The selectins: E-selectin, P-selectin, and L-selectin are adhesion molecules that are crucial for binding of circulating leukocytes to vascular endothelium during the inflammatory response to injury ...or infection. Accumulated evidence indicates that selectins regulate adhesion of circulating cancer cells to the walls of blood vessels. Selectin ligands are transmembrane glycoproteins expressed on leukocytes and cancer cells that promote bond formations with selectins to mediate inflammatory processes. Selectins and selectin ligands also participate in signal transduction to regulate diverse cellular functions. Sialyl Lewis X (sLe(x)) and sialyl Lewis A (sLe(a)) tetrasaccharides are carbohydrate motifs displayed on protein or lipid scaffolds that are critical components of functional selectin ligands. Selectin binding to sLe(x) and sLe(a) present on colon, gastric, bladder, pancreatic, breast, and prostate carcinomas enhances distant organ metastasis. High expression of sialyl Lewis ligands on these cancers is significantly correlated with a poor post-operative prognosis. This review will focus on the roles of E-selectin and P-selectin in cancer progression. Understanding the role of selectins in cancer supports the development of novel selectin-based therapies to control metastasis.
To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry.
Cross-sectional observational study including coronavirus disease 2019 patients ...hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies.
About 168 hospitals in 16 countries within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry.
Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation).
None.
Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69).
Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.
OBJECTIVES:The study goal was to concurrently evaluate agreement of a 9-point pulmonary ultrasound protocol and portable chest radiograph with chest CT for localization of pathology to the correct ...lung and also to specific anatomic lobes among a diverse group of intubated patients with acute respiratory failure.
DESIGN:Prospective cohort study.
SETTING:Medical, surgical, and neurologic ICUs at a 670-bed urban teaching hospital.
PATIENTS:Intubated adults with acute respiratory failure having chest CT and portable chest radiograph performed within 24 hours of intubation.
INTERVENTIONS:A 9-point pulmonary ultrasound examination performed at the time of intubation.
MEASUREMENTS AND MAIN RESULTS:Sixty-seven patients had pulmonary ultrasound, portable chest radiograph, and chest CT performed within 24 hours of intubation. Overall agreement of pulmonary ultrasound and portable chest radiograph findings with correlating lobe (“lobe-specific” agreement) on CT was 87% versus 62% (p < 0.001), respectively. Relaxing the agreement definition to a matching CT finding being present anywhere within the correct lung (“lung-specific” agreement), not necessarily the specific mapped lobe, showed improved agreement for both pulmonary ultrasound and portable chest radiograph respectively (right lung92.5% vs 65.7%; p < 0.001 and left lung83.6% vs 71.6%; p = 0.097). The highest lobe-specific agreement was for the finding of atelectasis/consolidation for both pulmonary ultrasound and portable chest radiograph (96% and 73%, respectively). The lowest lobe-specific agreement for pulmonary ultrasound was normal lung (79%) and interstitial process for portable chest radiograph (29%). Lobe-specific agreement differed most between pulmonary ultrasound and portable chest radiograph for interstitial findings (86% vs 29%, respectively). Pulmonary ultrasound had the lowest agreement with CT for findings in the left lower lobe (82.1%). Pleural effusion agreement also differed between pulmonary ultrasound and portable chest radiograph (right99% vs 87%; p = 0.009 and left99% vs 85%; p = 0.004).
CONCLUSIONS:A clinical, 9-point pulmonary ultrasound protocol strongly agreed with specific CT findings when analyzed by both lung- and lobe-specific location among a diverse population of mechanically ventilated patients with acute respiratory failure; in this regard, pulmonary ultrasound significantly outperformed portable chest radiograph.
Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the ...metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that ...biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.
Non-malignant chronic pain (NMCP) is one of the most common reasons for primary care visits. Pain management health care disparities have been documented in relation to patient gender, race, and ...socioeconomic status. Although not studied in relation to chronic pain management, studies have found that living in a rural community in the US is associated with health care disparities. Rurality as a social determinant of health may influence opioid prescribing. We examined rural and non-rural differences in opioid prescribing patterns for NMCP management, hypothesizing that distinct from education, income, racial or gender differences, rural residency is a significant and independent factor in opioid prescribing patterns.
2010 National Ambulatory Medical Care Survey (NAMCS) data were examined using bivariate and multivariate techniques. NAMCS data were collected using a multi-stage sampling strategy. For the multivariate analysis performed the SPSS complex samples algorithm for logistic regression was used.
In 2010 an estimated 9,325,603 US adults (weighted from a sample of 2745) seen in primary care clinics had a diagnosis of NMCP; 36.4% were prescribed an opioid. For US adults with a NMCP diagnosis bivariate analysis revealed rural residents had higher odds of having an opioid prescription than similar non-rural adults (OR = 1.515, 95% CI 1.513-1.518). Complex samples logistic regression analysis confirmed the importance of rurality and yielded that US adults with NMCP who were prescribed an opioid had higher odds of: being non-Caucasian (AOR =2.459, 95% CI 1.194-5.066), and living in a rural area (AOR =2.935, 95% CI 1.416-6.083).
Our results clearly indicated that rurality is an important factor in opioid prescribing patterns that cannot be ignored and bears further investigation. Further research on the growing concern about the over-prescribing of opioids in the US should now include rurality as a variable in data generation and analysis. Future research should also attempt to document the ecological, sociological and political factors impacting opioid prescribing and care in rural communities. Prescribers and health care policy makers need to critically evaluate the implications of our findings and their relationship to patient needs, best practices in a rural setting, and the overall consequences of increased opioid prescribing on rural communities.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Infectious morbidity and mortality in the first week of life is commonly caused by early-onset neonatal Group B streptococcus (GBS) disease. This infection is spread from GBS positive ...mothers to neonates by vertical transmission during delivery and results in serious illness for newborns. Intrapartum prophylactic antibiotics have decreased the incidence of early-onset neonatal GBS disease by 80%. Patients labeled with a penicillin allergy (PcnA) alternatively receive either vancomycin or clindamycin but effectiveness is controversial. We evaluated the influence of a reported PcnA label versus no PcnA label on inpatient maternal and neonatal outcomes. Methods Our goal was to examine the relationship between a PcnA label, maternal and neonatal outcomes, and hospital costs. We collected retrospective data with institutional IRB approval from 2016 - 2018 for hospitalized patients who were GBS positive, pregnant at time of admission, greater than or equai to 18 years of age, received antibiotic prophylaxis for GBS, were labeled as PcnA or non-PcnA, and completed a vaginal delivery. Patient characteristics and maternal/neonatal outcomes were examined. Statistical tests included calculations of means, medians, proportions, Mann-Whitney, two-sample t-tests, Chi-squared or Fisher's Exact tests, and generalized linear and logistic regression models. Significance was set at p < 0.05. Results Most PcnA patients were white, older, had a higher median body mass index and mean heart rate, and a greater proportion used tobacco than non-PcnA patients. In regression analyses, PcnA hospitalized patients received a shorter duration of antibiotic treatment than non-PcnA patients incidence rate ratio (IRR): 0.45, 95% CI: 0.38-0.53. PcnA patients were also more likely to have their baby's hospital LOS be > 48 h adjusted odds ratio (AOR): 1.35, 95% CI: 1.07-1.69 even though the PcnA mothers' LOS was not different from non-PcnA mothers. Cost of care, mortality, intensive care, median parity, mean gravidity, and miscarriage were similar between the groups. Conclusions In hospitalized obstetric patients, a PcnA label was associated with a shorter maternal course of antibiotic treatment and a longer neonatal LOS. Further prospective studies are needed to clarify the underlying reasons for these outcomes. Keywords: Hypersensitivity, Infant, Newborn, Penicillins, Pregnancy, Streptococcus
We describe the first comprehensive analysis of the midgut metabolome of Aedes aegypti, the primary mosquito vector for arboviruses such as dengue, Zika, chikungunya and yellow fever viruses. ...Transmission of these viruses depends on their ability to infect, replicate and disseminate from several tissues in the mosquito vector. The metabolic environments within these tissues play crucial roles in these processes. Since these viruses are enveloped, viral replication, assembly and release occur on cellular membranes primed through the manipulation of host metabolism. Interference with this virus infection-induced metabolic environment is detrimental to viral replication in human and mosquito cell culture models. Here we present the first insight into the metabolic environment induced during arbovirus replication in Aedes aegypti. Using high-resolution mass spectrometry, we have analyzed the temporal metabolic perturbations that occur following dengue virus infection of the midgut tissue. This is the primary site of infection and replication, preceding systemic viral dissemination and transmission. We identified metabolites that exhibited a dynamic-profile across early-, mid- and late-infection time points. We observed a marked increase in the lipid content. An increase in glycerophospholipids, sphingolipids and fatty acyls was coincident with the kinetics of viral replication. Elevation of glycerolipid levels suggested a diversion of resources during infection from energy storage to synthetic pathways. Elevated levels of acyl-carnitines were observed, signaling disruptions in mitochondrial function and possible diversion of energy production. A central hub in the sphingolipid pathway that influenced dihydroceramide to ceramide ratios was identified as critical for the virus life cycle. This study also resulted in the first reconstruction of the sphingolipid pathway in Aedes aegypti. Given conservation in the replication mechanisms of several flaviviruses transmitted by this vector, our results highlight biochemical choke points that could be targeted to disrupt transmission of multiple pathogens by these mosquitoes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Arterial stiffness is associated with an array of debilitating health conditions. While exercise typically has beneficial effects on both arterial stiffness and overall health, more research is ...needed to understand the associations of different types of fitness indices with arterial stiffness.
To investigate the relationship between balance, strength, cardiovascular fitness and physical activity with arterial stiffness (as measured by pulse wave velocity (PWV)) in older adults.
Eighty retirement-village residents (24 males, 56 females, age: 78.2 ± 6.4 years, weight: 69.4 ± 12.5 kg, height: 162.9 ± 8.5 cm) completed the Yale Physical Activity Survey, PWV measurement, 30-s sit-to-stand leg strength test, hand grip strength assessment, 4-stage balance test, and a 6-min walk fitness test. The number of exiting risk factors (smoking, previous heart incidents, previous stroke(s), having hypertension, or taking anti-hypertension medication) were tallied. Pearson's correlations were used to assess the relationship between PWV and health and fitness parameters. Results were interpreted using qualitative inference.
The number of risk factors (r = 0.57,
< 0.001), age (r = 0.51,
< 0.001) and systolic blood pressure (r = 0.50,
= 0.001) had strong, harmful associations with PWV. Total physical activity minutes/week (r = -0.31
= 0.01), total energy expenditure Kcal/week (r = -0.30,
= 0.01), and the 6-min walk test (r = -0.29,
= 0.01) had a moderate, beneficial association with PWV, while sit-to-stand (r = -0.27,
= 0.02) and balance (r = -0.27,
= 0.01) had a weak, beneficial association with PWV. Hand grip strength (r = 0.02,
= 0.94) and body mass index (r = -0.04,
= 0.75) had no significant associations with PWV.
All measured fitness indices had beneficial associations with PWV. However, having more risk factors, increased age, and higher systolic blood pressure had significant (harmful) associations with PWV in our older population.
Controlling cardiovascular risk factors, especially high systolic blood pressure, is likely to have the largest beneficial effect on PWV. Improving general physical activity, including walking capacity, may prove beneficial in improving PWV in an older population.
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