Quantitative predictions on auxin-induced polar distribution of PIN proteins during vein formation in leaves

The dynamic patterning of the plant hormone auxin and its efflux facilitator the PIN protein are the key regulator for the spatial and temporal organization of plant development. In particular auxin induces the polar localization of its own efflux facilitator. Due to this positive feedback auxin flow is directed and patterns of auxin and PIN arise. During the earliest stage of vein initiation in leaves auxin accumulates in a single cell in a rim of epidermal cells from which it flows into the ground meristem tissue of the leaf blade. There the localized auxin supply yields the successive polarization of PIN distribution along a strand of cells. We model the auxin and PIN dynamics within cells with a minimal canalization model. Solving the model analytically we uncover an excitable polarization front that triggers a polar distribution of PIN proteins in cells. As polarization fronts may extend to opposing directions from their initiation site we suggest a possible resolution to the puzzling occurrence of bipolar cells, such we offer an explanation for the development of closed, looped veins. Employing non-linear analysis we identify the role of the contributing microscopic processes during polarization. Furthermore, we deduce quantitative predictions on polarization fronts establishing a route to determine the up to now largely unknown kinetic rates of auxin and PIN dynamics.Comment: 9 pages, 4 figures, supplemental information included, accepted for publication in Eur. Phys. J.

Effect of different weaning age (21, 28 or 35 days) on production, growth and certain parameters of the digestive tract in rabbits

The effect of different weaning ages, that is, 21 (G21), 28 (G28) or 35 (G35) days, on growth and certain parameters of the digestive tract was examined in rabbits to assess the risk of early weaning attributable to the less-developed digestive system. On days 35 and 42, G35 rabbits had 10% to 14% and 10% higher BW, respectively ( P,0.05), than those weaned at days 21 and 28. In the 4th week of life, early weaned animals had 75% higher feed intake than G28 and G35 rabbits ( P,0.05). The relative weight of the liver increased by 62% between 21 and 28 days of age, and thereafter it decreased by 76% between 35 and 42 days of age ( P,0.05), with G21 rabbits having 29% higher weight compared with G35 animals on day 35 ( P,0.05). The relative weight of the whole gastrointestinal (GI) tract increased by 49% and 22% after weaning in G21 and G28 rabbits, respectively ( P,0.05). On day 28, the relative weight of the GI tract was 19% higher in G21 than in G28 rabbits, whereas on day 35 G21 and G28 animals had a 12% heavier GI tract compared with G35 rabbits ( P,0.05). Age influenced the ratio of stomach, small intestine and caecum within the GI tract; however, no effect of different weaning age was demonstrated. The pH value of the stomach and caecum decreased from 5.7 to 1.6 and from 7.1 to 6.3, respectively, whereas that of the small intestine increased from 6.8 to 8.4 ( P,0.05); the differences between groups were not statistically significant. Strictly anaerobic culturable bacteria were present in the caecum in high amounts (108), already at 14 days of age; no significant difference attributable to weaning age was demonstrable. The concentration of total volatile fatty acids (tVFA) was higher in G21 than in G28 and G35 throughout the experimental period ( P,0.05). The proportion of acetic and butyric acid within tVFA increased, whereas that of propionic acid decreased, resulting in a C3 : C4 ratio decreasing with age. Early weaning (G21) resulted in higher butyric acid and lower propionic acid proportions on day 28 ( P,0.05). No interaction between age and treatment was found, except in relative weight of the GI tract and caecal content. In conclusion, early weaning did not cause considerable changes in the digestive physiological parameters measured, but it resulted in 10% lower growth in rabbits

Diagnosis and Management of Iliac Artery Endofibrosis: Results of a Delphi Consensus Study

Objective Iliac endofibrosis is a rare condition that may result in a reduction of blood flow to the lower extremity in young, otherwise healthy individuals. The data to inform everyday clinical management are weak and therefore a Delphi consensus methodology was used to explore areas of consensus and disagreement concerning the diagnosis and management of patients with suspected iliac endofibrosis. Methods A three-round Delphi questionnaire approach was used among vascular surgeons, sports physicians, sports scientists, radiologists, and clinical vascular scientists with experience of treating this condition to explore diagnosis and clinical management issues for patients with suspected iliac artery endofibrosis. Analysis is based on 18 responses to round 2 and 14 responses to round 3, with agreement reported when 70% of respondents were in agreement. Results Initially there was agreement on the typical symptoms at presentation and the need for an exercise test in the diagnosis. Round 3 clarified that duplex ultrasound was a useful tool in the diagnosis of endofibrosis. There was consensus on the most appropriate type of surgery (endarterectomy and vein patch) and that endovascular interventions were inadvisable. The final round helped to inform aspects of the natural history and post-operative surveillance. Progression of the disease was likely with continued exercise but cessation may prevent progression. Surveillance after surgery is generally recommended yearly with at least a clinical assessment. Conclusions There is broad agreement about the presenting symptoms and the investigations required to confirm (or exclude) the diagnosis of iliac endofibrosis. There was consensus on the surgical approach to repair. Disagreement existed about the specific diagnostic criteria that should be applied during non-invasive testing and about post-operative care and resumption of exercise

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphom

Available evidence and outcome of off-label use of rituximab in clinical practice

Purpose: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. Methods: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. Results: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30months) in 69.2%of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). Conclusions: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice

What is the secondary patency of thrombosed bypasses of the lower limbs cleared by fibrinolysis in situ?

OBJECTIVES: In case of acute thrombosis, lower limbs bypasses can, in certain cases, be cleared by local intra-arterial fibrinolysis (LIF). The aim of this study was to evaluate the secondary patency of thrombosed bypasses after fibrinolysis. METHODS: This retrospective study includes all patients hospitalized for thrombosed bypasses of the lower limbs that were treated with in situ fibrinolysis using urokinase, between 2004 and 2013, in two French university hospital centers. Fibrinolysis was indicated in case of recent thrombosis (< 3 weeks) provoking acute limb ischemia without sensory-motor deficit and in the absence of general contraindications. The secondary patency of the grafts was defined as the time after fibrinolysis without a new thrombotic event. RESULTS: There were 207 patients, hospitalized for recent thrombosis of 244 bypasses. The LIF was efficient in 74% of the cases (n=180). Secondary patency of these bypasses, was 54.2% and 32.4% overall, 68.3% and 50.3% for the supra-inguinal bypasses and 48.3% and 21.5% for the infra-inguinal bypasses, at 1 year and 5 years respectively. There is a significant difference (p = 0.002) regarding the permeability of the supra-inguinal and infra-inguinal bypasses. The survival rate was 75% (± 6.4%) at 5 years and the limb salvage rate was 89% (± 3.3%), 78.2% (±5.1%) and 75% (±5.8%) at 1 year, 3 years et 5 years respectively. The only independent factor influencing the secondary patency of infra-inguinal bypasses that was significant in a multivariate analysis was the infragenicular localization of the distal anastomosis (p=0.023). CONCLUSIONS: LIF is an effective approach that often allows the identification of the underlying cause, permitting elective adjunctive treatment of the underlying cause. Although LIF is at least as effective as its therapeutic alternatives described in the literature, the secondary patency of the bypasses remains modest and encourages close monitoring, particularly in patients with an infragenicular bypass

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Effect of late weaning and use of alternative cages on performance of does, suckling and fattening rabbits under extensive reproductive management

The effects of the combined use of long lactation periods (46 days) with alternative cages on the reproductive and growth performance of 104 rabbit does and their litters during five consecutive reproductive cycles were studied. Half of does were housed in conventional polyvalent cages (39 cm×100 cm×30 cm) and the other half in alternative polyvalent cages (39 cm×100 cm×60 cm), with a raised platform. Half of the rabbit does in each type of cage were weaned at 32 and the other half at 46 days after parturition. Longer lactation negatively affected the body weight (P<0.001), fat and energy content (P<0.05) of rabbit does at the end of the lactation period, but this effect decreased with the number of parturitions. Fertility, prolificacy and doe mortality were not affected by lactation length. Late weaning led to higher litter size (by 8.9%) and litter weight (by 11.3%) at the end of growing period (P<0.001) and lower feed conversion ratio per cage during the experimental period (13.5%) than weaning at 32 day (P<0.001). These results were paralleled by lower mortality (12.6 vs. 17.6%; P<0.01) of young rabbits weaned later during the overall experimental period. Differences in performance as a result of different weaning ages were only observed during cycles with worst health status (third and fifth cycles) in which late weaning decreased mortality. Type of cage did not affect doe body weight and body condition, mortality, fertility, prolificacy and litter size during the five reproductive cycles. Nevertheless, at day 21 litter weight and feed conversion ratio between 3 and 21 day were 4.2% higher (P<0.01) and 5.0% lower (P<0.05), respectively, in animals housed in alternative rather than in conventional cages. Alternative cages also led to heavier litters at 59 days (P<0.01). It was concluded that the combined use of longer lactations and cages with higher available surface with a raised platform could be alternatives to improve animal welfare in farmed rabbit

Multiscale modelling of auxin transport in the plant-root elongation zone

In the root elongation zone of a plant, the hormone auxin moves in a polar manner due to active transport facilitated by spatially distributed influx and efflux carriers present on the cell membranes. To understand how the cell-scale active transport and passive diffusion combine to produce the effective tissue-scale flux, we apply asymptotic methods to a cell-based model of auxin transport to derive systematically a continuum description from the spatially discrete one. Using biologically relevant parameter values, we show how the carriers drive the dominant tissue-scale auxin flux and we predict how the overall auxin dynamics are affected by perturbations to these carriers, for example, in knockout mutants. The analysis shows how the dominant behaviour depends on the cells' lengths, and enables us to assess the relative importance of the diffusive auxin flux through the cell wall. Other distinguished limits are also identified and their potential roles discussed. As well as providing insight into auxin transport, the study illustrates the use of multiscale (cell to tissue) methods in deriving simplified models that retain the essential biology and provide understanding of the underlying dynamics

Histological and immunohistochemical features of the spleen in persistent polyclonal B-cell lymphocytosis closely mimic splenic B-cell lymphoma

Persistent polyclonal B-cell lymphocytosis (PPBL) is rare and intriguing hematological disorder predominantly reported in young to middle- aged smoking women. It is characterized by persistent moderate polyclonal B-cell lymphocytosis with circulating hallmark binucleated lymphocytes and elevated polyclonal serum IgM. Most patients have benign clinical course on long-term follow-up. Some pathologic features of PPBL may resemble malignant lymphoma, including morphology as well as frequent cytogenetic and molecular abnormalities. Significant symptomatic splenomegaly requiring splenectomy is very unusual for this disorder; therefore there is a lack of descriptions of the morphologic features of the spleen in the literature. We present here one of the first detailed descriptions of the morphologic and immunohistochemical features of the spleen from a young female with PPBL who developed massive splenomegaly during 6-year follow up. Splenectomy was performed for symptomatic relief and suspicion of malignant process. The morphological and immunohistochemical features of the spleen closely mimicked involvement by B-cell lymphoma, however there was no monotypic surface light chain restriction seen by flow cytometry and no clonal rearrangement of IgH gene was detected by molecular analysis. Evaluating a splenectomy sample in cases like this may present a diagnostic challenge to pathologists. Therefore, correlation with B cell clonality studies (by flow cytometry and molecular analysis), clinical findings and peripheral blood morphology searching for characteristic binucleated lymphocytes is essential to avoid misdiagnosing this benign process as B-cell lymphoma. We also present here a literature review on pathogenesis of PPBL