Highlights ► Endotoxin challenge in humans results in marked alterations in HDL particle composition with reduced phospholipids and increased serum amyloid A but without significant change in ...cholesterol of apo-AI. ► Endotoxin induced selective remodeling of HDL particles with induction of specific HDL lipases and reductions in CETP mass and LCAT activity. ► HDL efflux function was reduced after endotoxin challenge with reduced capacity of particles to mediate efflux via ABCA1 and SR-BI cholesterol transporter pathways; reduced efflux correlated with alterations in HDL composition and reduction in specific HDL sub-populations.► Overall, these data support the concept that atherogenic HDL dysfunction and impaired RCT occur in human inflammatory syndromes, independent of significant change in plasma HDL-C levels.
Triple negative breast cancer (TNBC) is an aggressive sub-type of the disease which accounts for a disproportionately high percentage of breast cancer morbidities and mortalities. For these reasons, ...a better understanding of TNBC biology is required and the development of novel therapeutic approaches are critically needed. Estrogen receptor beta (ERβ) is a reported tumor suppressor that is expressed in approximately 20% of primary TNBC tumors, where it is associated with favorable prognostic features and patient outcomes. Previous studies have shown that ERβ mediates the assembly of co-repressor complexes on DNA to inhibit the expression of multiple growth promoting genes and to suppress the ability of oncogenic transcription factors to drive cancer progression. To further elucidate the molecular mechanisms by which ERβ elicits its anti-cancer effects, we developed MDA-MB-231 cells that inducibly express a mutant form of ERβ incapable of directly binding DNA. We demonstrate that disruption of ERβ's direct interaction with DNA abolishes its ability to regulate the expression of well characterized immediate response genes and renders it unable to suppress TNBC cell proliferation. Loss of DNA binding also diminishes the ability of ERβ to suppress oncogenic NFκB signaling even though it still physically associates with NFκB and other critical co-factors. These findings enhance our understanding of how ERβ functions in this disease and provide a model system that can be utilized to further investigate the mechanistic processes by which ERβ elicits its anti-cancer effects.
Innate Immunity Modulates Adipokines in Humans Anderson, Paul D; Mehta, Nehal N; Wolfe, Megan L ...
The journal of clinical endocrinology and metabolism,
06/2007, Letnik:
92, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Context: Chronic inflammation converges in type 2 diabetes and atherosclerosis. Modulation of adipokine signaling by innate immunity in humans is of considerable interest given the role of adipokines ...in insulin resistance and atherosclerosis.
Objective: The aim of the study was to examine effects of low-grade endotoxemia, a model of human inflammation, on adipokines in vivo.
Design/Setting: An open-label, placebo-controlled, fixed-sequence clinical study was conducted at a General Clinical Research Center.
Patients: There were 20 healthy male (50%) and female volunteers aged 18–40 yr.
Intervention: Serial blood sampling and adipose biopsies were performed for 24 h before and after iv bolus endotoxin lipopolysaccharide (LPS), 3 ng/kg.
Main Outcome Measures: We measured plasma leptin, adiponectin, resistin, soluble leptin receptor, cytokines, insulin, and glucose; distribution of adiponectin among multimeric complexes; whole blood, monocyte and adipose mRNA for adipokines and their receptors.
Results: LPS induced fever, blood, and adipose TNF and IL-6 and increased homeostasis model assessment of insulin resistance. These were associated with increases in plasma leptin (from 4.1 ± 1.1 to 6.1 ± 1.9 ng/ml in men; 21.1 ± 4.4 to 27.4 ± 4.7 ng/ml in women; P < 0.005), doubling of the leptin:soluble leptin receptor ratio, and marked induction of whole blood resistin mRNA (13.7 ± 7.3-fold; P < 0.001) and plasma resistin (8.5 ± 2.75 to 43.2 ± 15.3 ng/ml; P < 0.001). Although total adiponectin levels and low and high molecular weight adiponectin complexes were unaltered by LPS treatment, whole blood mRNA for adiponectin receptors 1 (49%; P < 0.005) and 2 (65%; P < 0.001) was suppressed.
Conclusions: Modulation of adipokine signaling may contribute to the insulin resistant, atherogenic state associated with human inflammatory syndromes. Targeting of individual adipokines or their upstream regulation may prove effective in preventing acute and chronic inflammation-related metabolic complications.
To assess the effects of both male and female body mass index (BMI), individually and combined, on IVF outcomes.
Prospective cohort study.
University fertility center.
All couples undergoing first ...fresh IVF cycles, 2005-2010, for whom male and female weight and height information were available (n = 721 couples).
None.
Embryologic parameters, clinical pregnancy, and live birth incidence.
The average male BMI among the study population was 27.5 ± 4.8 kg/m(2) (range, 17.3-49.3 kg/m(2)), while the average female BMI (n = 721) was 25.2 ± 5.9 kg/m(2) (range, 16.2-50.7 kg/m(2)). Neither male nor female overweight (25-29.9 kg/m(2)), class I obese (30-34.9 kg/m(2)), or class II/III obese (≥35 kg/m(2)) status was significantly associated with fertilization rate, embryo score, or incidence of pregnancy or live birth compared with normal weight (18.5-24.9 kg/m(2)) status after adjusting for male and female age, partner BMI, and parity. Similar null findings were found between combined couple BMI categories and IVF success.
Our findings support the notion that weight status does not influence fecundity among couples undergoing infertility treatment. Given the limited and conflicting research on BMI and pregnancy success among IVF couples, further research augmented to include other adiposity measures is needed.
Introduction
Parastomal hernia is a debilitating complication of stoma creation. Parastomal hernia repair with mesh reduces recurrence rates in open and laparoscopic settings. Recent comparative ...studies conflict with previously pooled data on optimal mesh repair technique. The objective of this study is to examine parastomal hernia recurrence rates after Sugarbaker and keyhole repairs by performing an updated systematic review and meta-analysis of comparative studies.
Methods
A systematic review of PubMed, MEDLINE, EMBASE, the Cochrane database, SCOPUS, and the PROSPERO registry was performed according to PRISMA 2020 guidelines (PROSPERO ID: CRD42021290483). Studies comparing parastomal hernia recurrences after Sugarbaker and keyhole repairs were included. Studies with overlapping patient cohorts (duplicate data), non-comparative studies, studies that did not report the primary outcome of interest, and studies not in the English language were excluded. Study bias was assessed using the Newcastle–Ottawa scale. Pooled mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI) were calculated. Heterogeneity was assessed using the
I
2
statistic. Forest plots and funnel plots were generated. Study quality was analyzed using MINORS. Additional subgroup analysis of modern studies was performed.
Results
Ten comparative studies published between 2005 and 2021 from 5 countries were included for analysis comprising 347 Sugarbaker repairs and 246 keyhole repairs. There were no differences in patient age, sex, or BMI between the groups. There was no difference between the groups regarding surgical site infection (OR 0.78; CI 0.31–1.98;
P
= 0.61) or post-operative bowel obstruction (OR 0.76; CI 0.23–2.56;
P
= 0.66). Sugarbaker repairs were significantly less often associated with parastomal hernia recurrence when compared to keyhole repairs (OR 0.38; CI 0.18–0.78;
P
= 0.008). There was no significant heterogeneity among the studies comparing parastomal hernia recurrence (
I
2
= 32%;
P
= 0.15). Quality analysis revealed a median MINORS score of 11 (range 6–16). Subgroup analysis of studies performed after the previously published pooled analysis (2015–2021) revealed no significant difference in parastomal hernia recurrence between the two groups (OR 0.58; CI 0.24–1.38;
P
= 0.22) with a significant subgroup effect (
P
= 0.05).
Conclusions
Though there were lower rates of parastomal hernia recurrence with Sugarbaker repairs on overall analysis, this phenomenon disappeared on subgroup analysis of modern studies. Randomized controlled trials with contemporary cohorts would help further evaluate these repairs and minimize potential bias.
Disruptions in the hospital clinical workforce threaten quality and safety of care and retention of health professionals. It is important to understand which interventions would be well received by ...clinicians to address the factors associated with turnover.
To determine well-being and turnover rates of physicians and nurses in hospital practice, and to identify actionable factors associated with adverse clinician outcomes, patient safety, and clinicians' preferences for interventions.
This was a cross-sectional multicenter survey study conducted in 2021 with 21 050 physicians and nurses at 60 nationally distributed US Magnet hospitals. Respondents described their mental health and well-being, associations between modifiable work environment factors and physician and nurse burnout, mental health, hospital staff turnover, and patient safety. Data were analyzed from February 21, 2022, to March 28, 2023.
Clinician outcomes (burnout, job dissatisfaction, intent to leave, turnover), well-being (depression, anxiety, work-life balance, health), patient safety, resources and work environment adequacy, and clinicians' preferences for interventions to improve their well-being.
The study sample comprised responses from 15 738 nurses (mean SD age, 38.4 11.7 years; 10 887 (69%) women; 8404 53% White individuals) practicing in 60 hospitals, and 5312 physicians (mean SD age, 44.7 12.0 years; 2362 45% men; 2768 52% White individuals) practicing in 53 of the same hospitals, with an average of 100 physicians and 262 nurses per hospital and an overall clinician response rate of 26%. High burnout was common among hospital physicians (32%) and nurses (47%). Nurse burnout was associated with higher turnover of both nurses and physicians. Many physicians (12%) and nurses (26%) rated their hospitals unfavorably on patient safety, reported having too few nurses (28% and 54%, respectively), reported having a poor work environment (20% and 34%, respectively), and lacked confidence in management (42% and 46%, respectively). Fewer than 10% of clinicians described their workplace as joyful. Both physicians and nurses rated management interventions to improve care delivery as more important to their mental health and well-being than interventions directed at improving clinicians' mental health. Improving nurse staffing was ranked highest among interventions (87% of nurses and 45% of physicians).
This cross-sectional survey study of physicians and nurses practicing in US Magnet hospitals found that hospitals characterized as having too few nurses and unfavorable work environments had higher rates of clinician burnout, turnover, and unfavorable patient safety ratings. Clinicians wanted action by management to address insufficient nurse staffing, insufficient clinician control over workload, and poor work environments; they were less interested in wellness programs and resilience training.
Objectives This study sought to examine the role of lipoprotein-associated phospholipase A2 (Lp-PLA2 / PLA2G7 ) in human inflammation and coronary atherosclerosis. Background Lp-PLA2 has emerged as a ...potential therapeutic target in coronary heart disease. Data supporting Lp-PLA2 are indirect and confounded by species differences; whether Lp-PLA2 is causal in coronary heart disease remains in question. Methods We examined inflammatory regulation of Lp-PLA2 during experimental endotoxemia in humans, probed the source of Lp-PLA2 in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7 , the gene encoding Lp-PLA2 , with coronary artery calcification. Results In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA2 messenger ribonucleic acid decreased transiently, and plasma Lp-PLA2 mass declined modestly during endotoxemia. In vitro, Lp-PLA2 expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA2 activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification. Conclusions Circulating Lp-PLA2 did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2 . Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA2 to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA2 as a biomarker of Lp-PLA2 actions in the vasculature.
Abstract
Background
Candida auris, an emerging multidrug-resistant pathogen associated with increased mortality, can disseminate on hospital surfaces and resist disinfection. Transmission dynamics ...remain poorly understood at community hospitals. Immediately following identification of a C. auris infection in an unsuspected patient admitted to a semi-private room 6 days previously, we sought to limit and determine the extent of C. auris contamination at Rochester General (RG), a 528-bed hospital in New York, using available resources.
Methods
The index and roommate were placed on enhanced contact precautions and moved to private rooms. Their former room was terminally cleaned with peracetic acid/hydrogen peroxide (PAHP) and UV light. Ten high-touch environmental surfaces in the new rooms of the index and roommate, the nursing stations, and throughout the ward were sampled immediately before and after, and between daily cleaning. The nares, axillae, and groin of the index, the roommate, and all concurrent ward patients were also sampled. All patients on the involved ward were sequentially moved from their initial rooms into vacated rooms that were terminally cleaned with PAHP and UV light. Prior to the index event, RG laboratory began sending all possible C. auris isolates to the state public health laboratory for confirmation, and using PAHP for all cleaning. RG also leverages preexisting agreements with other referral laboratories to support outbreak investigations. Hand-hygiene compliance averaged 80–90% on the ward. Hospital leaders, laboratory, nursing, environmental services, and local public health personnel regularly participate in infection prevention efforts.
Results
C. auris was isolated from 3 of 132 surface samples on the eighth, nineth, and 15th day of ward occupancy, and 0 of 48 patient samples from 18 co-located patients. The index remained colonized until death on hospital Day 21. No surfaces were C. auris-positive 1 month later.
Conclusion
Compared with prior reports, dissemination at RG was limited. This, the first such quantitative assessment, illustrates how community hospitals can enhance surveillance and patient safety when formal agreements, vigilance, and multi-disciplinary and interagency teamwork exist before outbreaks occur.
Disclosures
All authors: No reported disclosures.
Objectives This study sought to examine the role of lipoprotein-associated phospholipase A2(Lp-PLA2/PLA2G7) in human inflammation and coronary atherosclerosis. Background Lp-PLA2has emerged as a ...potential therapeutic target in coronary heart disease. Data supporting Lp-PLA2are indirect and confounded by species differences; whether Lp-PLA2is causal in coronary heart disease remains in question. Methods We examined inflammatory regulation of Lp-PLA2during experimental endotoxemia in humans, probed the source of Lp-PLA2in human leukocytes under inflammatory conditions, and assessed the relationship of variation inPLA2G7, the gene encoding Lp-PLA2, with coronary artery calcification. Results In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA2messenger ribonucleic acid decreased transiently, and plasma Lp-PLA2mass declined modestly during endotoxemia. In vitro, Lp-PLA2expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms inPLA2G7with Lp-PLA2activity or mass, numerousPLA2G7single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms inCRPwere significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification. Conclusions Circulating Lp-PLA2did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2. Common genetic variation inPLA2G7is associated with subclinical coronary atherosclerosis. These data link Lp-PLA2to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA2as a biomarker of Lp-PLA2actions in the vasculature.
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