The interactions between pregnancy and breast cancer (BC) are complex. Overall, parity is associated with long-term protective effects against BC, however in a small group of susceptible patients, ...pregnancy can lead to the development of a form of BC with a particularly poor prognosis. Pregnancy-associated breast cancer (PABC) remains an under-studied but important and growing clinical problem worldwide. Several aspects of PABC, including risk factors and mechanisms involved in its occurrence and aggressiveness, are incompletely understood. This review aims to summarize the epidemiology, biology, patho-physiology and clinical characteristics of PABC. We emphasize that age at first pregnancy, absence of breastfeeding and family history stand out as possible risk factors for developing PABC that ought to be incorporated into clinical tools for assessing a woman's risk of developing PABC. Also, improved methods for identifying women at risk of developing PABC in the general population are needed.
•Pregnancy exerts a dual effect on the subsequent risk of developing breast cancer (BC).•Pregnancy-associated breast cancer (PABC) is a BC case that occurs during pregnancy or within 1 year following birth.•Mechanisms causing PABC are unclear due to hormonal and immune changes that occur during pregnancy and breast involution.•Older age- first pregnancy, no breastfeeding, and family history of BC are possible clinical biomarkers for developing PABC.•A higher awareness and improved methods for identifying women at risk in the general population are needed.
Background and Objective. Unilateral neglect due to parieto-temporo-frontal lesions has a negative impact on the success of rehabilitation, and prism adaptation (PA) enhances recovery from neglect. ...However, it is unclear if this effect holds also in severely impaired patients and/or in the postacute phase of rehabilitation. Moreover, it is not known whether PA affects all aspects of neglect recovery or ego-centered spatial orientation only. Methods. Sixteen patients in a postacute stage (on average 36 days after a large right cerebrovascular stroke) were entered into a series of single case design studies with 4 measurements: 2 before and 2 after 1 week of PA treatment. All patients had severe neglect (showing trunk, head, and eye deviation; canceling less than 20% of targets in a visual cancellation test). Lesions were transferred to a standard brain to analyze size and location. Results. Patients improved in cued body orientation and in the cancellation task, that is, in ego-centered neglect. However, none of the measures used to evaluate neglect of left side of objects irrespective of their position on the right or left side of the patient (allocentric neglect) showed an improvement. Treatment effects were not influenced by total lesion size, but lesions including the postcentral cortex were related to smaller recovery gains. Conclusion. PA is helpful in treating severely impaired patients in the postacute phase, but the effect is restricted to ego-centered neglect. Lesions in the postcentral cortex (middle occipito-temporal, middle temporal, and posterior parietal areas) seem to limit the effect of PA.
•The epidemiology of bacteraemia is dynamic and may vary between geographical regions.•Healthcare-associated (HCA) episodes showed significant differences in patient features, sources and ...aetiology.•Consideration of HCA bloodstream infection as a distinct category is confirmed as epidemiologically and clinically useful.
The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60–81 years) and 3656 (58.3%; 95% confidence interval 57.1–59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients’ profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.
High-risk hematological malignancies are a privileged setting for infection by opportunistic microbes, with invasive mycosis being one of the most serious complications. Recently, genetic background ...has emerged as an unanticipated risk factor. For this reason, polymorphisms for genes encoding archetypal receptors involved in the opsonic and nonopsonic clearance of microbes, pentraxin-3 (PTX3) and Dectin-1, respectively, were studied and correlated with the risk of infection. Fungal, bacterial, and viral infections were registered for a group of 198 patients with high-risk hematological malignancies. Polymorphisms for the pentraxin-3 gene (
) showed a significant association with the risk of fungal infection by
spp. and, especially, by
spp. This link remained even for patients undergoing antifungal prophylaxis, thus demonstrating the clinical relevance of PTX3 in the defense against fungi.
polymorphisms did not show any definite correlation with the risk of invasive mycosis, nor did they influence the expression of Dectin-1 isoforms generated by alternative splicing. The
mRNA expression level was significantly lower in samples from healthy volunteers who showed these polymorphisms, although no differences were observed in the extents of induction elicited by bacterial lipopolysaccharide and heat-killed
, thus suggesting that the expression of PTX3 at the start of infection may influence the clinical outcome.
mRNA expression can be a good biomarker to establish proper antifungal prophylaxis in immunodepressed patients.
Trichomonas gallinae is a worldwide parasite that causes oropharyngeal avian trichomonosis. During eight years, 60 axenic isolates were obtained from different bird species and characterized by three ...molecular methods: RAPD analysis and PCR-sequencing of ITS1/5.8S rRNA/ITS2 fragment and Fe-hydrogenase gene. We have found two genotypes of ITS1/5.8S rRNA/ITS2 widely distributed among bird populations, a new variant and also two sequences with mixed pattern. Genotype ITS-OBT-Tg-1 was associated with the presence of gross lesions in birds. We have found eight genotypes of the Fe-hydrogenase (A1, A2, C2, C2.1, C4, C5, C6 and C7), three of them are new reports (C5, C6 and C7), and also three sequences with mixed pattern. Subtype A1 of the Fe-hydrogenase was also related with the presence of lesions. RAPD analyses included most of the strains isolated from animals with lesions in one of the sub-clusters. Potentially pathogenic isolates of T. gallinae obtained in this study fulfill the following criteria with one exception: isolated from lesions+ITS-OBT-Tg-1 genotype+FeHyd A1+RAPD sub-cluster I2.
•Sixty isolates of T. gallinae were analyzed by RAPD and sequencing of ITS and FeHyd.•We found 4 new sequences of the Fe-hydrogenase and 1 of the ITS1/5,8SrRNA/ITS2.•Potentially pathogenic isolates of T. gallinae of this study are ITS-OBT-Tg-1, FeHyd A1, RAPD sub-cluster I2.
Increased glycolysis parallels immune cell activation, but the role of pyruvate remains largely unexplored. We found that stimulation of dendritic cells with the fungal surrogate zymosan causes ...decreases of pyruvate, citrate, itaconate, and α-ketoglutarate, while increasing oxaloacetate, succinate, lactate, oxygen consumption, and pyruvate dehydrogenase activity. Expression of IL10 and IL23A (the gene encoding the p19 chain of IL-23) depended on pyruvate dehydrogenase activity. Mechanistically, pyruvate reinforced histone H3 acetylation, and acetate rescued the effect of mitochondrial pyruvate carrier inhibition, most likely because it is a substrate of the acetyl-CoA producing enzyme ACSS2. Mice lacking the receptor of the lipid mediator platelet-activating factor (PAF; 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) showed reduced production of IL-10 and IL-23 that is explained by the requirement of acetyl-CoA for PAF biosynthesis and its ensuing autocrine function. Acetyl-CoA therefore intertwines fatty acid remodeling of glycerophospholipids and energetic metabolism during cytokine induction.
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•The fungal surrogate zymosan decreases pyruvate and supports acetyl-CoA production•The expression of IL-10 and IL-23 depends on pyruvate dehydrogenase activity•Autocrine platelet-activating factor (PAF) reinforces IL-10 and IL-23 induction•Acetyl-CoA is the nexus linking PAF biosynthesis to energetic metabolism
Márquez et al. show a regulatory mechanism of cytokine induction that involves acetylation of histones and a self-amplifying loop through the platelet-activating factor receptor. This mechanism links phospholipid remodeling in the Lands’ cycle with energetic metabolism in the tricarboxylic acid cycle. Acetyl-CoA is the nexus between both cycles.
Highlights • BM-MSCs and AT-MSCs induced a similar decrease in NK cell proliferation and cytokine secretion. • BM-MSCs show higher capacity than AT-MSCs to inhibit NK cell cytotoxic activity but the ...same susceptibility to NK cell lysis. • AT-MSCs are more potent in inhibiting DC differentiation than BM-MSCs, but both similarly reduced the ability of DCs to induce CD4+ T cell proliferation and cytokine production. • BM-MSCs and AT-MSCs induce a similar decrease in T cell proliferation and production of inflammatory cytokines after activation. • MSCs from different donors could exert different immunomodulatory potential on the same receptor.
To compare the real-life effectiveness and safety of ceftaroline fosamil (ceftaroline-F) and ceftobiprole medocaril (ceftobiprole-M) for infections in hospitalized patients.
This comparative, ...observational, retrospective, and multicenter Spanish study included patients receiving outpatient parenteral antimicrobial therapy (OPAT) and hospitalized patients treated for at least 48 h with ceftaroline-F or ceftobiprole-M between their first incorporation in the clinical protocol of each hospital and 31 July 2022.
Ceftaroline-F was administered to 227 patients and ceftobiprole-M to 212. In comparison to the latter, ceftaroline-F-treated participants were younger (63.02 vs. 66.40 years, OR 1.1; 95%CI: 1.001-1.05) and had higher rates of septic shock (OR 0.27; 95%CI: 0.09-0.81) and higher frequencies of targeted (57.7 vs. 29.7%; OR: 0.35; 95%CI: 0.18-0.69) and combined (89.0 vs. 45.8%, OR: 0.13; 95%CI: 0.06-0.28) therapies that were second line or more (82.4% vs. 64.6%%; OR 0.35; 95%CI: 0.18-0.69), and higher rates of infections due to Gram-positive cocci (92.7 vs. 64.7%,
= 0.001), bacteremia (51.9 vs. 21.7%,
= 0.001), infective endocarditis (24.2 vs. 2.4%,
= 0.0001), and mechanical ventilation-associated pneumonia (8.8 vs. 2.4%,
= 0.0001). Ceftobiprole-M was more frequently administered against polymicrobial infections (38.1 vs. 14.0%,
= 0.001), those produced by Gram-negative bacilli (19.7 vs. 6.0%,
= 0.0001), nosocomial pneumonia (33 vs. 10.6%,
= 0.0001), and skin and soft-tissue infections (25.4 vs. 10.1%,
= 0.0001). Patients treated with ceftaroline-F had a longer hospital stay (36 (IQR: 19-60) vs. 19.50 (IQR: 12-30.75,
= 0.0001) days), with no difference in infection-related mortality at 14 (13.2 vs. 8.0%,
= 0.078) or 28 (4.8 vs. 3.3%,
= 0.415) days or in dropout rate for adverse effects (2.2 vs. 0.9%;
= 1).
The fifth-generation cephalosporins, ceftaroline-F and ceftobiprole-M, are safe and effective in real life, with no difference between them in health outcomes.
Summary
The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft‐versus‐host disease (GvHD). ...Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214‐1 and CC214‐2. In vitro studies confirmed the superior ability of CC214‐1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214‐1 was more efficient in inhibiting naïve T cell activation and the expression of T‐cell activation markers. In addition, CC214‐1 induced specific tolerance against alloantigens, while preserving anti‐cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214‐2 significantly improved mice survival and decreased GvHD‐induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214‐1 on T lymphocytes and illustrates the role of CC214‐2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.
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