Introduction: Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of ‘serious’ by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients.
Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants.
Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient’s PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios. 相似文献
In the 21 st century,the public are more informed,mainly via the Internet,about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses.They often self-medicate themselves with various health products and over-the-counter(OTC) medicines apart from prescribed pharmaceutical drugs(PD).Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients;thus their usefulness is in doubt.The increasing popularity world-wide of using Chinese medicines(CM) and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects.In most cases the alleged causes of adverse effects are linked with herbal sources,although the authorised information on the interactions between CM-PD is not plentiful in the literature.There is an urgent need for such a data base.The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given.In actual practice the patients may receive both treatments intentionally or unintentionally,with or without the awareness of the practitioner.In these situations a reliable database for interactions between CM-PD will be extremely useful for consultation when treatment problems appear or during emergency situations.Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects.Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine.The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD.Examples will be given largely on those related to these disciplines as illustrations in this overview. 相似文献
In recent years, humanity has been confronted with a global pandemic due to coronavirus disease 2019 (COVID-19), which has caused an unprecedented health and economic crisis worldwide. Apart from the respiratory symptoms, which are considered the principal manifestations of COVID-19, it has been recognized that COVID-19 constitutes a systemic inflammatory process affecting multiple organ systems. Across the spectrum of organ involvement in COVID-19, acute liver injury (ALI) has been gradually gaining increasing attention by the international scientific community. COVID-19 associated liver impairment can affect a considerable proportion of COVID-19 patients and seems to correlate with the severity of the disease course. Indeed, COVID-19 patients hospitalized in the intensive care unit (ICU) run a greater risk of developing ALI due to the severity of their clinical condition and in the context of multi-organ failure. The putative pathophysiological mechanisms of COVID-19 induced ALI in ICU patients remain poorly understood and appear to be multifactorial in nature. Several theories have been proposed to explain the occurrence of ALI in the ICU setting, such as hypoperfusion and ischemia due to hemodynamic instability, passive liver congestion as a result of congestive heart failure, ischemia-reperfusion injury, hypoxia due to respiratory failure, mechanical ventilation itself, sepsis and septic shock, cytokine storm, endotheliitis with concomitant coagulopathy, drug-induced liver injury, parenteral nutrition and direct cytopathic viral effect. It should be noted that no specific therapy for COVID-19 induced ALI exists. Therefore, the therapeutic approach lies in preventive measures and is exclusively supportive once ALI ensues. The aim of the current review is to scrutinize the existing evidence on COVID-19 associated ALI in ICU patients, explore its clinical implications, shed light on the underlying pathophysiological mechanisms and propose potential therapeutic approaches. Ongoing research on the particular scientific field will further elucidate the pathophysiology behind ALI and address unresolved issues, in the hope of mitigating the tremendous health consequences imposed by COVID-19 on ICU patients. 相似文献
The upstroke of the ventricular action potential in the rabbit consits of two depolarizing components with different rates of rise. The effects of hypoxia on the resting potential (RP); the upstroke phases (I and II) and the maximum rate of rise of phase I (
max) were studied at different external K concentrations (K0). Perfused hearts were submitted to N2-equilibrated media containing 1.5 to 10 m
K0. Exposure of oxygenated hearts to different K0 changed the regenerative response from a fast rising action potential at 1.5 m
K0 to a depressed fast response at 7.5 and 10 m
K0. Hypoxia decreased the action potential amplitude (APA) at all K concentrations. In K0 ≤ 5 m
the reduction of APA was due to a decrease in the amplitude of phase II of the upstroke but the maximum rate of rise (
max) did not change. In contrast, phase I of the upstroke was markedly depressed by hypoxia in high K0, but phase II was unmodified and its
max compared well with values reported for other normoxic cardiac cells. Hyperkalemia per se did not slow conduction during normoxia but increased conduction time in hypoxia. The resting potential of hypoxic cells was closer to the K equilibrium potential than in the control. The RP v. K0/Ki relation suggested that electrogenic Na extrusion persists in hypoxia. The electrogenic fraction of the resting potential as determined from pump inhibition with 10−4
ouabain amounted to −6 mV. Our results did not indicate whether the differential effects of hypoxia on the upstroke components were potential dependent or were related to direct effects of K+ on the ionic currents that determine the action potential. The persistence of phase II during hypoxia in partly depolarized cells may assure the maintenance of propagated electrical activity under conditions that are likely to be encountered in vitro during cardiac ischemia. 相似文献
Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions occurring in around 1 per 300,000 live births. In TNDM, growth-retarded infants develop diabetes in the first few weeks of life, only to go into remission after a few months with possible relapse to permanent diabetes usually around adolescence or in adulthood. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. The very recently elucidated mutations in KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunits of the pancreatic K(ATP) channel involved in regulation of insulin secretion, account for a third to a half of the PNDM cases. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provides a tool for distinguishing transient from permanent neonatal diabetes mellitus in the neonatal period. Some patients (those with mutations in KCNJ11 and ABCC8) may be transferred from insulin therapy to sulphonylureas. 相似文献
Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD(67) expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 micromol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD(67) expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD(67) promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 micromol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD(67) expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors. 相似文献
The aim of this article is to discuss the conditions under which functional neuroimaging can contribute to the study of higher cognition. We begin by presenting two case studies—on moral and economic decision making—which will help us identify and examine one of the main ways in which neuroimaging can help advance the study of higher cognition. We agree with critics that functional magnetic resonance imaging (fMRI) studies seldom “refine” or “confirm” particular psychological hypotheses, or even provide details of the neural implementation of cognitive functions. However, we suggest that neuroimaging can support psychology in a different way—namely, by selecting among competing hypotheses of the cognitive mechanisms underlying some mental function. One of the main ways in which neuroimaging can be used for hypothesis selection is via reverse inferences, which we here examine in detail. Despite frequent claims to the contrary, we argue that successful reverse inferences do not assume any strong or objectionable form of reductionism or functional locationism. Moreover, our discussion illustrates that reverse inferences can be successful at early stages of psychological theorizing, when models of the cognitive mechanisms are only partially developed. 相似文献
In this month's issue of the Journal of Clinical Psychology, Vitiello and colleagues articulate an important research agenda that will help advance cognitive‐behavioral therapy for insomnia (CBT‐I) research and clinical practice. In addition to this ambitious agenda, we also propose that pursuing a parallel research program, focusing on treatment mechanisms and process will help move the CBT‐I field forward and optimize therapeutic dissemination and uptake. 相似文献