Nanotopography reveals metabolites that maintain the immunomodulatory phenotype of mesenchymal stromal cells.

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that are of considerable clinical potential in transplantation and anti-inflammatory therapies due to their capacity for tissue repair and immunomodulation. However, MSCs rapidly differentiate once in culture, making their large-scale expansion for use in immunomodulatory therapies challenging. Although the differentiation mechanisms of MSCs have been extensively investigated using materials, little is known about how materials can influence paracrine activities of MSCs. Here, we show that nanotopography can control the immunomodulatory capacity of MSCs through decreased intracellular tension and increasing oxidative glycolysis. We use nanotopography to identify bioactive metabolites that modulate intracellular tension, growth and immunomodulatory phenotype of MSCs in standard culture and during larger scale cell manufacture. Our findings demonstrate an effective route to support large-scale expansion of functional MSCs for therapeutic purposes.

Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing.

Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare orphan disease caused by dysregulated complement activation resulting in thrombotic microangiopathy. Although complement-mediated endothelial injury predominantly affects the renal microvasculature, extra-renal manifestations are present in a significant proportion of patients. While eculizumab has significantly improved the morbidity and mortality of this rare disease, optimizing therapeutic regimens of this highly expensive drug remains an active area of research in the treatment of aHUS. Case Presentation: This report describes the case of a previously healthy 4 year-old male who presented with rhabdomyolysis preceding the development of aHUS with anuric kidney injury requiring dialysis. Clinical stabilization required increased and more frequent eculizumab doses compared with the standardized weight-based guidelines. In the maintenance phase of his disease, pharmacokinetic analysis indicated adequate eculizumab levels could be maintained with an individualized dosing regimen every 3 weeks, as opposed to standard 2 week dosing, confirmed in this patient over a 4 year follow up period. Cost analyses show that weight-based maintenance dosing costs $312,000 per year, while extending the dosing interval to every 3 weeks would cost $208,000, a savings of $104,000 per year, relative to the cost of $72,000 from more frequent eculizumab dosing during his initial hospitalization to suppress his acute disease. Conclusion: This case exemplifies the potential of severe, multisystem involvement of aHUS presenting with extra-renal manifestations, including rhabdomyolysis as in this case, and highlights the possibility for improved clinical outcomes and higher value care with individualized eculizumab dosing in patients over the course of their disease.

Patient-selected music rhythmically-paired with in-patient rehabilitation: A case report on an individual with acute stroke.

Background: Stroke can result in disabling impairments, affecting functional mobility, balance, and gait. Individualized in-patient rehabilitation interventions improve balance and gait in patients with stroke. Rhythmic pairing of personally-selected music with rehabilitation interventions can be a practical form of personalized therapy that could improve functional outcomes. Objective: To describe an in-patient rehabilitation intervention that rhythmically paired patient-selected music with rehabilitative interventions for a patient with acute stroke. Case Description: The patient was a 48-year old male who sustained a right thalamic hemorrhagic stroke eight days prior to admittance to the in-patient rehabilitation facility. The Berg Balance Scale (BBS) (Balance), Performance Oriented Mobility Assessment-Gait portion (POMA-G) (Gait), and Functional Independence Measure® (FIM) Motor were completed on Day 1, Day 4, and Day 16 (Discharge) during the patient's in-patient rehabilitation stay. Outcomes: From intake to discharge, balance, gait and functional mobility significantly increased by 35, 9, and 31 points, respectively. Likewise, the patient reported positive attitudes toward the novel intervention. Conclusion: Incorporating patient-selected music with in-patient physical rehabilitation may be a feasible intervention for patients with acute stroke. Further research with an adequate sample size that randomly assigns patients to music and control conditions is necessary to confirm the promising findings from this case report.

Correction to "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma.

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

The American Board of Radiology radiation oncology Maintenance of Certification Part 3 Modular Examination: Evaluation of the first administration.

Based on data obtained from clinical practice analysis (CPA) surveys performed in 2010 and 2013, and with input from its maintenance of certification (MOC) advisory committee, the American Board of Radiology (ABR) recognized that the changing nature of radiation oncology practice patterns warranted revisions of its MOC Part III cognitive examination. One significant revision was the introduction of a modular examination that allowed diplomates to select specific areas of clinical interest. The module-based items represented 30% (60 of 200) of total examination content. The new modular examination was administered for the first time in October 2015. Logistics of examination development, administration, and diplomate post-examination survey responses are reviewed.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Chromate reduction is expedited by bacteria engineered to produce the compatible solute trehalose.

The toxicity and solubility of chromium(VI) can be decreased by certain microbes that reduce chromium(VI) to chromium(III). However, these bacteria do not escape unscathed from this process. Chromium(VI) reduction damages the essential macromolecules of living systems. Trehalose protects organisms from chemical stress but has not been tested in the context of bioremediation. We engineered bacteria to produce trehalose and found that they then reduced 1 mM chromium(VI) to chromium(III), whereas wild-type cells were only able to reduce half that amount. Thus, by providing bacteria with a biochemical defense against the side-effects of chromate reduction may be a new approach to cleaning up sites that are contaminated with high levels of chromate.

Disruption of telomere-telomere interactions associated with DNA damage in human spermatozoa.

Telomeres play a fundamental role in the organization of the sperm nucleus resulting in the looped chromosome configuration and non-random positioning of chromosomes. Telomeres localize in the nuclear periphery and interact dynamically by forming dimers and tetramers. The purpose of this study was to evaluate the relationship of telomere interactions to DNA damage, a factor known to adversely influence male fertility. Telomeres were localized by fluorescence in situ hybridization (FISH) using human chromosome pan-telomeric probe in ten samples with low and ten samples with high sperm DNA damage. The samples with a low DNA fragmentation index (DFI) had a mean number of telomere signals of 21.7±1.9 compared to a mean of 26.5±3.4 signals in the samples with a high DFI (p<.005). The percentage of cells with a typical telomere distribution of ≤23 telomere-telomere dimers was observed in 70.8%±15.6 samples with a low DFI compared to 44.2%±22.4 in samples with a high DFI (p<.05). These results suggest that sperm DNA damage is associated with disruption of the normal telomere-telomere interactions leading to possible loss of the looped chromosome configuration. Improperly packed and organized sperm chromatin might have a high probability of disrupting the extremely structured sequence of sperm chromosome deposition, activation, and processing by the oocyte at the time of fertilization. These results might provide additional information on the nature of sperm DNA damage and the role of such damage on fertilization and development of the zygote.

Sperm DNA damage: correlation to severity of semen abnormalities.

OBJECTIVES: To analyze the relationship between DNA damage and standard semen parameters (SSP) in patients who present for fertility evaluation. Evaluation of male fertility includes assessment of the SSP and increasingly sperm DNA damage. However, the relationship between DNA damage and SSP remains controversial. METHODS: Following Institutional Research Ethics Board approval, semen samples from 2586 unselected nonazoospermic patients were subjected to computer-assisted semen analysis and flow cytometry-based sperm DNA damage assessment expressed as the DNA fragmentation index. RESULTS: Sperm DNA damage was significantly negatively correlated to sperm SSP (concentration, motility, and normal morphology) and positively correlated to patient's age. DNA damage increased in association with the number of abnormalities in SSP. Patients with oligoasthenoteratozoospermia had significantly higher DNA damage and more frequent DNA damage over 30% compared with normozoospermic patients and patients with abnormalities in 1 or 2 SSP. CONCLUSIONS: Our results indicate that DNA damage is significantly correlated to SSP as well as age. In addition, the degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligoasthenoteratozoospermia. Complex and possibly age-related mechanisms of DNA damage in human spermatozoa may be responsible for the strong relationship between SSP and DNA fragmentation index.

7-Azaindole-3-acetic acid derivatives: potent and selective CRTh2 receptor antagonists.

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.

Cause-specific treatment in patients with high sperm DNA damage resulted in significant DNA improvement.

Assessment of sperm DNA damage has been suggested as a negative predictor of fertility potential. Multiple pathological factors acting at both the intra-testicular and post-testicular levels may contribute to sperm DNA damage. The relative contribution of each of these factors in an individual with high DNA damage (>30%) is unclear. The management of patients with elevated DNA damage is also challenging. The purpose of our retrospective study was to evaluate the clinical course of patients with sperm DNA damage over 30% and to assess the effect of non-specific (oral antioxidant) and cause-specific treatments on the quality of their sperm DNA. Results of our retrospective study suggest that the evaluated group with high DNA damage was diagnostically heterogeneous and comprised patients with varicoceles, bacteriospermia and idiopathic infertility. A three month course of antioxidant therapy reduced sperm DNA damage in only 30/61 (49%) patients with significant improvement between the initial and post-treatment DNA Fragmentation Index (DFI) results (46.8%+/-14.1 vs. 36.7%+/-16.6, p < .001). The positive effect of antioxidants could be age-dependent, as patients older that 40 years of age showed no improvement after such treatment. The cause-specific treatments showed superior results compared to antioxidants alone. Improvement was observed in 7/9 (78%) of patients after surgical varicocele repair between the initial and post-treatment DFI results (44.7%+/-12.8 vs. 28.4%+/-9.5, p < .03). The majority of the patients 13/14 (93%) with bacteriospermia had improvement in sperm DFI results after antibiotic treatment (50.4%+/-19.1 vs. 38.6%+/-18.7, p < .001).

Baseline mannose binding lectin levels may not predict infection among children with leukemia.

We measured baseline serum mannose binding lectin (MBL) levels in 91 patients with childhood leukemia to determine their predictive value for the development of febrile neutropenia or specific infections. Median MBL levels did not differ significantly between patients who developed febrile neutropenia, bacterial infection, or disseminated fungal infection and those who did not. In addition, low MBL levels were not associated with an increased cumulative incidence of infection or with a shorter time to first infection. This preliminary study suggests that baseline MBL levels may not be clinically useful to identify pediatric leukemia patients who are at increased risk of infection. Additional studies are required to determine whether serial MBL measurements may be valuable for this purpose.

2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists.

High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.

Leukocytospermia: relationship to sperm deoxyribonucleic acid integrity in patients evaluated for male factor infertility.

The purpose of our study was to analyze the relationship of leukocytospermia to sperm DNA damage as assessed by the DNA integrity assay. Results indicate that leukocytospermia has a significant negative effect on the standard semen parameters of concentration, motility, and morphology but at most a very weak effect on DNA integrity as measured by the DNA fragmentation assay.

Age-related decline in sperm deoxyribonucleic acid integrity in patients evaluated for male infertility.

The purpose of this study was to analyze the relationship of male age and DNA integrity in men presenting for investigation of infertility. We found that men 45 years and older had significantly greater DNA fragmentation than younger men.

DNA integrity is compromised in protamine-deficient human sperm.

The objective of this study was to examine the relationship between DNA integrity and protamines in human sperm. One hundred forty-nine male infertility patients were included in an Institutional Review Board-approved study. Sperm were evaluated for DNA fragmentation using the DNA Integrity Assay, a test equivalent to the sperm chromatin structure assay (SCSA). Additionally, nuclear proteins were extracted and the protamine-1/protamine-2 ratio (P1/P2), protamine-1 (P1), protamine-2 (P2), and total protamine concentrations were evaluated. We identified 37 patients with abnormally low P1/P2 ratios, 99 patients with normal P1/P2 ratios, and 13 patients with abnormally high P1/P2 ratios. DNA fragmentation was significantly elevated in patients with low P1/P2 ratios (37.1 +/- 6.02) vs those with normal and high P1/P2 ratios (26.7 +/- 1.9 and 23.8 +/- 3.2, respectively; P < .05) and was inversely correlated with the P1/P2 ratio (R(s) -0.18, P < .05), P1 concentration (R(s) -0.29, P < .001), P2 concentration (R(s) - 0.24, P < .005), and total protamine concentration (R(s) -0.28, P < .001). Furthermore, chi2 analysis revealed a significant increase in the incidence of marked DNA fragmentation in patients with diminished levels of either P1 or P2. The present study is the first to report that human sperm protamine content is significantly related to DNA fragmentation. In particular, sperm P1 and P2 concentrations inversely correlate with DNA fragmentation, indicating a protective role of the protamines against sperm DNA damage. In light of recent studies highlighting the negative effect of sperm DNA damage on ART outcomes, these findings indicate a possible clinical significance for human sperm protamine levels.

Human sperm DNA integrity: correlation with sperm cytoplasmic droplets.

OBJECTIVES: To examine the retention of sperm cytoplasmic droplets (CD) and DNA denaturation (DD) in semen from fertile and infertile men. METHODS: Semen samples were obtained from consecutive nonazoospermic men presenting for infertility evaluation (n = 101) and fertile men presenting for vasectomy (n = 13). The standard semen parameters (sperm concentration, motility, and morphology), sperm DD, and sperm CD were monitored. Sperm DD was evaluated by flow cytometry analysis of acridine orange-treated spermatozoa and expressed as the percentage of spermatozoa demonstrating denatured DNA. RESULTS: The mean (+/-SE) percentages of spermatozoa with CD and DD were significantly higher in infertile than in fertile men (sperm CD 15.7% +/- 0.8% versus 4.8% +/- 0.7% and sperm DD 22.0% +/- 1.5% versus 10.8% +/- 1.8%, respectively). Sperm CD and DD were positively correlated (r = 0.59). Also, sperm CD and DD values correlated inversely with the standard semen parameters. CONCLUSIONS: Our data demonstrate that the retention of sperm CD correlates positively with sperm DD and that significantly higher sperm DD and CD are found in infertile than in fertile men. These data suggest that the enhanced susceptibility of sperm DNA to denaturation is associated with the abnormal disposal of residual sperm cytoplasm in the testis and/or epididymis.

Analysis of factors affecting survival in dogs with aortic body tumors.

OBJECTIVE: To evaluate the effect of perioperative and operative variables on survival time in dogs with aortic body tumors. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Twenty-four client-owned dogs with histologically confirmed aortic body tumor. METHODS: Seventy-eight patient records of dogs seen at the University of Illinois Veterinary Teaching Hospital between 1989 and 1999 with a diagnosis of a heart-base mass were reviewed. Dogs without histologic conformation of an aortic body tumor were excluded. Age; sex; breed; the presence of pleural effusion, pericardial effusion, or abdominal effusion; evidence of cardiac arrhythmias; evidence of distant metastasis; treatment with pericardectomy; treatment with chemotherapy; and time from diagnosis until euthanasia or death were recorded on a spreadsheet. Cox proportional-hazard ratios were used to calculate the relationship of risk variables to survival time. Median survival time was determined using life-table analysis. RESULTS: Twenty-four dogs met the criteria for inclusion in the study. The median age of dogs with aortic body tumors was 9 years. All dogs had a surgical biopsy performed. Fourteen dogs had a pericardectomy at the time of the biopsy procedure. Of all factors analyzed, only treatment with pericardectomy had a significant influence on survival (P =.0029). Dogs that had pericardectomy survived longer (median survival, 730 days; range, 1-1,621 days) compared with dogs that did not have pericardectomy (median survival, 42 days; range, 1-180 days). This finding was independent of the presence or absence of pericardial effusion at the time of surgery. CLINICAL RELEVANCE: Dogs that are diagnosed with aortic body tumors may benefit from a pericardectomy at the time of surgical biopsy.