Effect of discharge opioid on persistent postoperative opioid use: a retrospective cohort study comparing tapentadol with oxycodone.

Opioid harm can vary by opioid type. This observational study examined the effect of opioid type (oxycodone vs. tapentadol) on rates of persistent postoperative opioid use ('persistence'). We linked hospital and community pharmacy data for surgical patients who were dispensed discharge opioids between 1 January 2016 and 30 September 2021. Patients were grouped by opioid experience ('opioid-naive' having received no opioids in the 3 months before discharge) and formulation of discharge opioid (immediate release only or modified release ± immediate release). Mixed-effects logistic regression models predicted persistence (continued use of any opioid at 90 days after discharge), controlling for key persistence risk factors. Of the 122,836 patients, 2.31% opioid-naive and 27.24% opioid-experienced patients met the criteria for persistence. For opioid-naive patients receiving immediate release opioids, there was no significant effect of opioid type. Tapentadol modified release was associated with significantly lower odds of persistence compared with oxycodone modified release, OR (95%CI) 0.81 (0.69-0.94) for opioid-naive patients and 0.81 (0.71-0.93) for opioid-experienced patients. Among patients who underwent orthopaedic surgery (n = 19,832), regardless of opioid experience or opioid formulation, the odds of persistence were significantly lower for those who received tapentadol compared with oxycodone. This was one of the largest and most extensive studies of persistent postoperative opioid use, and the first that specifically examined persistence with tapentadol. There appeared to be lower odds of persistence for tapentadol compared with oxycodone among key subgroups, including patients prescribed modified release opioids and those undergoing orthopaedic surgery.

Plasma amyloid-ß oligomers level is a biomarker for Alzheimer's disease diagnosis.

Amyloid beta (Aß), especially Aß oligomers, is important in Alzheimer's disease (AD) pathogenesis. We studied plasma Aß(40), Aß(42), and Aß oligomers levels in 44 AD patients and 22 non-demented controls. Cognitive functions were assessed by Chinese version of mini-mental state examination (MMSE), Abbreviated Metal Test (AMT), Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog). Plasma Aß monomers and oligomers levels were measured by ELISA. We found that the median plasma Aß(40) and Aß(42) levels were similar between AD and controls, and without significant correlation with cognition. Plasma Aß oligomers level was higher in AD than controls (642.54 ng/ml [range 103.33-2676.93] versus 444.18 ng/ml [range 150.19-1311.18], p=0.047), and negatively correlated with cognition. In multivariate logistic regression analysis, the highest tertile of Aß oligomers levels showed an increased risk of AD than the combined group of middle and lowest tertiles (OR=8.85, p=0.013), after adjustment of gender, age and APOE4 genotype. Increased plasma Aß oligomers level was associated with decreased MMSE and AMT scores (p=0.037, p=0.043, respectively) and increased ADAS-cog score (p=0.036), suggesting negative correlation with cognitive function. We concluded that plasma Aß oligomers level is an useful biomarker for AD diagnosis.

Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-kappaB.

Recent studies have found that liver X receptors (LXRs) agonists decrease brain inflammation and exert neuroprotective effect. The aim of this study was to examine the mechanisms of action of liver X receptor agonist GW3965 against brain injury following global cerebral ischemia in the rat. The 48 male SD (Sprague-Dawley) rats were randomly partitioned into three groups: sham, global ischemia (4-vessel occlusion for 15 min; 4VO) treated with vehicle and global ischemia treated with GW3965 (20 mg/kg, via i.p. injection at 10 min after reperfusion). The functional outcome was determined by neurological evaluation at 24 h post ischemia and by testing rats in T maze at 3 and 7 days after reperfusion. The rats' daily body weight, incidence of seizures and 72 h mortality were also determined. After Nissl staining and TUNEL in coronal brain sections, the numbers of intact and damaged cells were counted in the CA1 sector of the hippocampus. The expression of phosphorylated inhibitor of kappaB (p-IkappaBalpha), nuclear factor-kappaB (NF-kappaB) subunit p65, and cyclo-oxygenase-2 (COX-2) were analyzed with Western blot at 12 h after reperfusion. GW3965 tended to reduce 72 h mortality and the incidence of post-ischemic seizures. GW3965-treated rats showed an improved neuronal survivability in CA1 and a significant increase in the percentage of spontaneous alternations detected in T-maze on day 7 after ischemia. GW3965-induced neuroprotection was associated with a significant reduction in nuclear translocation of NF-kB p65 subunit and a decrease in the hippocampal expression of NF-kB target gene, COX-2. LXR receptor agonist protects against neuronal damage following global cerebral ischemia. The mechanism of neuroprotection may include blockade of NF-kappaB activation and the subsequent suppression of COX-2 in the post ischemic brain.

Microarray-based compendium of hepatic gene expression profiles for prototypical ADME gene-inducing compounds in rats and mice in vivo.

To examine species-specific aspects of the induction of absorption, distribution, metabolism and excretion (ADME)-related genes, we used 25 000 gene oligonucleotide microarrays to construct a rodent gene-response compendium that compared hepatic gene expression profiles and developed consensus aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) ligand signatures relevant to drug clearance. Twenty-six inducer compounds were chosen from the literature. Rats and mice received one of six dose levels (log2 dose escalation, 32-fold dose range) of each compound daily for 3 days. Animals were necropsied 6-9 h after the last dose, and tissues were collected for RNA analysis. Hepatic gene expression profiles were obtained using Rosetta Resolver expression analysis system, and ADME-related genes were extracted. Cross-talk among nuclear receptors or hepatoxicity at high dose levels resulted in large signatures (usually >1000 genes at p < 0.01) for most compounds. After ADME gene transcript enrichment, agglomerative clustering separated AhR ligands from CAR/PXR ligands, but it was difficult to distinguish CAR from PXR ligands. Consensus signatures were derived from groups of AhR, CAR and PXR ligands; and cross-talk among responding genes was determined. Many compounds had distinct log dose-response profiles, and relative potencies for ligands were established. Robust responses by CYP1A1, CYP2B10 (CAR responsive in mice) and CYP2B15 (CAR responsive in rats) and CYP3A1 (PXR responsive in rats) were used to benchmark the relative potency of different ligands and to determine the relative selectivity for AhR, CAR or PXR. By using a compendium of gene expression profiles, we defined species-specific induction patterns across the ADME transcriptome.

Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptome.

Oligonucleotide microarrays were used to study the variability of pharmacokinetics and drug metabolism (PKDM)-related gene expression in 75 normal human livers. The objective was to define and use absorption, distribution, metabolism and excretion (ADME) gene expression variability to discern co-regulated genes and potential surrogate biomarkers of inducible gene expression. RNA was prepared from donor tissue and hybridized on Agilent microarrays against an RNA mass balanced pool from all donors. Clustering of PKDM gene sets revealed donors with distinct patterns of gene expression that grouped genes known to be regulated by the nuclear receptor, pregnane X-receptor (PXR). Fold range metrics and frequency distributions from the heterogeneous human population were used to define the variability of individual PKDM genes in the 75 human livers and were placed in context by comparing expression data with basal ADME gene expression variability in an inbred and diet/environment controlled population of 27 Rhesus livers. The most variable genes in the hepatic transcriptome were mainly related to drug metabolism, intermediary metabolism, inflammation and cell cycle control. Unique patterns of expression across 75 individuals of inducible ADME gene expression allowed their expression to be correlated with the expression of many other genes. Correlated genes for AhR, CAR and PXR responsive genes (CYP1A2, CYP2B6 and CYP3A4) were identified that may be co-regulated and, therefore, provide clues to the identity of surrogate gene or protein markers for CYP induction. In conclusion, microarrays were used to define the variable expression of hepatic ADME genes in a diverse human population, the expression variability of ADME genes was compared with the expression variability in an inbred population of Rhesus monkeys, and genes were defined that may be co-regulated with important inducible CYP genes.

Connective tissue growth factor is a biomarker and mediator of kidney allograft fibrosis.

Chronic allograft nephropathy (CAN) is a leading cause of kidney graft failure following transplantation. Its causes are complex and include both immunological and nonimmunological factors. Here we have studied the development of CAN in a mouse model of kidney transplantation comparing isografts and allografts. Unlike the normal histology and normal serum creatinine of the uninephrectomized, nonrejecting isografted mice (0.219 +/- 0.024 mg/dL), allografted mice demonstrated severe renal dysfunction (mean serum creatinine 0.519 +/- 0.061 mg/dL; p < 0.005) with progressive inflammation and fibrosis of the kidney. These animals also showed an increased expression of connective tissue growth factor (CTGF), both systemically and within the graft. CTGF was highly expressed in tubuloepithelial cells of allografts, along with alpha-smooth muscle actin, a marker of myofibroblasts, and transcriptionally associated with other markers of fibrosis. In vitro studies of tubular epithelium indicate that CTGF is capable of inducing EMT, independent of TGF-beta. Finally, in human transplant recipients, serum and urine CTGF levels are significantly elevated compared to naïve individuals. Urinary levels correlated with the histological presence of CAN. These studies suggest a critical role of CTGF in graft fibrogenesis, for both mouse and man. Thus, CTGF has potential as a biomarker of CAN, and also a therapeutic target in managing graft fibrosis.

Molecular evaluation of BK polyomavirus nephropathy.

Understanding at a molecular level, the immunologic response of polyomavirus nephropathy (PVN), a critical cause of kidney graft loss, could lead to new targets for treatment and diagnosis. We undertook a transcriptional evaluation of kidney allograft biopsies from recipients with PVN or acute rejection (AR), as well as from recipients with stable allograft function (SF). In both the PVN and AR groups, Banff histologic scores and immunohistochemical analysis of inflammatory infiltrates were similar. Despite their different etiologies, the transcriptional profiles of PVN and AR were remarkably similar. However, transcription of genes previously linked to AR including CD8 (65.9 +/- 18.8) and related molecules IFN-gamma(55.1 +/- 17.0), CXCR3 (49.9 +/- 12.8) and perforin (153.8 +/- 50.4) were significantly higher in PVN compared to AR (30.9 +/- 2.0, 14.0 +/- 7.3, 12.1 +/- 7.3 and 15.6 +/- 3.8-fold, respectively; p < 0.01). Importantly, transcription of molecules associated with graft fibrosis including matrix collagens, TGFbeta, MMP2 and 9, as well as markers of epithelial-mesenchymal transformation (EMT) were significantly higher in PVN than AR. Thus, renal allografts with PVN transcribe proinflammatory genes equal in character and larger in magnitude to that seen during acute cellular rejection. BK infection creates a transcriptional microenvironment that promotes graft fibrosis. These findings provide new insights into the intrarenal inflammation of BK infection that promotes graft loss.

Oscillations in the near-infrared signal in patients with severe head injury.

OBJECTIVE: To use a non-invasive system, near infrared spectroscopy (NIRS) to detect oscillations in cerebral blood oxygenation in intensive care patients with severe traumatic brain injury. MATERIALS AND METHODS: 9 patients (7 male, 2 female) with a GCS < 8 were monitored in the intensive care units at King's College Hospital and the Royal London Hospital. A CCD-based spectrometer was coupled to the patient's forehead with one excitation and one detection optode. Spectra in the range of approximately 600-800 nm were collected at intervals of 2-4 seconds (subject to signal strength) and a curve-fitting algorithm applied, thus extracting time series data for oxyhaemoglobin (HbO), deoxyhaemoglobin (Hb) and cytochrome-c-oxidase (Cyt-c). The oxyhaemoglobin data was subjected to Fast Fourier Transform analysis. RESULTS: In all nine patients, unequivocal oscillations in the HbO signal were observed. The frequencies of these oscillations were at: 0.013-0.042 Hz (0.78-2.5 cycles min-1), 0.11 Hz (6.7 cycles min-1) and 0.19-0.28 Hz (12-16 cycles min-1). CONCLUSIONS: The presence of oscillations at 0.013-0.033 Hz, 0.11 Hz and 0.19-0.28 Hz are compatible with B-waves, vasomotion and respiratory cycles (respectively). However, due to the unknown contribution of the scalp to the NIR signal this data must be interpreted with care. Further work is required in order to investigate this.

Determination of the native form of FadD, the Escherichia coli fatty acyl-CoA synthetase, and characterization of limited proteolysis by outer membrane protease OmpT.

Several studies have described FadD, the Escherichia coli fatty acyl-CoA synthetase [also known as fatty acid:CoA ligase (AMP-forming); EC 6.2.1.3], as a 42-50 kDa enzyme. Based on sequencing and expression data from the fadD gene, other reports have suggested that FadD is a 62 kDa protein and represents the sole fatty acyl-CoA synthetase in E. coli. We report that the 62 kDa FadD enzyme is a substrate for the outer membrane protease OmpT in vitro, producing a 43 kDa C-terminal fragment and a 19 kDa N-terminal fragment. Immunoblotting with a FadD antibody revealed that only the 62 kDa form of the enzyme is present in vivo, but we utilized the proteolytic sensitivity of FadD to investigate its structure. Photoaffinity labelling experiments revealed that both intact FadD and the 43 kDa fragment bound a long-chain fatty acid. Intact and cleaved FadD were also purified to determine the effect of cleavage on function. When using oleate as a substrate, cleaved FadD displayed 2-fold higher K(m) and V(max) values compared with intact FadD, but the catalytic efficiencies (k(cat)/K(m)) of the two forms were similar. This indicated that cleavage did not adversely affect enzyme activity. Proteolysis of FadD by OmpT was altered by the presence of oleate or ATP, both of which are ligands for the fatty acyl-CoA synthetase. This suggested that FadD undergoes ligand-induced conformational changes and implies that the region surrounding the cleavage site is mobile, a common characteristic of linker domains.

A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses.

Murine bone marrow (BM) NK T cells can suppress graft-vs-host disease, transplant rejection, and MLRs. Human BM contains T cells with similar potential. Human BM was enriched for NK T cells, approximately 50% of which recognized the nonpolymorphic CD1d molecule. In contrast to the well-characterized blood-derived CD1d-reactive invariant NK T cells, the majority of human BM CD1d-reactive T cells used diverse TCR. Healthy donor invariant NK T cells rapidly produce large amounts of IL-4 and IFN-gamma and can influence Th1/Th2 decision-making. Healthy donor BM CD1d-reactive T cells were Th2-biased and suppressed MLR and, unlike the former, responded preferentially to CD1d(+) lymphoid cells. These results identify a novel population of human T cells which may contribute to B cell development and/or maintain Th2 bias against autoimmune T cell responses against new B cell Ag receptors. Distinct CD1d-reactive T cell populations have the potential to suppress graft-vs-host disease and stimulate antitumor responses.

Loss of IFN-gamma production by invariant NK T cells in advanced cancer.

Invariant NK T cells express certain NK cell receptors and an invariant TCRalpha chain specific for the MHC class I-like CD1d protein. These invariant NK T cells can regulate diverse immune responses in mice, including antitumor responses, through mechanisms including rapid production of IL-4 and IFN-gamma, but their physiological functions remain uncertain. Invariant NK T cells were markedly decreased in peripheral blood from advanced prostate cancer patients, and their ex vivo expansion with a CD1d-presented lipid Ag (alpha-galactosylceramide) was diminished compared with healthy donors. Invariant NK T cells from healthy donors produced high levels of both IFN-gamma and IL-4. In contrast, whereas invariant NK T cells from prostate cancer patients also produced IL-4, they had diminished IFN-gamma production and a striking decrease in their IFN-gamma:IL-4 ratio. The IFN-gamma deficit was specific to the invariant NK T cells, as bulk T cells from prostate cancer patients produced normal levels of IFN-gamma and IL-4. These findings support an immunoregulatory function for invariant NK T cells in humans mediated by differential production of Th1 vs Th2 cytokines. They further indicate that antitumor responses may be suppressed by the marked Th2 bias of invariant NK T cells in advanced cancer patients.

CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus.

A subset of CD161 (NK1) T cells express an invariant Valpha14Jalpha281 TCR-alpha chain (Valpha(invt) T cells) and produce Th2 and Th1 cytokines rapidly in response to CD1d, but their physiological function(s) remain unclear. We have found that CD1d-reactive T cells mediate to resistance against the acute, cytopathic virus diabetogenic encephalomyocarditis virus (EMCV-D) in relatively Th1-biased, C57BL/6-based backgrounds. We show now that these results generalize to Th2-biased, hypersensitive BALB/c mice. CD1d-KO BALB/c mice were more susceptible to EMCV-D. Furthermore, alpha-galactosylceramide (alpha-GalCer), a CD1d-presented lipid antigen that specifically activates Valpha(invt) T cells, protected wild-type (WT) mice against EMCV-D-induced encephalitis, myocarditis, and diabetes. In contrast, neither CD1d-KO nor Jalpha281-KO mice were protected by alpha-GALCER: Finally, disease in Jalpha281-KO mice was comparable to WT, indicating for the first time equivalent roles for CD1d-reactive Valpha(invt) and noninvariant T cells in resistance to acute viral infection. A model for how CD1d-reactive T cells can initiate immune responses, which synthesizes current results, is presented.

Taurocholate stimulates transcytotic vesicular pathways labeled by horseradish peroxidase in the isolated perfused rat liver.

The effect of taurocholate on transcytotic vesicular pathways labeled with horseradish peroxidase was assessed in isolated perfused rat liver preparations. Forty-five minutes after a horseradish peroxidase load in a recirculating system, continuous infusion of taurocholate but not taurodehydrocholate significantly increased horseradish peroxidase excretion in bile by 50% compared with controls. When horseradish peroxidase (25 mg) was pulse loaded for 1 minute in control perfusions, it appeared in bile in early (4-6 minutes) and late (20-25 minutes) peaks, the latter accounting for 90% of total horseradish peroxidase output. Taurocholate infusion significantly increased horseradish peroxidase output in both early and late peaks, whereas only a small increase in the early peak was observed with taurodehydrocholate. Colchicine pretreatment increased the early peak in bile but abolished the second peak. Electron micrographs from control livers revealed the accumulation of horseradish peroxidase-containing vesicles in pericanalicular regions at early (2 minutes) as well as late (18 minutes) periods. When a morphometric analysis of electron micrographs was performed from pericanalicular regions 2 minutes after a 1-minute pulse of horseradish peroxidase (500 mg), taurocholate but not taurodehydrocholate increased both the density and percent area of horseradish peroxidase-containing vesicles compared with controls. In contrast, colchicine pretreatment had no effect on the density of the early-appearing vesicles, although their individual sizes were reduced. Taurocholate but not taurodehydrocholate also increased the percent of tubular structures in the pericanalicular region. These findings indicate that taurocholate stimulates both early and late transcytotic vesicle pathways and therefore probably microtubule-independent vesicle pathway is present in hepatocytes that must be distinguished from paracellular routes.