Use of HDFx, a Novel Immunomodulator, to Stop the Germs from Winning in Hospitals and on The Battlefields : The Dangers of Antibiotic Resistance

Getting admitted to a civilian or battlefield hospital these days often poses considerable risks and dangers. The ever-growing number of emerging diseases worldwide makes treatment of patients difficult and sometimes impossible. Many antibiotics are no longer effective against the simplest infections, which result in further hospitalizations with increased costs to the patients and governments worldwide. Microorganisms of prime concern include methicillin-resistant Staphylococcus aureus, Clostridium difficile, multidrug and extensive drug-resistant Mycobacterium tuberculosis, Neisseria gonorrhoeae, and carbapenem- resistant Enterobacteriaceae, as well as bacteria that produce extensive spectram beta-lactamases, such as E. coli. An unusual decline in the discovery of new and effective antibiotics, these days, is only making matters worse

Synthetic Vasopressin and Oxytocin Analogs and Their Potential Use in Hemorrhagic, Traumatic and Septic Shock: A Personal Perspective

As one of us has stated many years ago, “shock is a significant and sustained loss of effective circulating blood volume. It will eventuate in hypoperfusion of critical peripheral tissues, thus leading to a deficit in transcapillary exchange function in critical organ regions. Clinically, there are five major types of circulatory shock: cardiogenic; septic; distributive; anaphylactic; and hypovolemic. Hypovolemic shock (HS) is, primarily, due to a marked decrease in venous return, falling arterial blood pressure, and ventricular preload, and usually is caused by hemorrhage, dehydration, excessive diarrhea, trauma, excessive fluid loss from severe burns, increased positive intrathoracic pressure, excessive urinary fluid loss resulting from diuretics, side effects of many chemotherapeutic agents and radiation in cancer patients, or depressed vasomotor tone in the microcirculatio

Insights into the Possible Mechanisms By Which Platelet-Activating Factor and PAF-receptors Function in Vascular Smooth Muscle in Magnesium Deficiency and Vascular Remodeling: Possible Links to Atherogenesis, Hypertension and Cardiac Failure

Platelet-activating factor (PAF) is a phospholipid mediator and cell signaling molecule which displays multiple biological and pathophysiological attributes, running the gamut from inflammation to cell differentiation and proliferation [1-4]. As is well-known, PAF interacts with specific membrane PAF-receptors (PAF-Rs) to initiate all cellular responses via specific G-proteincoupled receptors [1-4]. Although these initiated membrane receptor phenomena are mostly established for several tissuecell systems [1-8], exactly how PAF and PAF-Rs cause vascular remodeling in hypertension and atherosclerosis is not clear. A little more than 15 years ago, PAF was identified as a molecule that stimulated activation of nuclear factor-kappaB (NF-kB

Calcium:Magnesium Ratio in Local Groundwater and Incidence of Acute Myocardial Infarction among Males in Rural Finland

Several epidemiologic studies have shown an association between calcium and magnesium and coronary heart disease mortality and morbidity. In this small-area study, we examined the relationship between acute myocardial infarction (AMI) risk and content of Ca, Mg, and chromium in local groundwater in Finnish rural areas using Bayesian modeling and geospatial data aggregated into 10 km × 10 km grid cells. Data on 14,495 men 35–74 years of age with their first AMI in the years 1983, 1988, or 1993 were pooled. Geochemical data consisted of 4,300 measurements of each element in local groundwater. The median concentrations of Mg, Ca, and Cr and the Ca:Mg ratio in well water were 2.61 mg/L, 12.23 mg/L, 0.27 μg/L, and 5.39, respectively. Each 1 mg/L increment in Mg level decreased the AMI risk by 4.9%, whereas a one unit increment in the Ca:Mg ratio increased the risk by 3.1%. Ca and Cr did not show any statistically significant effect on the incidence and spatial variation of AMI. Results of this study with specific Bayesian statistical analysis support earlier findings of a protective role of Mg and low Ca:Mg ratio against coronary heart disease but do not support the earlier hypothesis of a protective role of Ca

Neuroadaptations in Human Chronic Alcoholics: Dysregulation of the NF-κB System

Anna Ökvist is with Karolinska Institute, Sofia Johansson is with Karolinska Institute, Alexander Kuzmin is with Karolinska Institute, Igor Bazov is with Karolinska Institute, Roxana Merino-Martinez is with Karolinska Institute, Igor Ponomarev is with UT Austin, R. Dayne Mayfield is with UT Austin, R. Adron Harris is with UT Austin, Donna Sheedy is with University of Sydney, Therese Garrick is with University of Sydney, Clive Harper is with University of Sydney, Yasmin L. Hurd is with Mount Sinai School of Medicine, Lars Terenius is with Karolinska Institute, Tomas J. Ekström is with Karolinska Institute, Georgy Bakalkin is with Karolinska Institute and Uppsala University, Tatjana Yakovleva is with Karolinska Institute and Uppsala University.Background -- Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-κB) family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics. Methods and Findings -- Analysis of DNA-binding of NF-κB (p65/p50 heterodimer) and the p50 homodimer as well as NF-κB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant κB binding factor in analyzed tissues. NF-κB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA) mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-κB target DNA sites, κB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with κB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex. Conclusions -- We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-κB, when repeated over years downregulate RELA expression and NF-κB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of κB regulated genes. Alterations in expression of p50 homodimer/NF-κB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.This work was supported by grants from the AFA Forsäkring to AK, YLH, TJE and GB, the Research Foundation of the Swedish Alcohol Retail Monopoly (SRA) and Karolinska Institutet to AK, TJE and GB, and the Swedish Science Research Council and the Swedish National Drug Policy Coordinator to GB. The Australian Brain Donor Programs NSW Tissue Resource Centre was supported by The University of Sydney, National Health and Medical Research Council of Australia, Neuroscience Institute of Schizophrenia and Allied Disorders, National Institute of Alcohol Abuse and Alcoholism and NSW Department of Health.Waggoner Center for Alcohol and Addiction Researc

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans