Effects of Anti-VEGF on Predicted Antibody Biodistribution: Roles of Vascular Volume, Interstitial Volume, and Blood Flow

BACKGROUND: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences. METHODOLOGY/PRINCIPAL FINDINGS: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice. CONCLUSIONS/SIGNIFICANCE: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF

The Politics of Evidence Use in Health Policy Making in Germany-the Case of Regulating Hospital Minimum Volumes.

This article examines the role of scientific evidence in informing health policy decisions in Germany, using minimum volumes policy as a case study. It argues that scientific evidence was used strategically at various stages of the policy process both by individual corporatist actors and by the Federal Joint Committee as the regulator. Minimum volumes regulation was inspired by scientific evidence suggesting a positive relationship between service volume and patient outcomes for complex surgical interventions. Federal legislation was introduced in 2002 to delegate the selection of services and the setting of volumes to corporatist decision makers. Yet, despite being represented in the Federal Joint Committee, hospitals affected by its decisions took the Committee to court to seek legal redress and prevent policy implementation. Evidence has been key to support, and challenge, decisions about minimum volumes, including in court. The analysis of the role of scientific evidence in minimum volumes regulation in Germany highlights the dynamic relationship between evidence use and the political and institutional context of health policy making, which in this case is characterized by the legislative nature of policy making, corporatism, and the role of the judiciary in reviewing policy decisions

Probiotics [LGG-BB12 or RC14-GR1] versus placebo as prophylaxis for urinary tract infection in persons with spinal cord injury [ProSCIUTTU]: a randomised controlled trial

© 2019, The Author(s). Study design: Randomised double-blind factorial-design placebo-controlled trial. Objective: Urinary tract infections (UTIs) are common in people with spinal cord injury (SCI). UTIs are increasingly difficult to treat due to emergence of multi-resistant organisms. Probiotics are efficacious in preventing UTIs in post-menopausal women. We aimed to determine whether probiotic therapy with Lactobacillus reuteri RC-14+Lactobacillus GR-1 (RC14-GR1) and/or Lactobacillus rhamnosus GG+Bifidobacterium BB-12 (LGG-BB12) are effective in preventing UTI in people with SCI. Setting: Spinal units in New South Wales, Australia with their rural affiliations. Methods: We recruited 207 eligible participants with SCI and stable neurogenic bladder management. They were randomised to one of four arms: RC14-GR1+LGG-BB12, RC14-GR1+placebo, LGG-BB12+ placebo or double placebos for 6 months. Randomisation was stratified by bladder management type and inpatient or outpatient status. The primary outcome was time to occurrence of symptomatic UTI. Results: Analysis was based on intention to treat. Participants randomised to RC14-GR1 had a similar risk of UTI as those not on RC14-GR1 (HR 0.67; 95% CI: 0.39–1.18; P = 0.17) after allowing for pre-specified covariates. Participants randomised to LGG-BB12 also had a similar risk of UTI as those not on LGG-BB12 (HR 1.29; 95% CI: 0.74–2.25; P = 0.37). Multivariable post hoc survival analysis for RC14-GR1 only vs. the other three groups showed a potential protective effect (HR 0.46; 95% CI: 0.21–0.99; P = 0.03), but this result would need to be confirmed before clinical application. Conclusion: In this RCT, there was no effect of RC14-GR1 or LGG-BB12 in preventing UTI in people with SCI

The impact of intolerance of uncertainty and cognitive behavioural instructions on safety learning

Background Difficulty updating threat associations to safe associations has been observed in individuals who score high in self-reported Intolerance of Uncertainty (IU). Here we sought to determine whether an instruction based on fundamental principles of Cognitive Behavioural Therapy could promote safety learning in individuals with higher levels of IU, whilst controlling for self-reported trait anxiety (STICSA). Methods We measured skin conductance response, pupil dilation and expectancy ratings during an associative threat learning task in which participants either received a cognitive behavioural instruction or no instruction prior to threat extinction (n = 92). Results Analyses revealed that both self-reported IU and STICSA similarly predicted differences in skin conductance response. Only individuals with lower IU/STICSA in the cognitive behavioural instruction condition displayed successful safety learning via skin conductance response. Conclusions These initial results provide some insight into how simple cognitive behavioural instructions combined with exposure are applied differently in individuals with varying levels of self-reported anxiety. The results further our understanding of the role of basic cognitive behavioural principles and self-reported anxiety in safety learning

Transcriptome Analysis of Female and Male Xiphophorus maculatus Jp 163 A

Background: Xiphophorus models are important for melanoma, sex determination and differentiation, ovoviviparity and evolution. To gain a global view of the molecular mechanism(s) whereby gene expression may influence sexual dimorphism in Xiphophorus and to develop a database for future studies, we performed a large-scale transcriptome study. Methodology/Principal Findings: The 454-FLX massively parallel DNA sequencing platform was employed to obtain 742,771 and 721,543 reads from 2 normalized cDNA libraries generated from whole adult female and male X. maculatus Jp 163 A, respectively. The reads assembled into 45,538 contigs (here, a "contig" is a set of contiguous sequences), of which, 11,918 shared homology to existing protein sequences. These numbers estimate that the contigs may cover 53% of the total number of Xiphophorus transcriptome. Putative translations were obtained for 11,918 cDNA contigs, of which, 3,049 amino acid sequences contain Pfam domains and 11,064 contigs encode secretory proteins. A total of 3,898 contigs were associated with 2,781 InterPro (IPR) entries and 5,411 contigs with 132 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. There were 10,446 contigs annotated with 69,778 gene ontology (GO) terms and the three corresponding organizing principles. Fifty-four potential sex differentially expressed genes have been identified from these contigs. Eight and nine of these contigs were confirmed by real-time PCR as female and male predominantly expressed genes respectively. Based on annotation results, 34 contigs were predicted to be differentially expressed in male and female and 17 of them were also confirmed by real-time PCR. Conclusions/Significance: This is the first report of an annotated overview of the transcriptome of X. maculatus and identification of sex differentially expressed genes. These data will be of interest to researchers using the Xiphophorus model. This work also provides an archive for future studies in molecular mechanisms of sexual dimorphism and evolution, and can be used in comparative studies of other fish

A randomized controlled trial to prevent glycemic relapse in longitudinal diabetes care: Study protocol (NCT00362193)

BACKGROUND: Diabetes is a common disease with self-management a key aspect of care. Large prospective trials have shown that maintaining glycated hemoglobin less than 7% greatly reduces complications but translating this level of control into everyday clinical practice can be difficult. Intensive improvement programs are successful in attaining control in patients with type 2 diabetes, however, many patients experience glycemic relapse once returned to routine care. This early relapse is, in part, due to decreased adherence in self-management behaviors. OBJECTIVE: This paper describes the design of the Glycemic Relapse Prevention study. The purpose of this study is to determine the optimal frequency of maintenance intervention needed to prevent glycemic relapse. The primary endpoint is glycemic relapse, which is defined as glycated hemoglobin greater than 8% and an increase of 1% from baseline. METHODS: The intervention consists of telephonic contact by a nurse practitioner with a referral to a dietitian if indicated. This intervention was designed to provide early identification of self-care problems, understanding the rationale behind the self-care lapse and problem solve to find a negotiated solution. A total of 164 patients were randomized to routine care (least intensive), routine care with phone contact every three months (moderate intensity) or routine care with phone contact every month (most intensive). CONCLUSION: The baseline patient characteristics are similar across the treatment arms. Intervention fidelity analysis showed excellent reproducibility. This study will provide insight into the important but poorly understood area of glycemic relapse prevention

Neurotransmitter Transporter-Like: A Male Germline-specific SLC6 Transporter Required for Drosophila Spermiogenesis

The SLC6 class of membrane transporters, known primarily as neurotransmitter transporters, is increasingly appreciated for its roles in nutritional uptake of amino acids and other developmentally specific functions. A Drosophila SLC6 gene, Neurotransmitter transporter-like (Ntl), is expressed only in the male germline. Mobilization of a transposon inserted near the 3′ end of the Ntl coding region yields male-sterile mutants defining a single complementation group. Germline transformation with Ntl cDNAs under control of male germline-specific control elements restores Ntl/Ntl homozygotes to normal fertility, indicating that Ntl is required only in the germ cells. In mutant males, sperm morphogenesis appears normal, with elongated, individualized and coiled spermiogenic cysts accumulating at the base of the testes. However, no sperm are transferred to the seminal vesicle. The level of polyglycylation of Ntl mutant sperm tubulin appears to be significantly lower than that of wild type controls. Glycine transporters are the most closely related SLC6 transporters to Ntl, suggesting that Ntl functions as a glycine transporter in developing sperm, where augmentation of the cytosolic pool of glycine may be required for the polyglycylation of the massive amounts of tubulin in the fly's giant sperm. The male-sterile phenotype of Ntl mutants may provide a powerful genetic system for studying the function of an SLC6 transporter family in a model organism

Proceedings of the 4^thBEAT-PCD Conference and 5^thPCD Training School

Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and situs abnormalities. As PCD is rare, it is important that scientists and clinicians foster international collaborations to share expertise in order to provide the best possible diagnostic and management strategies. ‘Better Experimental Approaches to Treat Primary Ciliary Dyskinesia’ (BEAT-PCD) is a multidisciplinary network funded by EU COST Action (BM1407) to coordinate innovative basic science and clinical research from across the world to drive advances in the field. The fourth and final BEAT-PCD Conference and fifth PCD Training School were held jointly in March 2019 in Poznan, Poland. The varied program of plenaries, workshops, break-out sessions, oral and poster presentations were aimed to enhance the knowledge and skills of delegates, whilst also providing a collaborative platform to exchange ideas. In this final BEAT-PCD conference we were able to build upon programmes developed throughout the lifetime of the COST Action. These proceedings report on the conference, highlighting some of the successes of the BEAT-PCD programme

Determination of sin2 θeff w using jet charge measurements in hadronic Z decays

The electroweak mixing angle is determined with high precision from measurements of the mean difference between forward and backward hemisphere charges in hadronic decays of the Z. A data sample of 2.5 million hadronic Z decays recorded over the period 1990 to 1994 in the ALEPH detector at LEP is used. The mean charge separation between event hemispheres containing the original quark and antiquark is measured for bb̄ and cc̄ events in subsamples selected by their long lifetimes or using fast D*'s. The corresponding average charge separation for light quarks is measured in an inclusive sample from the anticorrelation between charges of opposite hemispheres and agrees with predictions of hadronisation models with a precision of 2%. It is shown that differences between light quark charge separations and the measured average can be determined using hadronisation models, with systematic uncertainties constrained by measurements of inclusive production of kaons, protons and A's. The separations are used to measure the electroweak mixing angle precisely as sin2 θeff w = 0.2322 ± 0.0008(exp. stat.) ±0.0007(exp. syst.) ± 0.0008(sep.). The first two errors are due to purely experimental sources whereas the third stems from uncertainties in the quark charge separations

Association of Marek's Disease induced immunosuppression with activation of a novel regulatory T cells in chickens.

Marek’s Disease Virus (MDV) is an alphaherpesvirus that infects chickens, transforms CD4+ T cells and causes deadly lymphomas. In addition, MDV induces immunosuppression early during infection by inducing cell death of the infected lymphocytes, and potentially due to activation of regulatory T (Treg)-cells. Furthermore, immunosuppression also occurs during the transformation phase of the disease; however, it is still unknown how the disease can suppress immune response prior or after lymphoma formation. Here, we demonstrated that chicken TGF-beta+ Treg cells are found in different lymphoid tissues, with the highest levels found in the gut-associated lymphoid tissue (cecal tonsil: CT), fostering an immune-privileged microenvironment exerted by TGF-beta. Surprisingly, significantly higher frequencies of TGF-beta+ Treg cells are found in the spleens of MDV-susceptible chicken lines compared to the resistant line, suggesting an association between TGF-beta+ Treg cells and host susceptibility to lymphoma formation. Experimental infection with a virulent MDV elevated the levels of TGF-beta+ Treg cells in the lungs as early as 4 days post infection, and during the transformation phase of the disease in the spleens. In contrast to TGF-beta+ Treg cells, the levels of CD4+CD25+ T cells remained unchanged during the infection and transformation phase of the disease. Furthermore, our results demonstrate that the induction of TGF-beta+ Treg cells is associated with pathogenesis of the disease, as the vaccine strain of MDV did not induce TGF-beta+ Treg cells. Similar to human haematopoietic malignant cells, MDV-induced lymphoma cells expressed high levels of TGF-beta but very low levels of TGF-beta receptor I and II genes. The results confirm that COX-2/ PGE2 pathway is involved in immunosuppression induced by MDV-lymphoma cells. Taken together, our results revealed a novel TGF-beta+ Treg subset in chickens that is activated during MDV infection and tumour formation.Biotechnology and Biological Sciences Research Counci