Effects of pre- or postoperative morphine and of preoperative ketamine in experimental surgery in rats, evaluated by pain scoring and c-fos expression

Since Wall (1988) hypothesised a beneficial post surgical effect of preoperative analgesic treatment (so-called pre-emptive analgesic treatment) as a supplement to postoperative analgesic treatment, the concept has been subject to many scientific debates. According to the hypothesis, applying analgesics before the nociceptive stimulus is beneficial due to reduced wind-up and reduced central sensitisation resulting in diminished risk of postoperative hyperalgesia and allodynia (Woolf and Chong, 1993). The scientific literature provides conflicting evidence for this theory. Beneficial effect of preemptive analgesic treatment has been reported after pre-emptive treatment with local analgesics, opioids and NSAID´s compared with placebo (Woolf and Chong, 1993). Some clinical settings have showed beneficial analgesic effect of preemptive analgesia, when the same pre-emptive and postoperative treatments with lidocaine (Ejlersen et al., 1992; Doyle and Bowler, 1998) or opioids (Katz et al., 1992) were compared. However, Dahl et al. (1992) and Elhakim et al. (1995) did not obtained supportive results in their clinical studies.In the majority of studies using animal models addressing this concept, the nociceptive stimulus has been obtained by injection of irritating chemicals, in particular formalin. When somatic tissue is damaged or irritated, nociceptive receptors are activated by peripheral release of extracellular inflammatory mediators. The activated receptors lead the signal to the synapses in the dorsal horn of the spinal cord as a 2-phased signal. In the acute first phase, nociceptive stimuli are mediated centrally through Aä fibres fibres. During the slower and long-lasting second phase, the nociceptive stimuli are mediated mainly through C-fibres (Cross et al., 1994). The release of extracellular inflammatory mediators increases the peripheral excitability, which leads to hyperalgesia (Woolf, 1995). Repetitive peripheral nociceptive impulses mediated through C-fibres result in an increased central excitability of dorsal appears to be in part mediated through N-methylhorn neurones. This state is called wind-up and appears to be in part mediated through N-methyl- D-aspartate (NMDA) receptors on dorsal horn secondary nociceptive neurones. Transmission of multiple slow stimuli leads to release of glutamate, which removes the Mg++-block in the NMDA receptor and allows substantial Ca++-inflow (Urban et al., 1994). NMDA receptor antagonists bind to the same site as Mg++ and prevents Ca++- inflow (Hirota and Lambert, 1996; Kress, 1997). NMDA-receptor antagonists can prevent wind-up but not the initial responses of the neurones, whereas the reverse is true for opioids (Chapman and Dickenson, 1992). NMDA-antagonists have no effect on pain of the acute first phase, but may act synergistic to the analgesic effect of opioids (Chapman and Dickenson, 1992; Honoré et al., 1996). Only few studies deal with a postoperative experimental model in animals and those available are conflicting. Brennan et al. (1996) developed an elegant postoperative model in rats with surgical intervention on the plantar surface of the hind foot. In this study a relationship was found between behavioural pain observation scores and mechanical hyperalgesia. Ovariohysterectomized rats have also been used as animal models of postoperative pain (Lascelles et al. 1995). A commonly used method of determining the nociceptive activity caused by a peripheral stimulus is to identify and quantify the nuclear protein Fos expressed in secondary nociceptive neurones in the spinal cord. c-fos is an immediate early gene (IEG), that encodes for Fos. IEG’s are rapidly and transiently induced in neuronal cells within minutes of extracellular stimulation (Sheng and Greenberg, 1990). The c-fos mRNA accumulates, and reaches its peak after 30 to 40 minutes. The Fos level peaks approximately two hours after induction of c-fos (Harris, 1998). Since Hunt (1987) reported, that peripheral inflammation induced c-fos in neurones in the dorsal horn of the spinal cord, many studies have shown the relationship between nociception and cfos expression.The aim of the present investigation was to study the effect of pre-emptive versus postoperative opioid analgesic treatment by use of the surgical model of Brennan et al. (1996) and combine the pre-emptive and postoperative opioid treatment with pre-emptive ketamine. The effects were quantified by stereological estimation of the number of dorsal horn neurones expressing c-fos and pain scoring from the operated hind foot

Recovering the properties of high redshift galaxies with different JWST broad-band filters

Imaging with the James Webb Space Telescope (JWST) will allow for observing the bulk of distant galaxies at the epoch of reionisation. The recovery of their properties, such as age, color excess E(B-V), specific star formation rate (sSFR) and stellar mass, will mostly rely on spectral energy distribution fitting, based on the data provided by JWST's two imager cameras, namely the Near Infrared Camera (NIRCam) and the Mid Infrared Imager (MIRI). In this work we analyze the effect of choosing different combinations of NIRCam and MIRI broad-band filters, from 0.6 {\mu}m to 7.7 {\mu}m, on the recovery of these galaxy properties. We performed our tests on a sample of 1542 simulated galaxies, with known input properties, at z=7-10. We found that, with only 8 NIRCam broad-bands, we can recover the galaxy age within 0.1 Gyr and the color excess within 0.06 mag for 70% of the galaxies. Besides, the stellar masses and sSFR are recovered within 0.2 and 0.3 dex, respectively, at z=7-9. Instead, at z=10, no NIRCam band traces purely the {\lambda}> 4000 {\AA} regime and the percentage of outliers in stellar mass (sSFR) increases by > 20% (> 90%), in comparison to z=9. The MIRI F560W and F770W bands are crucial to improve the stellar mass and the sSFR estimation at z=10. When nebular emission lines are present, deriving correct galaxy properties is challenging, at any redshift and with any band combination. In particular, the stellar mass is systematically overestimated in up to 0.3 dex on average with NIRCam data alone and including MIRI observations improves only marginally the estimation.Comment: 21 pages, 11 figures, 4 tables. Accepted for publication at the ApJ

Plasma level of mannose-binding lectin is associated with the risk of recurrent pregnancy loss but not pregnancy outcome after the diagnosis

STUDY QUESTION: Are low or high plasma mannose-binding lectin (p-MBL) levels associated with recurrent pregnancy loss (RPL) and the reproductive and perinatal outcomes before and after RPL? SUMMARY ANSWER: The prevalence of low p-MBL levels was significantly higher in RPL patients, while high levels were significantly less prevalent. No association was found between p-MBL level and reproductive and perinatal outcomes before and after RPL. WHAT IS KNOWN ALREADY: Mannose-binding lectin (MBL) is an important component in the innate immune system. Low p-MBL levels have been associated with RPL, while the correlation with high levels has been poorly studied. Adverse perinatal outcomes are generally more frequent among RPL patients, but reports concerning the association between maternal p-MBL levels and perinatal outcomes, including birth weight (BW) and gestational age (GA), are conflicting. STUDY DESIGN, SIZE, DURATION: This study was a combined cross-sectional and cohort study of 267 RPL patients admitted to the RPL Center of Western Denmark between January 2016 and March 2020. RPL patients were followed until birth of a liveborn child or until end of follow-up, March 2021. A sample of 185 healthy female blood donors of reproductive age was used as a MBL reference group. PARTICIPANTS/MATERIALS, SETTING, METHODS: All RPL patients had ≥3 consecutive pregnancy losses, a regular menstrual cycle and no known significant chromosomal or uterine malformations. At the first consultation, routine blood samples including p-MBL measurement and detailed obstetrical and perinatal information were collected. p-MBL levels in RPL patients were compared to the MBL reference group. A logistic regression analysis adjusted for relevant confounders assessed the association between low p-MBL levels and an unsuccessful reproductive outcome in RPL patients in first pregnancy after admission. Perinatal outcomes before and after RPL were compared between RPL subgroups according to low (≤500 µg/l), intermediate (501–3000 µg/l) and high (>3000 µg/l) p-MBL levels. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly more RPL patients had low p-MBL levels (prevalence proportion ratio (PPR): 1.79, 95% CI: 1.34–2.38) and fewer had high p-MBL levels (PPR: 0.56, 95% CI: 0.40–0.79) compared to the reference group, while the prevalence of intermediate p-MBL level was not different between the groups (PPR: 0.86, 95% CI: 0.69–1.08). In the prospective study, low p-MBL level was not a significant risk factor for a pregnancy loss in the first pregnancy after admission after adjustment for age, BMI and smoking. Neither before nor after the RPL diagnosis were maternal p-MBL levels significantly associated with BW or GA. LIMITATIONS, REASONS FOR CAUTION: Only 161 (60.3%) patients had given birth after RPL during the follow-up period, which limited the possibility to detect clear associations between p-MBL levels and perinatal outcomes after RPL. WIDER IMPLICATIONS OF THE FINDINGS: In agreement with several previous studies, low p-MBL levels are strongly associated with RPL, while this study for the first time documents that high levels may play a protective role, which suggests a causal relationship. We suggest that larger prospective studies evaluate the association between p-MBL levels and RPL prognosis. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. We acknowledge the Department of Obstetrics and Gynaecology at Aalborg University Hospital for financial support. U.S.K. has reported personal fees from Merck, consulting fees from IBSA Nordic, and a grant from Gedeon Richter, Merck and IBSA Nordic outside of the submitted work. TRIAL REGISTRATION NUMBER: ID from clinicaltrials.gov is NCT04017754

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies

Assessment of the Effect of High or Low Protein Diet on the Human Urine Metabolome as Measured by NMR

The objective of this study was to identify urinary metabolite profiles that discriminate between high and low intake of dietary protein during a dietary intervention. Seventy-seven overweight, non-diabetic subjects followed an 8-week low-calorie diet (LCD) and were then randomly assigned to a high (HP) or low (LP) protein diet for 6 months. Twenty-four hours urine samples were collected at baseline (prior to the 8-week LCD) and after dietary intervention; at months 1, 3 and 6, respectively. Metabolite profiling was performed by 1H NMR and chemometrics. Using partial least squares regression (PLS), it was possible to develop excellent prediction models for urinary nitrogen (root mean square error of cross validation (RMSECV) = 1.63 mmol/L; r = 0.89) and urinary creatinine (RMSECV = 0.66 mmol/L; r = 0.98). The obtained high correlations firmly establish the validity of the metabolomic approach since urinary nitrogen is a well established biomarker for daily protein consumption. The models showed that trimethylamine-N-oxide (TMAO) is correlated to urinary nitrogen. Furthermore, urinary creatine was found to be increased by the HP diet whereas citric acid was increased by the LP diet. Despite large variations in individual dietary intake, differentiated metabolite profiles were observed at the dietary group-level