Hypertriglyceridemia: a potential side effect of propofol sedation in critical illness

Purpose: Hypertriglyceridemia (hyperTG) is common among intensive care unit (ICU) patients, but knowledge about hyperTG risk factors is scarce. The present study aims to identify risk factors favoring its development in patients requiring prolonged ICU treatment. Methods: Prospective observational study in the medicosurgical ICU of a university teaching hospital. All consecutive patients staying ≥4days were enrolled. Potential risk factors were recorded: pathology, energy intake, amount and type of nutritional lipids, intake of propofol, glucose intake, laboratory parameters, and drugs. Triglyceride (TG) levels were assessed three times weekly. Statistics was based on two-way analysis of variance (ANOVA) and linear regression with potential risk factors. Results: Out of 1,301 consecutive admissions, 220 patients were eligible, of whom 99 (45%) presented hyperTG (triglycerides >2mmol/L). HyperTG patients were younger, heavier, with more brain injury and multiple trauma. Intake of propofol (mg/kg/h) and lipids' propofol had the highest correlation with plasma TG (r 2=0.28 and 0.26, respectively, both p<0.001). Infection and inflammation were associated with development of hyperTG [C-reactive protein (CRP), r 2=0.19, p=0.004]. No strong association could be found with nutritional lipids or other risk factors. Outcome was similar in normo- and hyperTG patients. Conclusions: HyperTG is frequent in the ICU but is not associated with adverse outcome. Propofol and accompanying lipid emulsion are the strongest risk factors. Our results suggest that plasma TG should be monitored at least twice weekly in patients on propofol. The clinical consequences of propofol-related hyperTG should be investigated in further studie

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur

Hypothalamic ghrelin treatment modulates NPY-but not CRH-ergic activity in adrenalectomized rats subjected to food restriction: Evidence of a novel hypothalamic ghrelin effect

It has been proposed that ghrelin induces food intake by a mechanism due to the stimulation of hypothalamic NPY-ergic activity. It is recognized that bilateral adrenalectomy (ADX) enhances hypothalamic CRH-ergic function and reduces appetite. Thus, the aim of the present study was to test whether, icv-administered, ghrelin modulates NPY- and CRH-ergic functions after food restriction (FR) and glucocorticoid deprivation. For this purpose, 1 microg ghrelin was administered icv to ad libitum (AL) eating and to corticosterone (B)-depleted (ADX) and -replete (sham and ADX+B) male animals habituated, for 15 d, to FR. Food intake, hypothalamic function, and peripheral ghrelin, ACTH, and B concentrations were evaluated 2 h after ghrelin administration. Results indicate that while icv ghrelin treatment stimulated 2-h food intake in AL rats, it failed to do so in sham- and ADX+B-FR animals; moreover, 2-h food intake was inhibited by icv ghrelin treatment in ADX-FR rats. Regarding peripheral hormone levels: (a) basal circulating ghrelin levels, already enhanced (vs AL rats) by FR, significantly increased 2 h after icv ghrelin treatment in AL and sham-FR rats; (b) central ghrelin treatment stimulated ACTH secretion in circulation of AL and glucocorticoid-replete-FR rats; and (c) B circulating levels remained unchanged after ghrelin treatment, although they were in relation to the food intake condition of rats. Finally, hypothalamic NPY mRNA expression was enhanced by FR and, in response to icv ghrelin treatment, it decreased in ADX-FR rats only. ADX-enhanced hypothalamic CRH mRNA levels were reduced by ghrelin icv administration only when animals received B replacement therapy. Our data indicate an inhibitory effect of hypothalamic ghrelin on NPY-ergic activity in FR rats lacking endogenous glucocorticoid

The gut bacterial community affects immunity but not metabolism in a specialist herbivorous butterfly

1. Plant tissues often lack essential nutritive elements and may contain a range of secondary toxic compounds. As nutritional imbalance in food intake may affect the performances of herbivores, the latter have evolved a variety of physiological mechanisms to cope with the challenges of digesting their plant-based diet. Some of these strategies involve living in association with symbiotic microbes that promote the digestion and detoxification of plant compounds or supply their host with essential nutrients missing from the plant diet. In Lepidoptera, a growing body of evidence has, however, recently challenged the idea that herbivores are nutritionally dependent on their gut microbial community. It is suggested that many of the herbivorous Lepidopteran species may not host a resident microbial community, but rather a transient one, acquired from their environment and diet. Studies directly testing these hypotheses are however scarce and come from an even more limited number of species. 2. By coupling comparative metabarcoding, immune gene expression, and metabolomics analyses with experimental manipulation of the gut microbial community of prediapause larvae of the Glanville fritillary butterfly (Melitaea cinxia, L.), we tested whether the gut microbial community supports early larval growth and survival, or modulates metabolism or immunity during early stages of development. 3. We successfully altered this microbiota through antibiotic treatments and consecutively restored it through fecal transplants from conspecifics. Our study suggests that although the microbiota is involved in the up-regulation of an antimicrobial peptide, it did not affect the life history traits or the metabolism of early instars larvae. 4. This study confirms the poor impact of the microbiota on diverse life history traits of yet another Lepidoptera species. However, it also suggests that potential eco-evolutionary host-symbiont strategies that take place in the gut of herbivorous butterfly hosts might have been disregarded, particularly how the microbiota may affect the host immune system homeostasis.Peer reviewe

Effectiveness of a transition plan at discharge of patients hospitalized with heart failure: a before-and-after study.

We evaluated the effectiveness of a multidisciplinary transition plan to reduce early readmission among heart failure patients. We conducted a before-and-after study in a tertiary internal medicine department, comparing 3 years of retrospective data (pre-intervention) and 13 months of prospective data (intervention period). Intervention was the introduction in 2013 of a transition plan performed by a multidisciplinary team. We included all consecutive patients hospitalized with symptomatic heart failure and discharged to home. The outcomes were the fraction of days spent in hospital because of readmission, based on the sum of all days spent in hospital, and the rate of readmission. The same measurements were used for those with potentially avoidable readmissions. Four hundred thirty-one patients were included and compared with 1441 patients in the pre-intervention period. Of the 431 patients, 138 received the transition plan while 293 were non-completers. Neither the fraction of days spent for readmissions nor the rate of readmission decreased during the intervention period. However, non-completers had a higher rate of the fraction of days spent for 30 day readmission (19.2% vs. 16.1%, P = 0.002) and for potentially avoidable readmission (9.8% vs. 13.2%, P = 0.001). The rate of potentially avoidable readmission decreased from 11.3% (before) to 9.9% (non-completers) and 8.7% (completers), reaching the adjusted expected range given by SQLape® (7.7-9.1%). A transition plan, requiring many resources, could decrease potentially avoidable readmission but shows no benefit on overall readmission. Future research should focus on potentially avoidable readmissions and other indicators such as patient satisfaction, adverse drug events, or adherence

Observations of aerosols in the free troposphere and marine boundary layer of the subtropical Northeast Atlantic: discussion of processes determining their size distribution

During July 1994, submicron aerosol size distributions were measured at two sites on Tenerife, Canary Islands. One station was located in the free troposphere (FT), the other in the marine boundary layer (MBL). Transport toward these two sites was strongly decoupled: the FT was first affected by dust and sulfate-laden air masses advecting from North Africa and later by clean air masses originating over the North Atlantic, whereas the MBL was always subject to the northeasterly trade wind circulation. In the FT the submicron aerosol distribution was predominantly monomodal with a geometric mean diameter of 120 nm and 55 nm during dusty and clean conditions, respectively. The relatively small diameter during the clean conditions indicates that the aerosol originated in the upper troposphere rather than over continental areas or in the lower stratosphere. During dusty conditions the physical and chemical properties of the submicron aerosol suggest that it has an anthropogenic origin over southern Europe and that it remains largely externally mixed with the supermicron mineral dust particles during its transport over North Africa to Tenerife. Apart from synoptic variations, a strong diurnal variation in the aerosol size distribution is observed at the FT site, characterized by a strong daytime mode of ultrafine particles. This is interpreted as being the result of photoinduced nucleation in the upslope winds, which are perturbed by anthropogenic and biogenic emissions on the island. No evidence was found for nucleation occurring in the undisturbed FT. The MBL site was not strongly affected by European pollution during the period of the measurements. The MBL aerosol size distribution was bimodal, but the relative concentration of Aitken and accumulation mode varied strongly. The accumulation mode can be related to cloud processing of the Aitken mode but also to pollution aerosol which was advected within the MBL or entrained from the FT. No bursts of nucleation were observed within the MBL

The Resonance of Resonance: Critical Theory as a Sociology of World-Relations?

The main purpose of this paper is to examine Hartmut Rosa’s account of “resonance.” To this end, the analysis is divided into four parts. The first part focuses on the concept of resonance, including Rosa’s differentiation between horizontal, diagonal, and vertical “axes of resonance” and their role in the construction of different “world-relations.” The second part centers on the concept of alienation, notably the degree to which it constitutes an integral element of modern life forms and, in a larger sense, of the human condition. The third part grapples with the dialectic of resonance and alienation, shedding light on the assumption that they are antithetical to each other, while contending that their in-depth study provides normative parameters to distinguish between “the good life” and “the bad life.” The final part scrutinizes Rosa’s attempt to defend his outline of a sociological theory of resonance against objections raised by his critics and comprises a point-by-point assessment of his plea for a resonance-focused sociology of world-relations. The paper concludes by suggesting that, notwithstanding its limitations, Rosa’s approach represents one of the most promising developments in twenty-first-century critical theory

Contract-Based Resource Verification for Higher-Order Functions with Memoization

We present a new approach for specifying and verifying resource utilization of higher-order functional programs that use lazy evaluation and memoization. In our approach, users can specify the desired resource bound as templates with numerical holes e.g. as steps <= ? not asymptotic to size(l) + ? in the contracts of functions. They can also express invariants necessary for establishing the bounds that may depend on the state of memoization. Our approach operates in two phases: first generating an instrumented first-order program that accurately models the higher-order control flow and the effects of memoization on resources using sets, algebraic datatypes and mutual recursion, and then verifying the contracts of the first-order program by producing verification conditions of the form there exists for all using an extended assume/guarantee reasoning. We use our approach to verify precise bounds on resources such as evaluation steps and number of heap-allocated objects on 17 challenging data structures and algorithms. Our benchmarks, comprising of 5K lines of functional Scala code, include lazy mergesort, Okasaki's real-time queue and deque data structures that rely on aliasing of references to first-class functions; lazy data structures based on numerical representations such as the conqueue data structure of Scala's data-parallel library, cyclic streams, as well as dynamic programming algorithms such as knapsack and Viterbi. Our evaluations show that when averaged over all benchmarks the actual runtime resource consumption is 80% of the value inferred by our tool when estimating the number of evaluation steps, and is 88% for the number of heap-allocated objects

The Fetal Hypothalamus Has the Potential to Generate Cells with a Gonadotropin Releasing Hormone (GnRH) Phenotype

Neurospheres (NS) are colonies of neural stem and precursor cells capable of differentiating into the central nervous system (CNS) cell lineages upon appropriate culture conditions: neurons, and glial cells. NS were originally derived from the embryonic and adult mouse striatum subventricular zone. More recently, experimental evidence substantiated the isolation of NS from almost any region of the CNS, including the hypothalamus. Here we report a protocol that enables to generate large quantities of NS from both fetal and adult rat hypothalami. We found that either FGF-2 or EGF were capable of inducing NS formation from fetal hypothalamic cultures, but that only FGF-2 is effective in the adult cultures. The hypothalamic-derived NS are capable of differentiating into neurons and glial cells and most notably, as demonstrated by immunocytochemical detection with a specific anti-GnRH antibody, the fetal cultures contain cells that exhibit a GnRH phenotype upon differentiation. This in vitro model should be useful to study the molecular mechanisms involved in GnRH neuronal differentiation

Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case–control study

We examined the associations between sweets, sweetened and unsweetened beverages, and sugars and pancreatic cancer risk. We conducted a population-based case–control study (532 cases, 1,701 controls) and used multivariate logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Because associations were often different by sex, we present results for men and women combined and separately. Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk (total sweets: OR = 1.9, 95% CI: 1.0, 3.6; sweet condiments: OR = 1.9, 95% CI: 1.2, 3.1; chocolate candy: OR = 2.4, 95% CI: 1.1, 5.0; other mixed candy bars: OR = 3.3, 95% CI: 1.5, 7.3 for 1 + servings/day versus none/rarely). Sweets were not consistently associated with risk among women. Sweetened beverages were not associated with increased pancreatic cancer risk. In contrast, low-calorie soft drinks were associated with increased risk among men only; while other low-/non-caloric beverages (e.g., coffee, tea, and water) were unassociated with risk. Of the three sugars assessed (lactose, fructose, and sucrose), only the milk sugar lactose was associated with pancreatic cancer risk (OR = 2.0, 95% CI: 1.5, 2.7 comparing extreme quartiles). These results provide limited support for the hypothesis that sweets or sugars increase pancreatic cancer risk