RESUMEN

OBJECTIVE: To investigate if cancer in pregnancy causes a higher risk of venous thromboembolism (VTE) during pregnancy and postpartum compared with pregnant women without cancer. DESIGN: A historical prospective cohort study using data from nationwide registries. SETTING AND POPULATION: We assessed all pregnancies in Denmark between 1 January 1977 and 31 December 2017. METHODS: We linked information concerning cancer diagnosis, pregnancy and VTE diagnosis and potential confounders. Event rates of VTE for women with pre-pregnancy cancer, cancer in pregnancy and without cancer were calculated per 10 000 pregnancies and compared using logistic regression analysis. MAIN OUTCOME MEASURES: Occurrence of VTE during pregnancy or the postpartum period. RESULTS: A total of 3 581 214 pregnancies were included in the study and we found 1330 women with cancer in pregnancy. In pregnant women with cancer, the event rate of VTE was 75.2 per 10 000 pregnancies compared with 10.7 per 10 000 pregnancies in the no cancer group. The findings correspond to an increased adjusted odds ratio of 6.50 (95% CI3.5-12.1) in the cancer in pregnancy group in comparison with the no cancer group. CONCLUSIONS: Women with cancer in pregnancy have a markedly higher risk of pregnancy-associated VTE compared with women without cancer. In pregnancy-related VTE risk assessment, the presence of cancer alone may be sufficient to indicate thromboprophylaxis. TWEETABLE ABSTRACT: Cancer in pregnancy increases the risk of VTE during pregnancy and the postpartum period.

Asunto(s)

RESUMEN

BACKGROUND: Current methods for assessing strength of evidence prioritize the contributions of randomized controlled trials (RCTs). The objective of this study was to characterize strength of evidence (SOE) tools in recent use, identify their application to lifestyle interventions for improved longevity, vitality, or successful aging, and to assess implications of the findings. METHODS: The search strategy was created in PubMed and modified as needed for four additional databases: Embase, AnthropologyPlus, PsycINFO, and Ageline, supplemented by manual searching. Systematic reviews and meta-analyses of intervention trials or observational studies relevant to lifestyle intervention were included if they used a specified SOE tool. Data was collected for each SOE tool. Conditions necessary for assigning the highest SOE grading and treatment of prospective cohort studies within each SOE rating framework were summarized. The expert panel convened to discuss the implications of findings for assessing evidence in the domain of lifestyle medicine. RESULTS AND CONCLUSIONS: A total of 15 unique tools were identified. Ten were tools developed and used by governmental agencies or other equivalent professional bodies and were applicable in a variety of settings. Of these 10, four require consistent results from RCTs of high quality to award the highest rating of evidence. Most SOE tools include prospective cohort studies only to note their secondary contribution to overall SOE as compared to RCTs. We developed a new construct, Hierarchies of Evidence Applied to Lifestyle Medicine (HEALM), to illustrate the feasibility of a tool based on the specific contributions of diverse research methods to understanding lifetime effects of health behaviors. Assessment of evidence relevant to lifestyle medicine requires a potential adaptation of SOE approaches when outcomes and/or exposures obviate exclusive or preferential reliance on RCTs. This systematic review was registered with the International Prospective Register of Systematic Reviews, PROSPERO [CRD42018082148].

Asunto(s)

RESUMEN

Toll-like receptors (TLRs) are pattern recognition receptors important for the detection of pathogen-associated molecular patterns. They are localized on cellular membranes, on either the cell surface or the endosomes. Primary Sjögren's syndrome (pSS) is a systemic rheumatic autoimmune disease characterized by lymphocytic infiltrations in exocrine glands resulting in dryness in eyes and mouth. In a majority of patients, autoantibodies against Ro/SSA and/or La/SSB are present. Here we analysed mRNA levels of TLR1-10 and protein expression levels of most of them in human peripheral blood mononuclear cells from 20 patients with pSS and 20 healthy controls. Patients with pSS showed significantly higher mRNA levels of TLR8 than controls, while transcript levels of TLR9 were significantly lower. At the protein level, patients with pSS expressed significantly less TLR5 and significantly more TLR7 compared with healthy controls. TLR7 and 8 are encoded by genes localized on the X chromosome, which is especially interesting regarding the gender imbalance of pSS. The differential expression of various TLR in PBMC of patients with pSS might contribute to an altered recognition of nucleic acids, eventually resulting in the development of autoimmune disease.

Asunto(s)

RESUMEN

Primary Sjögren's syndrome (pSS) is a chronic, inflammatory autoimmune disease characterised by lymphocytic infiltrations in the exocrine glands, resulting in destruction of salivary and lacrimal glands. B cells have an important role in the disease, as detection of autoantibodies against SSA/Ro or SSB/La is one of the diagnostic criteria, being found in a majority of the patients. Toll-like receptors (TLR) are pattern recognition receptors. TLR-7 and -9 are found in endosomes and bind microbial nucleic acids. We have previously shown that pSS patients and healthy controls have similar expression pattern of TLR-7 and -9 in various B-cell populations. In this study we further analysed the responsiveness of B cells upon TLR stimulation. B cells isolated from peripheral blood of 21 pSS patients and 18 healthy controls were stimulated with TLR-7 and -9 ligands for 24 h before being analysed for the expression of certain surface markers and intracellular cytokine levels by flow cytometry. Secreted cytokines were measured by a multiplex cytokine assay. Patients with pSS had more naïve and less preswitched memory B cells compared to controls in unstimulated as well as via TLR-7 stimulated cells. Unstimulated and via TLR-7 stimulated B cells from pSS patients also had fewer IL-10(+) preswitched memory B cells. Moreover, TLR-7 and -9 stimulated B cells of pSS patients secreted increased amounts of several cytokines. B cells of pSS patients show a different responsiveness upon stimulation of TLR-7 and -9 compared to controls.

Asunto(s)

RESUMEN

Electron backscatter diffraction has been increasingly used to identify the crystallographic planes and orientation of cleavage facets with respect to the rolling direction in fracture surfaces. The crystallographic indices of cleavage planes can be determined either directly from the fracture surface or indirectly from metallographic sections perpendicular to the plane of the fracture surface. A combination of electron backscatter diffraction and 3D scanning electron microscopy imaging technique has been modified to determine crystallographic facet orientations. The main purpose of this work has been to identify the macroscopic crystallographic orientations of cleavage facets in the fracture surfaces of weld heat affected zones in a well-known steel fractured at low temperatures. The material used for the work was an American Petroleum Institute (API) X80 grade steel developed for applications at low temperatures, and typical heat affected zone microstructures were obtained by carrying out weld thermal simulation. The fracture toughness was measured at different temperatures (0°C, -30°C, -60°C and -90°C) by using Crack Tip Opening Displacement testing. Fracture surfaces and changes in microstructure were analyzed by scanning electron microscopy and light microscopy. Crystallographic orientations were identified by electron backscatter diffraction, indirectly from a polished section perpendicular to the major fracture surface of the samples. Computer assisted 3D imaging was used to measure the angles between the cleavage facets and the adjacent polished surface, and then these angles were combined with electron backscatter diffraction measurements to determine the macroscopic crystallographic planes of the facets. The crystallographic indices of the macroscopic cleavage facet planes were identified to be {100}, {110}, {211} and {310} at all temperatures.

RESUMEN

Dendritic cells (DC) are professional antigen-presenting cells that are capable of both activating immune responses and inducing tolerance. Several studies have revealed efficiency of therapeutic vaccination with tolerogenic DC (tolDC) in inhibition of experimental autoimmunity. The purpose of this study was to compare four different protocols for generation of tolDC - the antidiabetic drug troglitazone (TGZ DC), NF-κB inhibitor BAY 11-7082 (BAY DC), prostaglandin D2 metabolite 15d-PGJ2 (PGJ DC) and a combination of dexamethasone and 1α,25-dihydroxyvitamin D3 (DexVD3 DC) regarding phenotype, cytokine production and T cell stimulatory capacity. TGZ DC and BAY DC had a phenotype comparable to immature DC, while DexVD3 DC were more macrophage like. Analysis of cytokine production using cell culture supernatants from all DC populations revealed that DexVD3 DC were efficient producers of IL-10 and produced less pro-inflammatory cytokines. T cells primed with DexVD3 DC showed reduced proliferation, and further analyses of these T cells revealed that functionally effective type 1 regulatory T cells (Tr1) but not FoxP3(+) Treg were induced. Furthermore, DexVD3 DC promoted the induction of regulatory B cells (Breg). Together, these results indicate that DexVD3 DC have the best potential to be used in a tolerogenic antigen-presenting cell-based immunotherapy setting.

Asunto(s)

RESUMEN

Immunotherapy using dendritic cells (DC) has shown promising results. However, the use of an appropriate DC population is critical for the outcome of this treatment, and the search for an optimal DC subset is still ongoing. The DC used in immunotherapy today are usually matured with a cytokine cocktail consisting of TNF-α, IL-1ß, IL-6 and PGE(2). These cells have deficits in their cytokine production, particularly IL-12p70, mainly because of the presence of PGE(2). Bromelain is a pineapple stem extract containing a mixture of proteases that has been used clinically in adjuvant cancer treatment. In this study, we analysed the effect of bromelain on human monocyte-derived DC. We added bromelain to the cytokine cocktail and modified cytokine cocktails with either no PGE(2) or reduced amounts of PGE(2), respectively. Combining bromelain with the cytokine cocktails containing PGE(2) resulted in an increased surface expression of CD83, CD80 and CD86. The chemokine receptor CCR7 was also considerably upregulated in these DC populations compared with DC treated with the cytokine cocktail alone. Removal or reduction of PGE(2) from the cytokine cocktail did not increase the IL-12p70 secretion from stimulated DC, and addition of bromelain to the different cytokine cocktails resulted in only a minor increase in IL-12p70 production. Moreover, combining bromelain with the cytokine cocktails did not improve the T cell stimulatory capacity of the generated DC populations. In conclusion, bromelain treatment of monocyte-derived DC does not improve the functional quality compared with the standard cytokine cocktail.

Asunto(s)

RESUMEN

Proliferative gill disease (PGD) is an emerging problem in Norwegian culture of Atlantic salmon (Salmo salar). Parasites (Ichthyobodo spp.) and bacteria (Flexibacter/Flavobacterium) may cause PGD, but for most cases of PGD in farmed salmon in Norway, no specific pathogen has been identified as the causative agent. However, Neoparamoeba sp. and several bacteria and viruses have been associated with this disease. In the spring of 2006, a new poxvirus, salmon gill poxvirus (SGPV), was discovered on the gills of salmon suffering from PGD in fresh water in northern Norway. Later the same year, this virus was also found on gills of salmon at two marine sites in western Norway. All farms suffered high losses associated with the presence of this virus. In this study, we describe the entry and morphogenesis of the SGP virus in epithelial gill cells from Atlantic salmon. Intracellular mature virions (IMVs) are the only infective particles that seem to be produced. These are spread by cell lysis and by "budding" of virus packages, containing more that 100 IMVs, from the apical surface of infected cells. Entry of the IMVs appears to occur by attachment to microridges on the cell surface and fusion of the viral and cell membranes, delivering the cores into the cytoplasm. The morphogenesis starts with the emergence of crescents in viroplasm foci in perinuclear areas of infected cells. These crescents consist of two tightly apposed unit membranes (each 5 nm thick) that seem to be derived from membranes of the endoplasmic reticulum. The crescents develop into spheres, immature virions (IVs), that are 350 nm in diameter and surrounded by two unit membranes. The maturation of the IVs occurs by condensation of the core material and a change from spherical to boat-shaped particles, intracellular mature virions (IMVs), that are about 300 nm long. Hence, the IMVs from the SGP virus have a different morphology compared to other vertebrate poxviruses that are members of the subfamily Chordopoxvirinae, and they are more similar to members of subfamily Entomopoxvirinae, genus Alphaentomopoxvirus. However, it is premature to make a taxonomic assignment until the genome of the SGP virus has been sequenced, but morphogenesis clearly shows that this virus is a member of family Poxviridae.

Asunto(s)

RESUMEN

Betanodaviruses have been isolated and detected in both farmed and wild fish species worldwide. They are classified in five clusters, and all are connected to mortalities in farmed fish. The clusters do not represent specific geographical areas or host species, but one cluster, barfin flounder nervous necrosis virus (BFNNV), is mainly associated with cold water fish species. This study presents the first species-specific clade within the BFNNV cluster. This clade consists of six isolates from wild and farmed Atlantic cod in Norway and is genetically distinct from other betanodaviruses in the North Atlantic. Screening of farmed and wild cod in Norway shows that betanodaviruses are present in wild fish on the west coast of Norway, including migratory cod, but so far we have not detected any betanodavirus-positive wild cod in northern Norway. The presence of significant amounts of betanodaviruses in wild cod represents a serious challenge for the management of viral nervous necrosis in farmed cod in Norway. Betanodavirus-positive farmed cod were present both in western and northern Norway. Mortalities in three cod farms were suspected to be caused by betanodaviruses; however, in two of these, other pathogens may have been responsible for or strongly contributed to the mortalities.

Asunto(s)

RESUMEN

In the present study, 24 smolt production sites were screened for the presence of infectious salmon anaemia virus (ISAV) with the help of a specific real-time RT PCR assay, and 22 of these sites had smolts that were positive. If these smolt production sites are representative for the prevalence of ISAV in Norwegian smolts, then most marine production sites must be considered to be positive for ISAV. In addition, 92 European ISAV isolates have been genotyped based on the hemagglutinin-esterase gene (HE), and their distribution pattern was analysed. This pattern has been coupled to information about the origin of smolt, eggs, and broodfish in those cases where it has been possible to obtain such information, and with information about ISAV in neighbouring farms. The pattern suggests that an important transmission route for the ISAV could be that the salmon farming industry in Norway is circulating some of the isolates in the production cycle, i.e. some sort of vertical or transgenerational transmission may occur. It has also been shown that avirluent ISAV isolates are fairly common in Norwegian farmed salmon. Based on this, it is hypothesized that the change from avirulent to virulent ISAV isolates is a stochastic event that is dependent on the replication frequency of the virus and the time available for changes in a highly polymorphic region (HPR) of the HE gene to occur. This, and the possibility that only avirluent ISAV isolates are vertically transmitted, may explain why ISA most often occurs at marine sites and why no more than about 15 farms get ISA every year in Norway.

Asunto(s)

RESUMEN

The first cases of heart and skeletal muscle inflammation (HSMI), in Atlantic salmon Salmo salar were registered in 1999 in the Hitra/Frøya area of Norway. The disease has since spread south to Rogaland, i.e. the southernmost county with salmon farming in Norway. The disease outbreaks usually start 5 to 9 mo after release into seawater but may occur as early as 2 wk after sea release. The present study focuses on possible pathogens associated with HSMI. It was not possible to find any parasites or bacteria that could explain HSMI, and none of the well-known viruses (infectious salmon anaemia virus, Norwegian salmonid alphavirus, infectious pancreatic necrosis virus, Atlantic salmonid paramyxovirus) were consistently present. Use of transmission electron microscopy showed the presence of epitheliocystis agent in 3 of 4 farms included in this study, and several virus-like particles. Type I and Type II virus particles, previously described for salmon suffering from haemorrhagic smolt syndrome (HSS), and erythrocytic inclusion body syndrome (EIBS) virus were consistently present in salmon suffering from HSMI in all 4 farms included in this study. The 2 HSS viruses (Type I and Type II) were also cultured in Atlantic salmon kidney (ASK) cells from salmon suffering from HSMI. However, a causal relationship between the observed virus particles and HSMI remains to be demonstrated.

Asunto(s)

RESUMEN

Studies of infectious salmon anemia virus (ISAV; genus Isavirus, family Orthomyxoviridae) haemagglutinin-esterase (HE) gene sequences have shown that this gene provides a tool for genotyping and, hence, a tool to follow the dissemination of ISAV. The problem with using only the HE gene is that ISAV has a segmented genome and one segment may not tell the whole story about the origin and history of ISAV from outbreaks. To achieve a better genotyping system, the present study has focused on segment 5, the fusion (F) protein gene, which contains sequence variation at about the same level as the HE gene. The substitution rates of the HE and F gene sequences, based on 54 Norwegian ISAV isolates, are 6.1(+/-0.3)x10(-6) and 8.6(+/-5.0)x10(-5) nt per site per year, respectively. The results of phylogenetic analysis of the two gene segments have been compared and, with the exception of a few cases of reassortment, they tell the same story about the ISAV isolates. A combination of the two segments is recommended as a tool for future genotyping of ISAV. Inserts (INs) of 8-11 aa may occur close to the cleavage site of the precursor F(0) protein in some ISAV isolates. The nucleotide sequence of two of these INs shows 100% sequence identity to parts of the 5' end of the F protein gene, whilst the third IN is identical to a part of the nucleoprotein gene. This shows that recombination is one of the evolutionary mechanisms shaping the genome of ISAV. The possible importance of the INs with respect to virulence remains uncertain.

Asunto(s)

RESUMEN

Salmonid alphavirus (SAV) (family Togaviridae) causes mortality in Atlantic salmon (Salmo salar L.) and rainbow trout (Oncorhynchus mykiss W.) in Norway, France, UK, and Ireland. At least three subtypes of SAV exist: SPDV in UK/Ireland, SDV in France/UK, and the recently reported Norwegian salmonid alphavirus (NSAV) in western Norway. During 2003 and 2004, disease caused by NSAV was reported for the first time in northern Norway, more than 800 km away from the enzootic area in western Norway. The present study has investigated the phylogenetic relationships among 20 NSAV isolates, based on a 1221-nt-long segment covering part of the capsid gene, E3, and part of the E2 gene, collected over a period of eight years. The results revealed genetic homogeneity among NSAV isolates, including those from northern Norway. The SDV or SPDV subtypes were not found in diseased Norwegian fish. A substitution rate of 1.70 (+/-1.03) x 10(-4) nt subst/site/year was obtained for the NSAV subtype by maximum likelihood analysis. The second aim of this study was to clarify whether NSAV changes genotypically in cell culture by culturing a NSAV isolate through 20 passages in CHSE-214 cells. Sequencing of almost the entire genome (11530 nt) after 20 passages revealed four nucleotide substitutions, all resulting in amino acid substitutions. One of these substitutions, serine to proline in E2 position 206, was also found to have occurred in field isolates.

Asunto(s)

Asunto(s)