2,455 research outputs found

    A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation

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    Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV-killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5μl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging inpatient populations

    Lipid mediators in immune dysfunction after severe inflammation.

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    Sepsis, trauma, burns, and major surgical procedures activate common systemic inflammatory pathways. Nosocomial infection, organ failure, and mortality in this patient population are associated with a quantitatively different reprioritization of the circulating leukocyte transcriptome to the initial inflammatory insult, greater in both magnitude and duration, and secondary to multiple observed defects in innate and adaptive immune function. Dysregulation of inflammatory resolution processes and associated bioactive lipid mediators (LMs) mechanistically contribute to this phenotype. Recent data indicate the potential efficacy of therapeutic interventions that either reduce immunosuppressive prostaglandins (PGs) or increase specialized proresolving LMs. Here, we reassess the potential for pharmacological manipulation of these LMs as therapeutic approaches for the treatment of critical illness (CI)

    New Fathers' Perinatal Depression and Anxiety-Treatment Options: An Integrative Review.

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    More than 10% of fathers experience depression and anxiety during the perinatal period, but paternal perinatal depression (PPND) and anxiety have received less attention than maternal perinatal mental health problems. Few mainstream treatment options are available for men with PPND and anxiety. The aim of this literature review was to summarize the current understanding of PPND and the treatment programs specifically designed for fathers with perinatal depression. Eight electronic databases were searched using a predefined strategy, and reference lists were also hand searched. PPND and anxiety were identified to have a negative impact on family relationships, as well as the health of mothers and children. Evidence suggests a lack of support and tailored treatment options for men having trouble adjusting to the transition to fatherhood. Of the limited options available, cognitive behavioral therapy, group work, and blended delivery programs, including e-support approaches appear to be most effective in helping fathers with perinatal depression and anxiety. The review findings have important implications for the understanding of PPND and anxiety. Future research is needed to address the adoption of father-inclusive and father-specific models of care to encourage fathers' help-seeking behavior. Inclusion of male-specific requirements into support and treatment options can improve the ability of services to engage new fathers. Psychotherapeutic intervention could assist to address the cognitive differences and dissonance for men adjusting to the role of father, including male identity and role expectations

    Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer’s disease: a cross-sectional metabolomic analysis

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    Copyright \ua9 2024 Pan, Donaghy, Roberts, Chouliaras, O’Brien, Thomas, Heslegrave, Zetterberg, McGuinness, Passmore, Green and Kane.Background: In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis. Methods: A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 \ub1 8.2 years), probable AD (n = 15; 76.1 \ub1 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 \ub1 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data. Results: The PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q ≤ 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809–0.996; sensitivity = 0.90; specificity = 0.90). Discussion: Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts

    Serotype-specific correlates of protection for pneumococcal carriage: an analysis of immunity in 19 countries.

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    Background: Pneumococcal conjugate vaccines (PCVs) provide direct protection against disease in those vaccinated, and interrupt transmission through the prevention of nasopharyngeal carriage. Methods: We analysed immunogenicity data from 5224 infants who received PCV in prime-boost schedules. We defined any increase in antibody between the one-month post-priming visit and the booster dose as an indication of nasopharyngeal carriage ('seroincidence'). We calculated antibody concentrations using receiver-operator characteristic curves, and used generalised additive models to compute their protective efficacy against seroincidence. To support seroincidence as a marker of carriage, we compared seroincidence in a randomised immunogenicity trial in Nepal with the serotype-specific prevalence of carriage in the same community. Findings: In Nepalese infants, seroincidence of carriage closely correlated with serotype-specific carriage prevalence in the community. In the larger data set, antibody concentrations associated with seroincidence were lowest for serotypes 6B and 23F (0.50 µg/mL and 0.63 µg/mL respectively), and highest for serotypes 19F and 14 (2.54 µg/mL and 2.48 µg/mL respectively). The protective efficacy of antibody at these levels was 62% and 74% for serotypes 6B and 23F, and 87% and 84% for serotypes 19F and 14. Protective correlates were on average 2.15 times higher in low/lower middle income countries than in high/upper middle income countries (GMR 2.15, 95%CI 1.46-3.17, p=0.0024). Interpretation: Antibody concentrations associated with protection vary between serotypes. Higher antibody concentrations are required for protection in low-income countries. These findings are important for global vaccination policy, to interrupt transmission by protecting against carriage

    Sarkopenija – skrandžio vėžio chirurgijoje neįvertintas rizikos veiksnys

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    Surgery remains the only potentially curative option for gastric cancer, although it is related to high postoperative morbidity and mortality rate. Approximately every second gastric cancer patient is diagnosed with sarcopenia, which is a significant risk factor for postoperative complications and poor long-term outcomes. However, sarcopenia is underestimated in routine clinical practice, since it remains the interest of clinical trials. Sarcopenia diagnostic criteria are not fully standardized, but it consists of tests for muscle strength, quantity and quality. They include grip strength, chair stand test, computed tomography, magnetic resonance imaging, ultrasound, bioelectrical impedance analysis and densitometry tests. Regarding the growing evidence for sarcopenia impact on surgical gastric cancer treatment results, it is a high probability that sarcopenia assessment will come to routine clinical practice. Although, until then there is a need for further clinical trials to standardize the diagnostic and to find effective treatment strategies.Chirurgija yra pagrindinis skrandžio vėžio gydymo metodas, leidžiantis tikėtis visiško pasveikimo. Operacijos dėl skrandžio vėžio yra didelės apimties, jos susijusios su didele pooperacinių komplikacijų rizika.&nbsp;Maždaug pusei sergančiųjų skrandžio vėžiu nustatoma sarkopenija. Tai reikšmingas pooperacinių komplikacijų rizikos veiksnys, lemiantis prastesnius atokiuosius gydymo rezultatus.Sarkopenija vis dar yra tik klinikinių tyrimų objektas, šiandienos rutininėje klinikinėje praktikoje ji nevertinama. Sarkopenijos diagnostika apima tyrimus, kuriais siekiama nustatyti raumenų jėgą, masę ir kokybę, tačiau diagnostikos metodika nėra galutinai standartizuota. Diag­nostikai taikomi plaštakos griebimo&nbsp;jėgos, „sėsti&nbsp;–&nbsp;stoti“ testo, kompiuterinės tomografijos, magnetinio rezonanso, ultragarso, bioimpedanso ir densitometrijos tyrimai.Sarkopenijos reikšmė skrandžio vėžiui gydyti vis labiau auga. Tikėtina, kad netolimoje ateityje sarkopenijos vertinimas ir gydymas taps kasdienės klinikinės praktikos dalimi. Taigi tikslinga atlikti papildomus klinikinius tyrimus, kurie padėtų standartizuoti diagnostiką ir rasti efektyvius gydymo metodus

    Sustained attention in mild cognitive impairment with Lewy bodies and Alzheimer\u27s disease

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    \ua9 The Author(s), 2023. Published by Cambridge University Press on behalf of International Neuropsychological Society. Objective: Attentional impairments are common in dementia with Lewy bodies and its prodromal stage of mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). People with MCI may be capable of compensating for subtle attentional deficits in most circumstances, and so these may present as occasional lapses of attention. We aimed to assess the utility of a continuous performance task (CPT), which requires sustained attention for several minutes, for measuring attentional performance in MCI-LB in comparison to Alzheimer\u27s disease (MCI-AD), and any performance deficits which emerged with sustained effort. Method: We included longitudinal data on a CPT sustained attention task for 89 participants with MCI-LB or MCI-AD and 31 healthy controls, estimating ex-Gaussian response time parameters, omission and commission errors. Performance trajectories were estimated both cross-sectionally (intra-task progress from start to end) and longitudinally (change in performance over years). Results: While response times in successful trials were broadly similar, with slight slowing associated with clinical parkinsonism, those with MCI-LB made considerably more errors. Omission errors were more common throughout the task in MCI-LB than MCI-AD (OR 2.3, 95% CI: 1.1-4.7), while commission errors became more common after several minutes of sustained attention. Within MCI-LB, omission errors were more common in those with clinical parkinsonism (OR 1.9, 95% CI: 1.3-2.9) or cognitive fluctuations (OR 4.3, 95% CI: 2.2-8.8). Conclusions: Sustained attention deficits in MCI-LB may emerge in the form of attentional lapses leading to omissions, and a breakdown in inhibitory control leading to commission errors

    On-demand semiconductor single-photon source with near-unity indistinguishability

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    Single photon sources based on semiconductor quantum dots offer distinct advantages for quantum information, including a scalable solid-state platform, ultrabrightness, and interconnectivity with matter qubits. A key prerequisite for their use in optical quantum computing and solid-state networks is a high level of efficiency and indistinguishability. Pulsed resonance fluorescence (RF) has been anticipated as the optimum condition for the deterministic generation of high-quality photons with vanishing effects of dephasing. Here, we generate pulsed RF single photons on demand from a single, microcavity-embedded quantum dot under s-shell excitation with 3-ps laser pulses. The pi-pulse excited RF photons have less than 0.3% background contributions and a vanishing two-photon emission probability. Non-postselective Hong-Ou-Mandel interference between two successively emitted photons is observed with a visibility of 0.97(2), comparable to trapped atoms and ions. Two single photons are further used to implement a high-fidelity quantum controlled-NOT gate.Comment: 11 pages, 11 figure
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