A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone

© 2011 Li et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background - Endocrine disrupting chemicals (e.g., estrogens, androgens and their mimics) are known to affect reproduction in fish. 17α-ethynylestradiol is a synthetic estrogen used in birth control pills. 17β-trenbolone is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter in livestock. Both 17α-ethynylestradiol and 17β-trenbolone have been found in the aquatic environment and affect fish reproduction. In this study, we developed a physiologically-based computational model for female fathead minnows (FHM, Pimephales promelas), a small fish species used in ecotoxicology, to simulate how estrogens (i.e., 17α-ethynylestradiol) or androgens (i.e., 17β-trenbolone) affect reproductive endpoints such as plasma concentrations of steroid hormones (e.g., 17β-estradiol and testosterone) and vitellogenin (a precursor to egg yolk proteins). Results - Using Markov Chain Monte Carlo simulations, the model was calibrated with data from unexposed, 17α-ethynylestradiol-exposed, and 17β-trenbolone-exposed FHMs. Four Markov chains were simulated, and the chains for each calibrated model parameter (26 in total) converged within 20,000 iterations. With the converged parameter values, we evaluated the model's predictive ability by simulating a variety of independent experimental data. The model predictions agreed with the experimental data well. Conclusions - The physiologically-based computational model represents the hypothalamic-pituitary-gonadal axis in adult female FHM robustly. The model is useful to estimate how estrogens (e.g., 17α-ethynylestradiol) or androgens (e.g., 17β-trenbolone) affect plasma concentrations of 17β-estradiol, testosterone and vitellogenin, which are important determinants of fecundity in fish.The Medical Research Foundation of Oregon, U.S. Environmental Protection Agency, and the National Center for Computational Toxicology of the EPA Office of Research and Development

Low risk of revision after reverse shoulder arthroplasty for acute proximal humeral fractures

Background: Reverse shoulder arthroplasty (RSA) has gained popularity in the treatment of proximal humeral fractures (PHFs), especially in elderly patients. The purpose of this study was to investigate the use of RSA implants for acute PHFs and risk of revision, as well as risk factors for revision.Methods: RSA implants for acute PHFs were identified from the Nordic Arthroplasty Register Association registry data from 2004 to 2016. Kaplan-Meier survival analysis was used to calculate implant survival. Cox multiple regression analysis was used to calculate the adjusted revision rate for sex, age, country of operation, and year of surgery.Results: The study included 1523 RSA implants for PHFs (84% women; average age, 77 years; average follow-up time, 2.5 years). The 5-year cumulative implant survival rate was 97% (confidence limits, 95.5% and 98%). Revision was performed for 33 implants (2%). The most common reason for revision was instability, occurring in 11 cases (0.7%), followed by fracture, occurring in 6 (0.4%), and infection, occurring in 5 (0.3%). Four different arthroplasty brands were used in this cohort, with the Delta Xtend in two-thirds of cases (n = 1025). Age younger than 60 years and male sex were associated with slightly higher rates of revision; however, these differences did not reach statistical significance (hazard ratio of 2.02 with P = .075 and hazard ratio of 3.23 with P = .057, respectively).Conclusion: The use of RSA for acute PHFs is increasing in the Nordic countries. The short-term risk of revision is low. The main reason for revision of RSA for this indication is instability.</p

Linking species concepts to natural product discovery in the post-genomic era

A widely accepted species concept for bacteria has yet to be established. As a result, species designations are inconsistently applied and tied to what can be considered arbitrary metrics. Increasing access to DNA sequence data and clear evidence that bacterial genomes are dynamic entities that include large numbers of horizontally acquired genes have added a new level of insight to the ongoing species concept debate. Despite uncertainties over how to apply species concepts to bacteria, there is clear evidence that sequence-based approaches can be used to resolve cohesive groups that maintain the properties of species. This cohesion is clearly evidenced in the genus Salinispora, where three species have been discerned despite very close relationships based on 16S rRNA sequence analysis. The major phenotypic differences among the three species are associated with secondary metabolite production, which occurs in species-specific patterns. These patterns are maintained on a global basis and provide evidence that secondary metabolites have important ecological functions. These patterns also suggest that an effective strategy for natural product discovery is to target the cultivation of new Salinispora taxa. Alternatively, bioinformatic analyses of biosynthetic genes provide opportunities to predict secondary metabolite novelty and reduce the redundant isolation of well-known metabolites. Although much remains to be learned about the evolutionary relationships among bacteria and how fundamental units of diversity can be resolved, genus and species descriptions remain the most effective method of scientific communication

Interventional bronchoscopy for benign tracheobronchial diseases under cardiopulmonary bypass support: case reports and literature review

The use of cardiopulmonary bypass as an adjunct to airway surgery for non-malignant diseases in adults is not well established in the UK. We are reporting two cases which demonstrate the additional benefits of using cardiopulmonary bypass during difficult bronchoscopy and complex airway stenting. The first case presents an emergency indication for cardiopulmonary bypass in a life-threatening but benign condition. The second case presented, utilises cardiopulmonary bypass standby as adjunct to a potentially life threatening procedure. A review of the literature is also provided

Low arthroplasty survival after treatment for proximal humerus fracture sequelae: 3,245 shoulder replacements from the Nordic Arthroplasty Register Association

Background and purpose - Proximal humerus fractures (PHF) may result in sequelae indicating arthroplasty. We report cumulative survival rates and reasons for revision after arthroplasty for proximal humerus fracture sequelae (PHFS). Patients and methods - Data were derived from the Nordic Arthroplasty Register Association. The Kaplan-Meier method was used to illustrate survival rates. A scaled Schoenfeld residual plot was used to report the risk of revision for men relative to women in patients who were treated with reverse shoulder arthroplasty (RSA). Revision was defined as removal or exchange of any component or the addition of a glenoid component. Results - 30,190 primary arthroplasties were reported from 2004 to 2016, of which 3,245 were for PHFS. The estimated 1-, 5-, and 10-year cumulative survival rates (95% CI) were 96% (95-97), 90% (89-92), and 86% (83-88) for stemmed hemiarthroplasty and 94% (92-95), 89% (87-91), and 86% (82-90) for RSA with a median time to revision of 18 months (IQR 9-44) and 3 months (IQR 0-17). The risk of revision for men relative to women in patients who were treated with RSA was 3.2 (1.9-5.1) 0-1 year after surgery and 1.9 (0.9-4.1) 1-8 years after surgery. The estimated 1-, 5-, and 10-year cumulative survival rates (95% CI) were 94% (92-96), 88% (85-90), and 80% (75-86) for men and 95% (94-96), 86% (84-89), and 81% (77-84) for young patients. Interpretation - Shoulder arthroplasty for PHFS was associated with lower survival rates, compared with previously published results of shoulder arthroplasty for acute PHF. The low arthroplasty survival rates for men and young patients especially are worrying

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: A cohort study

<p>Abstract</p> <p>Background</p> <p>The mortality in patients with persistent low CD4 count despite several years of HAART with sustained viral suppression is poorly documented. We aimed to identify predictors for inadequate CD4 cell recovery and estimate mortality in patients with low CD4 count but otherwise successful HAART.</p> <p>Method</p> <p>In a nationwide cohort of HIV patients we identified all individuals who started HAART before 1 January 2005 with CD4 cell count ≤ 200 cells/μL and experienced three years with sustained viral suppression. Patients were categorized according to CD4 cell count after the three years suppressed period (≤ 200 cells/μL; immunological non-responders (INRs), >200 cells/μL; immunological responders (IRs)). We used logistic regression and Kaplan-Meier analysis to estimated risk factors and mortality for INRs compared to IRs.</p> <p>Results</p> <p>We identified 55 INRs and 236 IRs. In adjusted analysis age > 40 years and > one year from first CD4 cell count ≤ 200 cells/μL to start of the virologically suppressed period were associated with increased risk of INR. INRs had substantially higher mortality compared to IRs. The excess mortality was mainly seen in the INR group with > one year of immunological suppression prior to viral suppression and injection drug users (IDUs).</p> <p>Conclusion</p> <p>Age and prolonged periods of immune deficiency prior to successful HAART are risk factors for incomplete CD4 cell recovery. INRs have substantially increased long-term mortality mainly associated with prolonged immunological suppression prior to viral suppression and IDU.</p

Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment

\ua9 The Author(s) 2024. The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer’s Disease-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis

Clinical knee findings in floor layers with focus on meniscal status

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to examine the prevalence of self-reported and clinical knee morbidity among floor layers compared to a group of graphic designers, with special attention to meniscal status.</p> <p>Methods</p> <p>We obtained information about knee complaints by questionnaire and conducted a bilateral clinical and radiographic knee examination in 134 male floor layers and 120 male graphic designers. After the exclusion of subjects with reports of earlier knee injuries the odds ratio (OR) with 95% confidence intervals (CI) of knee complaints and clinical findings were computed among floor layers compared to graphic designers, using logistic regression. Estimates were adjusted for effects of body mass index, age and knee straining sports. Using radiographic evaluations, we conducted side-specific sensitivity analyses regarding clinical signs of meniscal lesions after the exclusion of participants with tibiofemoral (TF) osteoarthritis (OA).</p> <p>Results</p> <p>Reports of knee pain (OR = 2.7, 95% CI = 1.5–4.6), pain during stair walking (OR = 2.2, 95% CI = 1.3–3.9) and symptoms of catching of the knee joint (OR = 2.9, 95% CI = 1.4–5.7) were more prevalent among floor layers compared to graphic designers. Additionally, significant more floor layers than graphic designers had clinical signs suggesting possible meniscal lesions: a positive McMurray test (OR = 2.4, 95% CI = 1.1–5.0) and TF joint line tenderness (OR = 5.4, 95% CI = 2.4–12.0). Excluding floor layers (n = 22) and graphic designers (n = 15) with radiographic TF OA did not alter this trend between the two study groups: a positive McMurray test (OR = 2.2, 95% CI = 1.0–4.9), TF joint line tenderness (OR = 5.0, 95% CI = 2.0–12.5).</p> <p>Conclusion</p> <p>Results indicate that floor layers have a high prevalence of both self-reported and clinical knee morbidity. Clinical knee findings suggesting possible meniscal lesions were significant more prevalent among floor layers compared to a group of low-level exposed graphic designers and an association with occupational kneeling could be possible. However, causality cannot be confirmed due to the cross-sectional study design.</p