Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2−/− mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes

Simulador de Técnicas de Depuração Extra-Renal/Hemofiltração: Uso da Simulação para Treino no Manuseamento deste Dispositivo

Introdução: A simulação possibilita o ensino e treino de técnicas de suporte de vida complexas sem riscos para o doente. Até ao momento, as únicas opções de treino no manuseamento de terapêuticas de depuração extra-renal contínua (TDEC) eram a aprendizagem directa em doentes submetidos a esta técnica ou mediante observação dos efeitos da manipulação do circuito não conectado ao doente. Por este motivo foi elaborado um simulador de TDEC, usado em cursos de simulação realizados para treino de equipas de cuidados intensivos pediátricos (UCIP). Objectivos: Analisar a performance e utilidade de um novo simulador que possibilita o controlo externo do dispositivo de TDEC, simulando "in situ" cenários que mimetizam condições de doentes tratados com TDEC. Métodos: Foi criado um dispositivo que, uma vez conectado ao aparelho de TDEC, permite o controlo em tempo real de todas as pressões de hemofiltração, de acordo com as condições clínicas e acções dos participantes. Foram simulados diversos cenários e complicações possíveis em doentes submetidos a estas técnicas e avaliada a performance deste dispositivo "in vitro". A satisfação dos participantes foi avaliada mediante a aplicação de um inquérito. Resultados: Foram realizados 4 cursos de TDEC de Maio de 2009 a Março de 2012. Incluídos 60 participantes, todos com experiência clínica prévia em UCIP. Realizados 32 cenários, abrangendo complicações relacionados com o cateter, coagulação dos filtros e ajuste inadequado dos parâmetros de hemofiltração. Nos cenários simulados, o dispositivo simulador permitiu, em tempo real, mudanças simples e rápidas nas pressões do monitor de TDEC e em resposta às atitudes tomadas pelos participantes para a sua resolução. Não foram registadas intercorrências relacionadas com disfunção do dispositivo. Os participantes consideraram-no muito útil como ferramenta de aprendizagem activa, permitindo uma gestão realista das condições clínicas simuladas, com potencial impacto sobre a sua futura prática diária. Os instrutores consideraram-no fácil de manusear e realista. Conclusões: Este simulador permite uma simulação mais fidedigna dos cenários de TDEC, resolvendo o problema da interferência do instrutor no cenário simulado. Este poderia melhorar as capacidades dos simuladores de alta fidelidade disponíveis e utilizar-se como uma ferramenta docente na formação de profissionais de saúde

Babesia microti-like en un perro inmunocompetente

La babesiosis canina es una enfermedad infecciosa de distribución mundial causada por parásitos intraeritrocitarios transmitidos por garrapatas. Si bien ha sido tradicionalmente asumido que sólo dos de las 73 especies de babesias identificadas causan enfermedad en la especie canina, Babesia canis y Babesia gibsoni, recientes publicaciones demuestran que una tercera especie (Babesia microti-like) también puede parasitar a perros. Este último parásito, genéticamente relacionado con Babesia microti, es el origen de una enfermedad endémica entre la población canina del noroeste de España. Este trabajo presenta un caso no experimental de esta forma de Babesia microti-like en un perro cocker spaniel de 9 años, sin antecedentes de inmunodeficiencia ni de esplenectomía, que se presenta en la clínica veterinaria con signos de hipertermia, hemoglobinuria, escalofríos y apatía. Una muy intensa parasitemia (24%), junto con trombopenia y una acusada anemia hemolítica regenerativa fueron los hallazgos más caractéristicos. En la extensión de sangre periférica se visualizaron múltiples merozoitos intraeritrocitarios (parasitemia de un 24%) de pequeño tamaño (1-2 um) y presentación única en cada hematíe. Cuarenta y ocho horas después del comienzo de los síntomas, y tras tratamiento específico con dipropionato de imidocarb el perro evolucionó hacia la curación

ASY1 acts as a dosage-dependent antagonist of telomere-led recombination and mediates crossover interference in Arabidopsis.

During meiosis, interhomolog recombination produces crossovers and noncrossovers to create genetic diversity. Meiotic recombination frequency varies at multiple scales, with high subtelomeric recombination and suppressed centromeric recombination typical in many eukaryotes. During recombination, sister chromatids are tethered as loops to a polymerized chromosome axis, which, in plants, includes the ASY1 HORMA domain protein and REC8-cohesin complexes. Using chromatin immunoprecipitation, we show an ascending telomere-to-centromere gradient of ASY1 enrichment, which correlates strongly with REC8-cohesin ChIP-seq data. We mapped crossovers genome-wide in the absence of ASY1 and observe that telomere-led recombination becomes dominant. Surprisingly, asy1/+ heterozygotes also remodel crossovers toward subtelomeric regions at the expense of the pericentromeres. Telomeric recombination increases in asy1/+ occur in distal regions where ASY1 and REC8 ChIP enrichment are lowest in wild type. In wild type, the majority of crossovers show interference, meaning that they are more widely spaced along the chromosomes than expected by chance. To measure interference, we analyzed double crossover distances, MLH1 foci, and fluorescent pollen tetrads. Interestingly, while crossover interference is normal in asy1/+, it is undetectable in asy1 mutants, indicating that ASY1 is required to mediate crossover interference. Together, this is consistent with ASY1 antagonizing telomere-led recombination and promoting spaced crossover formation along the chromosomes via interference. These findings provide insight into the role of the meiotic axis in patterning recombination frequency within plant genomes.Research was supported by grants from the European Research Council Consolidator award SynthHotSpot and Proof-of-Concept award HEIREC and BBSRC ERA-CAPs Grant BB/M004937/1

ICTV virus taxonomy profile: Bromoviridae

Bromoviridae is a family of plant viruses with tri-segmented, positive-sense, single-stranded RNA genomes of about 8 kb in total. Genomic RNAs are packaged in separate virions that may also contain subgenomic, defective or satellite RNAs. Virions are variable in morphology (spherical or bacilliform) and are transmitted between hosts mechanically, in/on the pollen and non-persistently by insect vectors. Members of the family are responsible for major disease epidemics in fruit, vegetable and fodder crops such as tomato, cucurbits, bananas, fruit trees and alfalfa. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Bromoviridae, which is available at www.ictv.global/report/bromoviridae

Typhoid and Paratyphoid Cost of Illness in Pakistan: Patient and Health Facility Costs from the Surveillance for Enteric Fever in Asia Project II

Background: The objective of this study was to estimate the cost of illness from enteric fever (typhoid and paratyphoid) at selected sites in Pakistan. Methods: We implemented a cost-of-illness study in 4 hospitals as part of the Surveillance for Enteric Fever in Asia Project (SEAP) II in Pakistan. From the patient and caregiver perspective, we collected direct medical, nonmedical, and indirect costs per case of enteric fever incurred since illness onset by phone after enrollment and 6 weeks later. From the health care provider perspective, we collected data on quantities and prices of resources used at 3 of the hospitals, to estimate the direct medical economic costs to treat a case of enteric fever. We collected costs in Pakistani rupees and converted them into 2018 US dollars. We multiplied the unit cost per procedure by the frequency of procedures in the surveillance case cohort to calculate the average cost per case. Results: We collected patient and caregiver information for 1029 patients with blood culture-confirmed enteric fever or with a nontraumatic terminal ileal perforation, with a median cost of illness per case of US $196.37 (IQR, US$72.89-496.40). The median direct medical and nonmedical costs represented 8.2% of the annual labor income. From the health care provider perspective, the estimated average direct medical cost per case was US $50.88 at Hospital A, US$52.24 at Hospital B, and US $11.73 at Hospital C. Conclusions: Enteric fever can impose a considerable economic burden in Pakistan. These new estimates of the cost of illness of enteric fever can improve evaluation and modeling of the costs and benefits of enteric fever prevention and control measures, including typhoid conjugate vaccines

Infección por Theileria annae en un perro esplenectomizado

La babesiosis canina es una enfermedad infecciosa de distribución mundial debida a la proliferación en los hematíes del perro de unas babesias específicas transmitidas por garrapatas. Si bien ha sido tradicionalmente asumido que las únicas especies que causan enfermedad en la especie canina son Babesia canis y Babesia gibsoni, publicaciones recientes demuestran que una tercera especie (Theileria annae) también puede causar una enfermedad muy severa. Este trabajo presenta el segundo caso publicado de esta forma de Theileria annae en un perro de 14 años, de raza Basset Hound, esplenectomizado cinco meses antes, que se presentó en la clínica veterinaria con signos de hipertermia, hemoglobinuria, temblores y apatía. El estudio de laboratorio constató una acusada anemia hemolítica regenerativa y una intensa trombocitopenia como datos más característicos. En la extensión de sangre periférica se visualizaron múltiples merozoítos intra (22%) y extraeritrocitarios de pequeño tamaño (1-2 micras), forma anular y presentación única en la mayoría de hematíes. La prontitud del diagnóstico y del tratamiento específico con dipropionato de imidocarb hizo que el cuadro clínico evolucionase con rapidez hacia la curación, en contra de lo que es habitual en los animales esplenectomizados.

Parasitación por Babesia canis en Galicia

Un estudio analítico llevado a cabo sobre 213 perros, infectados por el piroplasma Babesia canis en Galicia durante el año 1996, sugiere que una intensa anemia hemolítica regenerativa junto con una trombocitopenia son las características constantes de la infección, además de observarse en algunos casos una evolución a insuficiencia renal

The atypical chemokine receptor ACKR2 is protective against sepsis

Sepsis is a systemic inflammatory response as a result of uncontrolled infections. Neutrophils are the first cells to reach the primary sites of infection and chemokines play a key role in recruiting neutrophils. However, in sepsis chemokines could also contribute to neutrophil infiltration to vital organs leading to multiple organ failure. ACKR2 is an atypical chemokine receptor, which can remove and degrade inflammatory CC chemokines. The role of ACK2 in sepsis is unknown. Using a model of cecal ligation and puncture (CLP), we demonstrate here that ACKR2 deficient (−/−) mice exhibited a significant reduction in the survival rate compared to similarly treated wild type (WT) mice. However, neutrophil migration to the peritoneal cavity and bacterial load were similar between WT and ACKR2−/− mice during CLP. In contrast, ACKR2−/− mice showed increased neutrophil infiltration and elevated CC chemokine levels in the lung, kidney and heart compared to the WT mice. In addition, ACKR2−/− mice also showed more severe lesions in the lung and kidney than those in the WT mice. Consistent with these results, WT mice under non-severe sepsis (90% survival) had higher expression of ACKR2 in these organs than mice under severe sepsis (no survival). Finally, the lungs from septic patients showed increased number of ACKR2+ cells compared to those of non-septic patients. Our data indicate that ACKR2 may have a protective role during sepsis, and the absence of ACKR2 leads to exacerbated chemokine accumulation, neutrophil infiltration and damage to vital organs