probably at a level comparable to that of the present during the intervening Eem/Sangamonian highstand. The area's seismic signature is characterized by several levels of channelization, separated by major, area-wide high-amplitude reflectors. The lowermost aerial reflector represents the Saale boulder clay. The largest channel system, which cuts this reflector, was incised during the Older Dryas cooling event and filled during the Allerod warming period. It was subsequently re-incised during the Younger Dryas and refilled during the early Holocene. The most pronounced and extensive reflector represents the base of the Holocene, and almost everywhere equals the planed-off top of the Eem highstand section. This reflector is overlain by aggradational facies, separated by one level of channelization and one planed-off (ravinement?) surface. The most prominent type of seismic facies above the lowermost level of channelization is a set of progradational clinoforms, which is interpreted as a preserved ebb-tidal delta system. This system is associated with the first Holocene shoreline of ca. 7500 yrs BP. The eastern part of the study area contains sand ridges with a complex pattern of internal cross-stratification. Ridge-crest sediments are very well-sorted with a mean grain size of 2.8-2.6 φ (ca. 0.15 mm), whereas sediments in the troughs are well-sorted with a mean grain size of 1.8-0.8 φ (0.25–0.5 mm). Origin of these ridges is tentatively thought to be related to reworking since 5000 yrs BP, when the dynamic regime was more or less similar to that of the present and sediment supply had decreased substantially.

BACKGROUND AND OBJECTIVES: Interleukin-7 (IL-7) has been studied for its possible immunorestorative capacities following stem cell transplantation and has been shown to enhance post-transplant immune recovery predominantly by peripheral T-cell expansion. A major concern of IL-7 is its possible aggravating effect on graft-versus-host and host-versus-graft reactivity. DESIGN AND METHODS: To study the effect of IL-7 on host-versus-graft reactivity, we applied IL-7 in an experimental transplantation model using RAG-1-/- mice supplied with B6 CD45.1 congenic T cells as recipients of T-cell depleted allogeneic bone marrow grafts. RESULTS: Rejection of minor antigen-mismatched bone marrow was significantly reduced in IL-7 treated recipients compared with PBS treated control mice. Rejection was observed in 2 out of 18 IL-7 treated mice compared with 9 out of 17 PBS treated mice (11% vs. 53%; p=0.012). IL-7 administration resulted in enhanced recovery of peripheral blood CD4+CD25+ regulatory T cells (Treg) with a concomitant increase in peripheral blood Foxp3 mRNA expression. IL-7Ra (CD127) was expressed by the vast majority of CD4+Foxp3+ T cells. The incidence of graft rejection following fully MHC mismatched bone marrow transplantation was not reduced nor enhanced by IL-7 administration. INTERPRETATION AND CONCLUSIONS: Post-transplant IL-7 administration protects against minor antigen-mismatched bone marrow rejection, which may be due to enhanced Treg recovery

The alpha(2A)-adrenergic receptor (AR) subtype mediates antinociception induced by the alpha(2)AR agonists clonidine, dexmedetomidine, norepinephrine, and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14,304) as well as antinociceptive synergy of UK-14,304 with opioid agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and deltorphin II. Differential localization of alpha(2)-adrenergic (alpha(2A)-, alpha(2B)-(,) alpha(2C)-) and opioid (mu-, delta-, kappa-) subtypes suggests differential involvement of subtype pairs in opioid-adrenergic analgesic synergy. The present study applies a novel imidazoline(1)/alpha(2)-adrenergic receptor analgesic, moxonidine, to test for involvement of alpha(2B)- and alpha(2C)ARs in antinociception and antinociceptive synergy, because spinal antinociceptive activity of moxonidine shows minimal dependence on alpha(2A)AR. Intrathecal administration of moxonidine produced similar (2-3-fold) decreases in both mutant mice with a functional knockout of alpha(2A)AR (D79N-alpha(2A)AR) and alpha(2C)AR knockout (KO) mice. The potency of moxonidine was not altered in alpha(2B)KO mice, indicating that this subtype does not participate in moxonidine-induced spinal antinociception. Moxonidine-mediated antinociception was dose dependently inhibited by the selective alpha(2)-receptor antagonist SK&F 86466 in both D79N-alpha(2A) mice and alpha(2C)KO mice, indicating that alpha(2)AR activation is required in the absence of either alpha(2A)- or alpha(2C)AR. Spinal administration of antisense oligodeoxynucleotides directed against the alpha(2C)AR decreased both alpha(2C)AR immunoreactivity and the antinociceptive potency of moxonidine. Isobolographic analysis demonstrates that moxonidine-deltorphin antinociceptive synergy is present in the D79N-alpha(2A) mice but not in the alpha(2C)AR-KO mice. These results confirm that the alpha(2C)AR subtype contributes to spinal antinociception and synergy with opioids.

Abstract 832 Recovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation (alloSCT) is considered pivotal for full immune competence. Failure to recover thymopoiesis after alloSCT is suggested by the absence of newly developed T-cells that contain signal joint T-cell Receptor Excision Circles (sjTREC), which are produced during T-cell receptor rearrangement. Higher age, reduced pre-transplant thymic function, and graft versus host disease have all been associated with impaired thymic recovery after alloSCT. However, it is still unclear to what extent insufficient thymic recovery itself predicts for subsequent opportunistic infections and non-relapse mortality (NRM). A detailed, prospective survey of all post-engraftment infectious complications, NRM, overall survival (OS), and lymphocyte subsets and thymic recovery during long-term follow-up after alloSCT was performed in 83 high-risk recipients of T cell depleted related or unrelated donor grafts after myeloablative conditioning. A cumulative incidence of common toxicity criteria (CTC) grade 3 and 4 severe infections at 12 months after alloSCT was 66% with a median number of 1.6 severe infectious episodes per patient. The rate of severe post-engraftment infections was 0.64 per 100 patient days during the first year and 0.16 in the second year. After a median follow-up of 118 months, OS was 52%, as determined by a NRM of 25% and relapse mortality of 23%. Outcome was significantly predicted for by the European Group for Blood and Marrow Transplantation (EBMT)-risk score (Gratwohl et al, Cancer, 2009), based on age, gender, risk-status, donor-type and time to SCT (p=0.01). Lymphocyte recovery was slow with median CD4+ T cells exceeding 200/ul by 12 months post alloSCT. At that time, median sjTREC content measured 5.629/ml, which was significantly lower than the median sjTREC content in stem cell donors (19.044/ml, p=0.001). The recovery rate of overall lymphocyte counts as well as T cell subsets did not consistently predict for opportunistic infections and NRM. Patients without thymic recovery at 2, 6, 9, or 12 months were at 3- to 9-fold higher risk for severe infections, which remained significant following multivariable analysis (hazard ratio (HR)-6 months: 0.30 (95%CI 0.09–1.02, p=0.04), HR-12 months: 0.11 (0.01-0.93 p=0.02)). Impaired thymic recovery also translated into a higher risk for NRM (HR-6 months: 0.06 (0.01-0.47 p=0.008), HR-12 months: 0.00 (0.00-1.42 p=0.0005)) and outweighed pre-transplant risk factors including age, donor-type, risk-status when evaluated individually or collectively as the EBMT risk score. Impaired thymic recovery at 6 months was also predictive for lower OS (HR; 0.35 (0.12-1.00 p=0.05)). In conclusion, these results indicate that patients, who fail to recover thymopoiesis after alloSCT are at very high risk for severe infections and adverse clinical outcome, independent of other pre-transplant risk factors and despite intensive monitoring and prophylactic antimicrobial measures. These results indicate that monitoring thymopoiesis after alloSCT may be applied more routinely and strategies to reduce NRM should be directed at thymic regeneration. Disclosures: No relevant conflicts of interest to declare.

In standard seismic applications arrays of receivers are used to increase the signal to noise ratio of the recording. The directivity of the receiving system is also improved in a certain direction that can be chosen by appropriate phasing of the array elements. These arrays are so-called linear array. This means that only linear operations (like element weighting and addition) are applied in combining the outputs of the individual elements.

Reconstruction of large mucosal defects of the floor of the mouth is typically performed with keratinizing skin. Drawbacks include donor site defects and hair bearing of the flaps. Cultured mucosal substitutes (CMSs) have been developed for clinical use to replace keratinizing skin. Acellular dermis is often used as a dermal carrier for autologous cells, because it reduces wound contraction and is easier for the surgeon to handle than, for example, collagen gels. A major problem of CMSs using acellular dermis is variation in epidermal quality. To improve the quality of the CMSs, human fibroblasts were incorporated into the acellular dermis and seeded with human keratinocytes. To study the role of the fibroblasts in epidermal morphology and basement membrane formation, CMSs were stained for differentiation markers beta1 integrin, cytokeratin 10, and involucrin after 1 and 2 weeks in culture. Basement membrane formation was analyzed using laminin 5 and collagen IV and VII staining; proliferation was analyzed using Ki-67 staining. The epidermises of fibroblast-containing CMSs matured faster into a well-organized epithelium than did those that did not contain CMSs. A 52.7% increase in basal cells, a 53.5% increase in mitosis index, and a 78.0% increase in keratinocyte cell layers were observed. Addition of fibroblasts reduced culturing time and enhanced proliferation, maturation, and quality of the epidermis.

SUMMARY Syllabic prominence and word division in the construction pre-adjunct—head in Afrikaans. In this paper opposing features of syllabic prominence are shown to correlate with word division and word junction in Afrikaans.

SUMMARY The linguistic word is both a pre-scientific, intuitive concept of language and a scientifically determinable unit of specific languages. In the case of Afrikaans, the word concept has been obscured by rules regulating the written and printed word division, based on a stage of the language long since superseded by another stage approaching that obtaining in modern English, in which, inter alia, overt morphological word-class markings, e.g., those of the adjective, are no longer operative. Rules of word division based on outdated premises constantly come into conflict with the facts of the language as used to-day. These facts are the subject of study in this paper. The linguistic word has certain general features shared by all or most languages, e.g. syntactic isolatability, transferability and replaceability, besides a definite semantic uniqueness and the possession of categorical characteristics. The Afrikaans word shares these features with the known languages and has, in addition, its own word ...