Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status

Introduction In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. Methods Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. Results Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)0.60 × (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C0 vs. 4.5 (0.3 – 38.9) nmol/L at C1, P < 0.001). Conclusions Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients

Combination of X-ray crystallography, SAXS and DEER to obtain the structure of the FnIII-3,4 domains of integrin a6b4

Integrin alpha6beta4 is a major component of hemidesmosomes that mediate the stable anchorage of epithelial cells to the underlying basement membrane. Integrin alpha6beta4 has also been implicated in cell proliferation and migration and in carcinoma progression. The third and fourth fibronectin type III domains (FnIII-3,4) of integrin beta4 mediate binding to the hemidesmosomal proteins BPAG1e and BPAG2, and participate in signalling. Here, it is demonstrated that X-ray crystallography, small-angle X-ray scattering and double electron– electron resonance (DEER) complement each other to solve the structure of the FnIII-3,4 region. The crystal structures of the individual FnIII-3 and FnIII-4 domains were solved and the relative arrangement of the FnIII domains was elucidated by combining DEER with site-directed spin labelling. Multiple structures of the interdomain linker were modelled by Monte Carlo methods complying with DEER constraints, and the final structures were selected against experimental scattering data. FnIII-3,4 has a compact and cambered flat structure with an evolutionary conserved surface that is likely to correspond to a protein-interaction site. Finally, this hybrid method is of general application for the study of other macromolecules and complexes

Capsule endoscopy interpretation: the role of physician extenders

Background and aims: capsule endoscopy (CE) allows for a new era in small-bowel examination. Nevertheless, physicians’ time for CE-interpretation remains longer than desirable. Alternative strategies to physicians have not been widely investigated. The aim of this study was to evaluate the accuracy of physician extenders in CE-interpretation. Material and methods: one CE-experienced gastroenterologist and two physician extenders reviewed independently 20 CEprocedures. Each reader was blinded to the findings of their colleagues. A consensus formed by the readers and a second CE-experienced gastroenterologist was used as gold standard. Number, type and location of images selected, character of CEexams and their relationship with indications were recorded. Gastric emptying time (GEt), small-bowel transit time (SBTt) and time spent by readers were also noted. Results: sensitivity and specificity for “overall” lesions was 79 and 99% for the gastroenterologist; 86 and 43% for the nurse; and 80 and 57% for the resident. All 34 “major” lesions considered by consensus were found by the readers. Agreement between consensus and readers for images classification and procedures interpretation was good to excellent (κ from 0.55 to 1). No significant differences were found in the GEt and SBTt obtained by consensus and readers. The gastroenterologist was faster than physician extenders (mean time spent was 51.9 ± 13.5 minutes versus 62.2 ± 19 and 60.9 ± 17.1 for nurse and resident, respectively; p < 0.05). Conclusions: physician extenders could be the perfect complement to gastroenterologists for CE-interpretation but gastroenterologists should supervise their findings. Future cost-efficacy analyses are required to assess the benefits of this alternative

A DNA-Modified Live Vaccine Prime-Boost Strategy Broadens the T-Cell Response and Enhances the Antibody Response against the Porcine Reproductive and Respiratory Syndrome Virus.

The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) induces reproductive disorders in sows and respiratory illnesses in growing pigs and is considered as one of the main pathogenic agents responsible for economic losses in the porcine industry worldwide. Modified live PRRSV vaccines (MLVs) are very effective vaccine types against homologous strains but they present only partial protection against heterologous viral variants. With the goal to induce broad and cross-protective immunity, we generated DNA vaccines encoding B and T antigens derived from a European subtype 1 strain that include T-cell epitope sequences known to be conserved across strains. These antigens were expressed either in a native form or in the form of vaccibodies targeted to the endocytic receptor XCR1 and CD11c expressed by different types of antigen-presenting cells (APCs). When delivered in skin with cationic nanoparticles and surface electroporation, multiple DNA vaccinations as a stand-alone regimen induced substantial antibody and T-cell responses, which were not promoted by targeting antigens to APCs. Interestingly, a DNA-MLV prime-boost strategy strongly enhanced the antibody response and broadened the T-cell responses over the one induced by MLV or DNA-only. The anti-nucleoprotein antibody response induced by the DNA-MLV prime-boost was clearly promoted by targeting the antigen to CD11c and XCR1, indicating a benefit of APC-targeting on the B-cell response. In conclusion, a DNA-MLV prime-boost strategy, by enhancing the potency and breadth of MLV vaccines, stands as a promising vaccine strategy to improve the control of PRRSV in infected herds

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.

BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0·5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov)

Nomenclature and semantic description of vascular lesions in small bowel capsule endoscopy: an international Delphi consensus statement

Background and study aims \u2002Nomenclature and descriptions of small bowel (SB) vascular lesions in capsule endoscopy (CE) are scarce in the medical literature. They are mostly based on the reader's opinion and thus differ between experts, with a potential negative impact on clinical care, teaching and research regarding SBCE. Our aim was to better define a nomenclature and to give a description of the most frequent vascular lesions in SBCE. Methods \u2002A panel of 18 European expert SBCE readers was formed during the UEGW 2016 meeting. Three experts constructed an Internet-based four-round Delphi consensus, but did not participate in the voting process. They built questionnaires that included various still frames of vascular lesions obtained with a third-generation SBCE system. The 15 remaining participants were asked to rate different proposals and description of the most common SB vascular lesions. A 6-point rating scale (varying from 'strongly disagree' to 'strongly agree') was used successive rounds. The consensus was reached when at least 80\u200a% voting members scored the statement within the 'agree' or 'strongly agree'. Results \u2002Consensual terms and descriptions were reached for angiectasia/angiodysplasia, erythematous patch, red spot/dot, and phlebectasia. A consensual description was reached for more subtle vascular lesions tentatively named "diminutive angiectasia" but no consensus was reached for this term. Conclusion \u2002An international group has reached a consensus on the nomenclature and descriptions of the most frequent and relevant SB vascular lesions in CE. These terms and descriptions are useful in daily practice, for teaching and for medical research purposes

Cisplatin and Doxorubicin Induce Distinct Mechanisms of Ovarian Follicle Loss; Imatinib Provides Selective Protection Only against Cisplatin

Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin) were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001) and doxorubicin (3 fold, p<0.01). TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01) but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s) the patient is exposed to

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure

We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores