Efficacy of three BCG strains (Connaught, TICE and RIVM) with or without secondary resection (re-TUR) for intermediate/high-risk non-muscle-invasive bladder cancers: results from a retrospective single-institution cohort analysis

Purpose: (I) To evaluate the clinical efficacy of three different BCG strains in patients with intermediate-/high-risk non-muscle-invasive bladder cancer (NMIBC). (II) To determine the importance of performing routine secondary resection (re-TUR) in the setting of BCG maintenance protocol for the three strains. Methods: NMIBCs who received an adjuvant induction followed by a maintenance schedule of intravesical immunotherapy with BCG Connaught, TICE and RIVM. Only BCG-naïve and those treated with the same strain over the course of follow-up were included. Cox proportional hazards model was developed according to prognostic factors by the Spanish Urological Oncology Group (CUETO) as well as by adjusting for the implementation of re-TUR. Results: n = 422 Ta-T1 patients (Connaught, n = 146; TICE, n = 112 and RIVM, n = 164) with a median (IQR) follow-up of 72 (60-85) were reviewed. Re-TUR was associated with improved recurrence and progression outcomes (HRRFS: 0.63; 95% CI 0.46-0.86; HRPFS: 0.55; 95% CI 0.31-0.86). Adjusting for CUETO risk factors and re-TUR, BGC TICE and RIVM provided longer RFS compared to Connaught (HRTICE: 0.58, 95% CI 0.39-0.86; HRRIVM: 0.61, 95% CI 0.42-0.87) while no differences were identified between strains for PFS and CSS. Sub-analysis of only re-TUR cases (n = 190, 45%) showed TICE the sole to achieve longer RFS compared to both Connaught and RIVM. Conclusion: Re-TUR was confirmed to ensure longer RFS and PFS in intermediate-/high-risk NMIBCs but did not influence the relative single BCG strain efficacy. When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to the other strains for RFS outcomes

Can sacrificial feeding areas protect aquatic plants from herbivore grazing? Using behavioural ecology to inform wildlife management

Effective wildlife management is needed for conservation, economic and human well-being objectives. However, traditional population control methods are frequently ineffective, unpopular with stakeholders, may affect non-target species, and can be both expensive and impractical to implement. New methods which address these issues and offer effective wildlife management are required. We used an individual-based model to predict the efficacy of a sacrificial feeding area in preventing grazing damage by mute swans (Cygnus olor) to adjacent river vegetation of high conservation and economic value. The accuracy of model predictions was assessed by a comparison with observed field data, whilst prediction robustness was evaluated using a sensitivity analysis. We used repeated simulations to evaluate how the efficacy of the sacrificial feeding area was regulated by (i) food quantity, (ii) food quality, and (iii) the functional response of the forager. Our model gave accurate predictions of aquatic plant biomass, carrying capacity, swan mortality, swan foraging effort, and river use. Our model predicted that increased sacrificial feeding area food quantity and quality would prevent the depletion of aquatic plant biomass by swans. When the functional response for vegetation in the sacrificial feeding area was increased, the food quantity and quality in the sacrificial feeding area required to protect adjacent aquatic plants were reduced. Our study demonstrates how the insights of behavioural ecology can be used to inform wildlife management. The principles that underpin our model predictions are likely to be valid across a range of different resource-consumer interactions, emphasising the generality of our approach to the evaluation of strategies for resolving wildlife management problems

Irradiation-Induced Up-Regulation of HLA-E on Macrovascular Endothelial Cells Confers Protection against Killing by Activated Natural Killer Cells

BACKGROUND: Apart from the platelet/endothelial cell adhesion molecule 1 (PECAM-1, CD31), endoglin (CD105) and a positive factor VIII-related antigen staining, human primary and immortalized macro- and microvascular endothelial cells (ECs) differ in their cell surface expression of activating and inhibitory ligands for natural killer (NK) cells. Here we comparatively study the effects of irradiation on the phenotype of ECs and their interaction with resting and activated NK cells. METHODOLOGY/PRINCIPAL FINDINGS: Primary macrovascular human umbilical vein endothelial cells (HUVECs) only express UL16 binding protein 2 (ULBP2) and the major histocompatibility complex (MHC) class I chain-related protein MIC-A (MIC-A) as activating signals for NK cells, whereas the corresponding immortalized EA.hy926 EC cell line additionally present ULBP3, membrane heat shock protein 70 (Hsp70), intercellular adhesion molecule ICAM-1 (CD54) and HLA-E. Apart from MIC-B, the immortalized human microvascular endothelial cell line HMEC, resembles the phenotype of EA.hy926. Surprisingly, primary HUVECs are more sensitive to Hsp70 peptide (TKD) plus IL-2 (TKD/IL-2)-activated NK cells than their immortalized EC counterpatrs. This finding is most likely due to the absence of the inhibitory ligand HLA-E, since the activating ligands are shared among the ECs. The co-culture of HUVECs with activated NK cells induces ICAM-1 (CD54) and HLA-E expression on the former which drops to the initial low levels (below 5%) when NK cells are removed. Sublethal irradiation of HUVECs induces similar but less pronounced effects on HUVECs. Along with these findings, irradiation also induces HLA-E expression on macrovascular ECs and this correlates with an increased resistance to killing by activated NK cells. Irradiation had no effect on HLA-E expression on microvascular ECs and the sensitivity of these cells to NK cells remained unaffected. CONCLUSION/SIGNIFICANCE: These data emphasize that an irradiation-induced, transient up-regulation of HLA-E on macrovascular ECs might confer protection against NK cell-mediated vascular injury

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance

Barnyard grasses were processed with rice around 10000 years ago

Rice (Oryza sativa) is regarded as the only grass that was selected for cultivation and eventual domestication in the Yangtze basin of China. Although both macro-fossils and micro-fossils of rice have been recovered from the Early Neolithic site of Shangshan, dating to more than 10,000 years before present (BP), we report evidence of phytolith and starch microfossils taken from stone tools, both for grinding and cutting, and cultural layers, that indicating barnyard grass (Echinochloa spp.) was a major subsistence resource, alongside smaller quantities of acorn starches (Lithocarpus/Quercus sensu lato) and water chestnuts (Trapa). This evidence suggests that early managed wetland environments were initially harvested for multiple grain species including barnyard grasses as well as rice, and indicate that the emergence of rice as the favoured cultivated grass and ultimately the key domesticate of the Yangtze basin was a protracted process

Distinctive features of spatial planning nearby estuaries – an exploratory analysis of water-related rules in municipal master plans in Portugal

Land-use types and related intensities are often associated with pressures and disturbances on estuarine envi- ronmental values and ecosystem services provided by water. Although with varied legal frameworks across countries, broadly, spatial planning has been expected to contribute to the protection of environmentally sen- sitive areas, such as estuaries. Among the various planning tools are the plan’s land-use control rules. This article studies the incorporation of water-related terms in the regulations of municipal master plans to assess if land-use rules established on estuarine areas are significantly different from others, such as in upstream areas. It does so by developing a content analysis of a set of plans’ regulations located in estuarine and upstream areas of two river basins of Mainland Portugal. The results show greater incorporation of water-related terms in plans’ reg- ulations located in estuarine areas. Moreover, they show a greater diversity of water-related topics, types, and focus of rules on estuarine areas, whereas on upstream areas the regulatory approaches look poorer. Although the incorporation of water-related terms is globally higher in younger plans, and to a certain extent, in more arti- ficialized and dense territories, a clear distinctiveness of water-related concerns in land-use regulations of municipal plans on estuarine areas remains visible. Surprisingly, the results bring to the fore fragilities of land- use regulations on upstream areas worthy of attention in future studies. The methodology used for content analysis disclosed a valuable path for future research as it is easily expandable to take into consideration different land-uses or to be applied to different regions, to further refine if the distinctive features are explicitly related with estuarine areas or with other types of water problems.publishe

Nogo-Receptors NgR1 and NgR2 Do Not Mediate Regulation of CD4 T Helper Responses and CNS Repair in Experimental Autoimmune Encephalomyelitis

Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4+ Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure

Help-seeking pathways in early psychosis

INTRODUCTION: Understanding the help-seeking pathways of patients with a putative risk of developing psychosis helps improving development of specialised care services. This study aimed at obtaining information about: type of health professionals contacted by patients at putative risk for psychosis on their help-seeking pathways; number of contacts; type of symptoms leading to contacts with health professionals; interval between initial contact and referral to a specialised outpatient service. METHOD: The help-seeking pathways were assessed as part of a prospective study in 104 patients with suspected at-risk states for psychosis. RESULTS: The mean number of contacts prior to referral was 2.38. Patients with psychotic symptoms more often contacted mental health professionals, whereas patients with insidious and more unspecific features more frequently contacted general practitioners (GPs). CONCLUSIONS: GPs have been found to under-identify the insidious features of emerging psychosis (Simon et al. (2005) Br J Psychiatry 187:274–281). The fact that they were most often contacted by patients with exactly these features calls for focussed and specialised help for primary care physicians. Thus, delays along the help-seeking pathways may be shortened. This may be of particular relevance for patients with the deficit syndrome of schizophrenia

Effect of tube diameter and capillary number on platelet margination and near-wall dynamics

The effect of tube diameter $D$ and capillary number $Ca$ on platelet margination in blood flow at $\approx 37\%$ tube haematocrit is investigated. The system is modelled as three-dimensional suspension of deformable red blood cells and nearly rigid platelets using a combination of the lattice-Boltzmann, immersed boundary and finite element methods. Results show that margination is facilitated by a non-diffusive radial platelet transport. This effect is important near the edge of the cell-free layer, but it is only observed for $Ca > 0.2$, when red blood cells are tank-treading rather than tumbling. It is also shown that platelet trapping in the cell-free layer is reversible for $Ca \leq 0.2$. Only for the smallest investigated tube ($D = 10 \mu\text{m}$) margination is essentially independent of $Ca$. Once platelets have reached the cell-free layer, they tend to slide rather than tumble. The tumbling rate is essentially independent of $Ca$ but increases with $D$. Tumbling is suppressed by the strong confinement due to the relatively small cell-free layer thickness at $\approx 37\%$ tube haematocrit.Comment: 16 pages, 10 figure