Stripe formation in bacterial systems with density-suppressed motility

Engineered bacteria in which motility is reduced by local cell density generate periodic stripes of high and low density when spotted on agar plates. We study theoretically the origin and mechanism of this process in a kinetic model that includes growth and density-suppressed motility of the cells. The spreading of a region of immotile cells into an initially cell-free region is analyzed. From the calculated front profile we provide an analytic ansatz to determine the phase boundary between the stripe and the no-stripe phases. The influence of various parameters on the phase boundary is discussed.Comment: 5 pages, 3 figures. Phys. Rev. Lett. in press (2012

Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

AbstractHepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment

Selective nonoperative management of high grade splenic trauma

The Evidence-based Telemedicine - Trauma & Acute Care Surgery (EBT-TACS) Journal Club performed a critical review of the literature and selected three up-to-date articles on the management of splenic trauma. Our focus was on high-grade splenic injuries, defined as AAST injury grade III-V. The first paper was an update of the 2003 Eastern Association for the Surgery of Trauma (EAST) practice management guidelines for nonoperative management of injury to the spleen. The second paper was an American Association for the Surgery of Trauma (AAST) 2012 plenary paper evaluating the predictive role of contrast blush on CT scan in AAST grade IV and V splenic injuries. Our last article was from Europe and investigates the effects of angioembolization of splenic artery on splenic function after high-grade splenic trauma (AAST grade III-V). The EBT-TACS Journal Club elaborated conclusions and recommendations for the management of high-grade splenic trauma.A reunião de revista Telemedicina baseada em evidências - Cirurgia do Trauma e Emergência (TBE-CiTE) realizou uma revisão crítica da literatura e selecionou três artigos atuais sobre o tratamento do trauma de baço. O foco foi em lesão de baço grave, definida pela American Association for the Surgery of Trauma (AAST) como graus III a V. O primeiro artigo foi uma atualização do protocolo de 2003 da Eastern Association for the Surgery of Trauma (EAST) para o tratamento não operatório de trauma do baço. O segundo artigo foi apresentado na plenária de 2012 da AAST avaliando o papel do extravasamento de contraste na tomografia computadorizada em pacientes com lesão grave de baço (AAST IV-V). O último artigo é europeu e investigou o efeito da angioembolização da artéria esplênica na função do baço após lesão esplênica grave (AAST III-V). A reunião de revista TBE-CiTE elaborou conclusões e recomendações para o tratamento de lesão grave do baço.24625

The Tribology of Sliding Elastic Media

The tribology of a sliding elastic continuum in contact with a disordered substrate is investigated analytically and numerically via a bead-spring model. The deterministic dynamics of this system exhibits a depinning transition at a finite driving force, with complex spatial-temporal dynamics including stick-slip events of all sizes. These behaviors can be understood completely by mapping the system to the well-known problem of a directed-path in {\em higher-dimensional } random media.Comment: Uuencode file: 4 pages, small changes in the previous versio

Early renal impairment affects hormonal regulators of calcium and bone metabolism and Wnt signalling and the response to vitamin D supplementation in healthy older adults

Bone and renal metabolism are regulated by common factors and there is extensive cross-talk between these organs (the ‘renal-bone-axis’). Ageing is associated with physiological changes including reduced bone mass, renal function and tissue sensitivity to regulatory hormones, impacting the renal-bone axis. We aimed to investigate the influence of estimated Glomerular Filtration Rate (eGFR) on plasma concentrations of vitamin D metabolites, Wnt signalling and bone metabolism in a dose ranging vitamin D3 RCT (12,000IU, 24,000IU, 48,000IU/month for 1 year; n=379, >70 y) with a baseline eGFR >30 ml/min/1.73m2. Participants were categorised on basis of eGFR (≥60 or <60 ml/min/1.73m2) based on 5 commonly used algorithms for eGFR. Differences between eGFR categories were tested with ANCOVA. Before supplementation commenced, a lower eGFR was associated with significantly higher concentrations of c-terminal and intact Fibroblast Growth Factor-23 (cFGF23; iFGF23), intact Parathyroid Hormone (iPTH) and Sclerostin (SOST) and lower Klotho, 1,25-dihydroxy Vitamin D (1,25(OH)2D) and Dickkopf-related Protein 1 (DKK1) concentrations. Differences between eGFR groups in 25-hydroxy Vitamin D (25(OH)D), 24,25-dihydroxy Vitamin D (24,25(OH)2D) and iPTH were only detected with eGFR based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification in Diet for Renal Disease (MDRD-4) algorithms. Differences in Bone Mineral Density and Content (BMD; BMC) and bone turnover markers were detected only with Cockcroft-Gault (CG). Pre- and post- supplementation comparisons showed differences in the response to supplementation by eGFR group. Plasma 25(OH)D, 24,25(OH)2D, 1,25(OH)2D and DKK1 increased and iPTH and C-terminal telopeptide (CTX) decreased in both groups. Plasma iFGF23, bone specific alkaline phosphatase (BAP) and Procollagen 1 intact N-terminal Propeptide (PINP) increased and phosphate decreased only in the group with eGFR ≥60 ml/min/1.73m2. Findings were largely consistent across all eGFR algorithms. Post-supplementation, cFGF23, iFGF23, iPTH and SOST remained significantly higher in the lower eGFR group. Plasma 1,25(OH)2D and Klotho did no longer differ between eGFR groups. This was found for all eGFR algorithms, with the exception of iPTH and iFGF23, which were not significantly different with eGFR based on CG. Differences in BMD and BMC were detected with CKD-EPI-creatinine and MDRD-4 but not GC. This study showed that even a moderate decline in eGFR is associated with alterations in vitamin D metabolism, Wnt signalling and bone turnover markers. Renal function influenced the response to vitamin D supplementation. Supplementation increased Vitamin D metabolites in the group with moderate renal impairment to concentrations comparable to those found in the group with normal renal function. However, although CTX decreased, an increase in bone formation markers was not found in the group with eGFR <60 ml/min/1.73m2. In conclusion, vitamin D supplementation had beneficial effects on markers of the renal-bone axis in older people with both normal and impaired renal function

Static and Dynamic Properties of Inhomogeneous Elastic Media on Disordered Substrate

The pinning of an inhomogeneous elastic medium by a disordered substrate is studied analytically and numerically. The static and dynamic properties of a $D$-dimensional system are shown to be equivalent to those of the well known problem of a $D$-dimensional random manifold embedded in $(D+D)$-dimensions. The analogy is found to be very robust, applicable to a wide range of elastic media, including those which are amorphous or nearly-periodic, with local or nonlocal elasticity. Also demonstrated explicitly is the equivalence between the dynamic depinning transition obtained at a constant driving force, and the self-organized, near-critical behavior obtained by a (small) constant velocity drive.Comment: 20 pages, RevTeX. Related (p)reprints also available at http://matisse.ucsd.edu/~hwa/pub.htm

Disorder-Induced Depinning Transition

The competition in the pinning of a directed polymer by a columnar pin and a background of random point impurities is investigated systematically using the renormalization group method. With the aid of the mapping to the noisy-Burgers' equation and the use of the mode-coupling method, the directed polymer is shown to be marginally localized to an arbitrary weak columnar pin in 1+1 dimensions. This weak localization effect is attributed to the existence of large scale, nearly degenerate optimal paths of the randomly pinned directed polymer. The critical behavior of the depinning transition above 1+1 dimensions is obtained via an $\epsilon$-expansion.Comment: 47 pages in revtex; postscript files of 6 figures include

Vitamin D supplementation for 12 months in older adults alters regulators of bone metabolism but does not change Wnt signalling pathway markers

Vitamin D status and supplementation regulates bone metabolism and may modulate Wnt-signalling. We studied the response of hormonal regulators of bone metabolism, markers of Wnt signalling and bone turnover and BMD and BMC in a randomised vitamin D intervention trial (12,000IU, 24,000IU, 48,000IU/month for 1 year; men and women >70y; n=379; ISRCTN35648481). Associations with total and free 25(OH)D concentrations were analysed by linear regression. Baseline vitamin D status was (mean ± SD) 25(OH)D: 40.0 +/- 20.1 nmol/L. Supplementation dose-dependently increased total and free 25(OH)D concentrations and decreased plasma phosphate and PTH (all p<0.05). The PINP:CTX ratio, cFGF23 and iFGF23 significantly increased with no between-group differences, while Klotho was unchanged. 1,25(OH)2D and PINP significantly increased in the 24 and 48,000IU groups. SOST, OPG, RANKL, BMD, BMC and CTX remained unchanged. Subgroup analyses with baseline 25(OH)D<25nmol/L (n= 94) provided similar results. Baseline total and free 25(OH)D concentrations were positively associated with 1,25(OH)2D, 24,25(OH)2D (p<0.001), DBP (p<0.05), BMD and BMC (P<0.05). Associations with PTH (p<0.001), cFGF23 (p<0.01) and BAP (p<0.05) were negative. After supplementation, total and free 25(OH)D concentrations remained positively associated only with 24,25(OH)2D (p<0.001), DBP (p<0.001) and negatively with eGFR (p<0.01). PTH and SOST were significantly associated only with free 25(OH)D. There were no significant relationships with BMD and BMC after supplementation. The decrease in PTH and increase in PINP:CTX ratio suggest a protective effect of supplementation on bone metabolism although no significant effect on BMD or pronounced changes in regulators of Wnt signalling were found. The increase in FGF23 warrants caution due to its negative association with skeletal and cardiovascular health. Associations of total and free 25(OH)D with biomarkers were similar and known positive associations between vitamin D status and BMD were confirmed. The change in associations after supplementation might suggest a threshold effect

Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented