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PubMed2025

Clinical carbapenem-resistant Enterobacterales in a University Hospital in Dakar, Senegal: genomic insights into Enterobacter hormaechei ST182 strains carrying blaNDM-5 and blaOXA-48 genes .

Senegal has witnessed the emergence and spread of carbapenem-resistant Enterobacterales (CRE), which often cause deadly infections. Accordingly, this study aimed to determine the antimicrobial susceptibility and prevalence of carbapenemases, as well as to perform a whole-genome sequence analysis of clinical CRE isolates from a university hospital in Dakar, Senegal. MALDI-TOF MS and VITEK2 systems were used for bacterial identification and antimicrobial susceptibility testing (AST). Carbapenemase- and cephalosporinase-encoding genes were screened using simplex end-point polymerase chain reaction. Whole-genome sequencing (WGS) was performed using the Illumina MiSeq platform. The CRE isolates were resistant to almost all the 34 antimicrobials tested. Nevertheless, colistin and amikacin remained active, with susceptibility rates of 96% and 71%, respectively. Only the carbapenemase genes blaOXA-48 (53.8%; 15/28) and blaNDM (35.7%; 10/28) and the cephalosporinase gene blaCMY-1 (25%; 7/28) were identified. In this context, two extensively drug-resistant Enterobacter hormaechei isolates were subjected to WGS analysis. These isolates were assigned as sequence type (ST) 182 and carried several genes related to antimicrobial resistance (AMR), metal tolerance, and virulence. An IncL/M plasmid with 61,054 bp in length was identified as carrying the blaOXA-48 gene, whereas an IncFIB(pECLA)/IncFII(pECLA)/IncX3 mutireplicon plasmid with 217,745 bp in length was detected as harboring the blaNDM-5 gene and other genes related to AMR and metal tolerance. Our study presents the first landscape of clinical CRE circulating in Senegal, along with additional genomic analysis of E. hormaechei ST182 strains, which could be useful for mitigating the burden associated with CRE in this country.IMPORTANCEThe investigation of global critical priority CRE isolates has become crucial to reduce morbidity and mortality associated with AMR. This study revealed that colistin and amikacin can be considered good alternatives for treating CRE-associated infections in Dakar. In addition, the genomic approach revealed that the CRE isolates carried both a wide resistome and virulome. Moreover, the abundance of horizontal gene transfer regions in the genomes suggests the great implications of mobile genetic elements in the spread of AMR in Dakar. Furthermore, this study reported the complete sequences of chromosomes and blaOXA-48 and blaNDM-5-carrying plasmids. Our findings are of great importance because complete genome sequences are still rarely characterized in the West African region. Finally, this study highlights the importance of strengthening genomic surveillance of CRE in sub-Saharan African countries to mitigate the burden associated with these pathogens.

Senegal↗

PubMed2001

Role of slotting fees and trade promotions in shaping how tobacco is marketed in retail stores.

OBJECTIVE: To examine how the retail environment in which tobacco is sold has changed because of the slotting fees and trade promotions paid by the tobacco companies. Public policy options for dealing with this environment are also evaluated. DATA SOURCES: A literature review, telephone interviews, and observation. RESULTS: The tobacco companies have been dramatically increasing the volume of slotting fees and trade promotions they pay to retailers, creating a more tobacco friendly retail environment containing self service displays and ample point-of-sale advertising. Critics express concern that these payments have kept prices lower and more varied than they might be otherwise, created more opportunities for pilferage and underage selling, and provided more youth exposure to tobacco promotions. Public policy makers could either ban these payments, institute policies designed to mitigate their harmful effects, or leave the situation as it is, relying on enforcement of existing statutes as well as market forces to reduce harm. Actions that might mitigate harmful effects would include putting minimum retail prices on tobacco products, banning self service displays, requiring retailers to be licensed, and adding more warning signs at the point of sale. CONCLUSION: Additional research is needed before determining the most appropriate public policy stance.

Advertising↗

PubMed2026

Acetazolamide to prevent ventilatory drive withdrawal in REM sleep apnoea: a randomised controlled trial.

BACKGROUND: Obstructive sleep apnoea (OSA) pathogenesis during rapid-eye movement (REM) sleep has been linked to dips in ventilatory drive and downstream genioglossus hypotonia. The carbonic anhydrase inhibitor acetazolamide is known to increase ventilatory drive and improve OSA severity. Therefore, we tested the effect of acetazolamide on REM-predominant OSA severity (apnoea hypopnoea index (AHI) and hypoxic burden, co-primary outcomes) and underlying physiological mechanisms (ventilatory drive, ventilation and pharyngeal muscle activity). METHODS: 11 participants with REM-predominant OSA per baseline polysomnography (REM AHI/non-REM AHI≥2) were allocated to receiving acetazolamide 500 mg for three nights (first night at half dose) or placebo according to a randomised, crossover, double-blind design. Detailed physiological polysomnography with recording of diaphragm and genioglossus electromyography was conducted after each intervention, with a 1-week washout in between. RESULTS: As hypothesised, acetazolamide reduced AHI by 35.5% (95% CI 23.1% to 46.3%) and hypoxic burden by 35.9% (95% CI 21.1% to 48.4%) vs placebo (p<0.001), meeting the primary endpoint. Mechanistic analysis in REM revealed that, unexpectedly, acetazolamide did not mitigate dips in ventilatory drive versus placebo (first decile (+0.1 (-1.0 to 1.3) L/min, p=0.8). Rather, acetazolamide reduced collapsibility (increased ventilation at eupneic drive: +1.4 (1.2 to 1.8) L/min) and raised muscle responsiveness (ventilation vs drive slope: +32 (25 to 41) %ventilation/drive, p<0.001; genioglossus versus drive slope: +0.33 (0.13 to 0.54) %max/(L/min), p=0.001). CONCLUSIONS: Acetazolamide modestly improved REM OSA, with meaningful improvements in upper airway physiology, but failed to mitigate the dips in ventilatory drive responsible for REM OSA. TRIAL REGISTRATION NUMBER: NCT05589792.

Humans↗

PubMed2004

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats.

We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist, the involvement of EP4 receptors in duodenal HCO(3)(-) secretion induced by PGE(2) and mucosal acidification in rats. Mucosal acidification was achieved by exposing a duodenal loop to 10 mM HCl for 10 min, and various EP agonists were given intravenously 10 min before the acidification. Secretion of HCO(3)(-) was dose-dependently stimulated by AE1-329 (EP4 agonist), the maximal response being equivalent to that induced by sulprostone (EP1/EP3 agonist) or PGE(2). The stimulatory action of AE1-329 and PGE(2) but not sulprostone was attenuated by AE3-208, a specific EP4 antagonist. This antagonist also significantly mitigated the acid-induced HCO(3)(-) secretion. Coadministration of sulprostone and AE1-329 caused a greater secretory response than either agent alone. IBMX potentiated the stimulatory action of both sulprostone and AE1-329, whereas verapamil mitigated the effect of sulprostone but not AE1-329. Chemical ablation of capsaicin-sensitive afferent neurons did not affect the response to any of the EP agonists used. We conclude that EP4 receptors are involved in the duodenal HCO(3)(-) response induced by PGE(2) or acidification in addition to EP3 receptors. The process by which HCO(3)(-) is secreted through these receptors differs regarding second-messenger coupling. Stimulation through EP4 receptors is mediated by cAMP, whereas that through EP3 receptors is regulated by both cAMP and Ca(2+); yet there is cooperation between the actions mediated by these two receptors. The neuronal reflex pathway is not involved in stimulatory actions of these prostanoids.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Pyruvate-fortified cardioplegia suppresses oxidative stress and enhances phosphorylation potential of arrested myocardium.

Cardioplegic arrest for bypass surgery imposes global ischemia on the myocardium, which generates oxyradicals and depletes myocardial high-energy phosphates. The glycolytic metabolite pyruvate, but not its reduced congener lactate, increases phosphorylation potential and detoxifies oxyradicals in ischemic and postischemic myocardium. This study tested the hypothesis that pyruvate mitigates oxidative stress and preserves the energy state in cardioplegically arrested myocardium. In situ swine hearts were arrested for 60 min with a 4:1 mixture of blood and crystalloid cardioplegia solution containing 188 mM glucose alone (control) or with additional 23.8 mM lactate or 23.8 mM pyruvate and then reperfused for 3 min with cardioplegia-free blood. Glutathione (GSH), glutathione disulfide (GSSG), and energy metabolites [phosphocreatine (PCr), creatine (Cr), P(i)] were measured in myocardium, which was snap frozen at 45 min arrest and 3 min reperfusion to determine antioxidant GSH redox state (GSH/GSSG) and PCr phosphorylation potential {[PCr]/([Cr][P(i)])}. Coronary sinus 8-isoprostane indexed oxidative stress. Pyruvate cardioplegia lowered 8-isoprostane release approximately 40% during arrest versus control and lactate cardioplegia. Lactate and pyruvate cardioplegia dampened (P < 0.05 vs. control) the surge of 8-isoprostane release following reperfusion. Pyruvate doubled GSH/GSSG versus lactate cardioplegia during arrest, but GSH/GSSG fell in all three groups after reperfusion. Myocardial [PCr]/([Cr][P(i)]) was maintained in all three groups during arrest. Pyruvate cardioplegia doubled [PCr]/([Cr][P(i)]) versus control and lactate cardioplegia after reperfusion. Pyruvate cardioplegia mitigates oxidative stress during cardioplegic arrest and enhances myocardial energy state on reperfusion.

Acid-Base Equilibrium↗

PubMed2006

Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression.

Pulmonary artery smooth muscle cell (PASMC) relaxation at birth results from an increase in cytosolic cGMP, cGMP-dependent and kinase-mediated activation of the Ca2+-sensitive K+ channel (KCa), and closure of voltage-operated Ca2+ channels (VOCC). How chronic intrauterine pulmonary hypertension compromises perinatal pulmonary vasodilation remains unknown. We tested the hypothesis that chronic intrauterine pulmonary hypertension selectively modifies gene expression to mitigate perinatal pulmonary vasodilation mediated by the cGMP kinase-KCa-VOCC pathway. PASMC were isolated from late-gestation fetal lambs that had undergone either ligation of the ductus arteriosus (hypertensive) or sham operation (control) at 127 days of gestation and were maintained under either hypoxic (approximately 25 Torr) or normoxic (approximately 120 Torr) conditions in primary culture. We studied mRNA levels for cGMP kinase Ialpha (PKG-1alpha), the alpha-chain of VOCC (Cav1.2), and the alpha-subunit of the KCa channel. Compared with control PASMC, hypertensive PASMC had decreased VOCC, KCa, and PKG-1alpha expression. In response to sustained normoxia, expression of VOCC and KCa channel decreased and expression of PKG-1alpha increased. In contrast, sustained normoxia had no effect on PKG-1alpha levels and an attenuated effect on VOCC and KCa channel expression in hypertensive PASMC. Protein expression of PKG-1alpha was consistent with the mRNA data. We conclude that chronic intrauterine pulmonary hypertension decreases PKG expression and mitigates the genetic effects of sustained normoxia on pulmonary vasodilation, because gene expression remains compromised even after sustained exposure to normoxia.

Animals↗

PubMed2004

Can we prevent a second 'Gulf War syndrome'? Population-based healthcare for chronic idiopathic pain and fatigue after war.

In the 1991 Gulf War less than 150 of nearly 700,000 deployed US troops were killed in action. Today, however, over 1 in 7 US veterans of the war has sought federal healthcare for related-health concerns, and fully 17% of UK Gulf War veterans describe themselves as suffering from the 'Gulf War syndrome', a set of poorly defined and heterogeneous ailments consisting mainly of chronic pain, fatigue, depression and other symptoms. Even though over 250 million dollars of federally funded medical research has failed to identify a unique syndrome, the debate regarding potential causes continues and has included oil well smoke, contagious infections, exposure to chemical and biological warfare agents, and posttraumatic stress disorder. Historical analyses completed since the Gulf War have found that postwar syndromes consisting of chronic pain, fatigue, depression and other symptoms have occurred after every war in the 20th century. These syndromes have gone by a variety of names such as Da Costa's syndrome, irritable heart, shell shock, neurocirculatory asthenia, and battle fatigue. Though the direct causes of these syndromes are typically elusive, it is clear that war sets in motion an undeniable cycle of physical, emotional, and fiscal consequences for war veterans and for society. These findings lead to important healthcare questions. Is there a way to prevent or mitigate subsequent postwar symptoms and associated depression and disability? We argue that while idiopathic symptoms are certain to occur following any war, a population-based approach to postwar healthcare can mitigate the impact of postwar syndromes and foster societal, military, and veteran trust. This article delineates the model, describes its epidemiological foundations, and details examples of how it is being adopted and improved as part of the system of care for US military personnel, war veterans and families. A scientific test of the model's overall effectiveness is difficult, yet healthcare systems for combatants and their families are already being put to pragmatic tests as troops return from war in Iraq and Afghanistan and from other military challenges.

Chronic Disease↗

PubMedDate not supplied

Physical exercise retards the development of chronic nephropathy in the ageing rat as efficiently as food restriction does.

BACKGROUND: Obesity combined with decreasing physical fitness in the ageing Western populations promotes a number of degenerative diseases, including chronic kidney disease. It has further been shown in rodent models that prevention of obesity by food restriction mitigates development of kidney lesions. Whether lifelong physical activity also has a positive effect is not known. OBJECTIVE: To compare the effects of physical exercise and food restriction on the development of chronic kidney lesions in ageing rats. METHODS: Male Sprague-Dawley rats were divided into groups: voluntarily running in wheels (RW), food restriction to the degree necessary to attain pair weight to RW rats (PW), forced running in treadmills (TM) and sedentary controls housed individually (S1) or 4 in each cage (S4). The interventions began at the age of 5 months and kidneys were sampled and analysed histologically at the ages of 15, 19 and 23 months. RESULTS: Total score for kidney lesions (sum of the scores for glomerular changes, interstitial non-purulent inflammation, proteinaceous casts in tubules and increased amount of connective tissue, the possible maximum being 10.0) increased from 0.5 +/- 0.2 at 5 months of age to 1.6 +/- 0.3 for RW, 2.3 +/- 0.4 for PW, 4.5 +/- 0.4 for TM, 3.6 +/- 0.5 for S1 and 5.4 +/- 0.6 for S4 at the age of 23 months. The increase from 5 months of age was gradual for all groups through 15, 19 and 23 months. The patterns for the various lesions followed the same pattern with the exception of connective tissue, which did not increase. CONCLUSION: Voluntary running in wheels is as effective in mitigating kidney lesions as is food restriction, while forced running in a treadmill is not effective in this respect.

Aging↗

PubMed1997

Effect of dibutyryl cyclic adenosine monophosphate on skeletal muscle reperfusion injury in the rat.

To clarify the action of dibutyryl cyclic adenosine monophosphate (DBcAMP) on reperfused ischemic muscle, experiments were conducted using the hindlimbs of 18 male Lewis rats. At the midportion of the thigh all tissues except for the femoral artery and vein were transected, and a route for continuous intravenous infusion was secured in a contralateral limb vein. After inducing total ischemia by clamping the femoral artery and vein with a vascular clamp for 4 h, the limb was reperfused for 1 h. Blood flow was then compared using the hydrogen gas clearance method in a group in which DBcAMP 10 mg was continuously infused from a vein in the contralateral hindlimb from 1 h prior to the induction of ischemia to 1 h after the completion of ischemia (DBcAMP group), a group in which saline was infused in the same manner (control group), and a group which was subjected to biopsy alone (biopsy group). The percent change in blood flow was significantly higher in the DBcAMP group than in the control group at 15 and 30 min after the release of the clamp. Adenosine triphosphate (ATP), phosphocreatine (PCr), and lipid peroxide (LPO) were measured in tissue samples obtained 1 h after reperfusion. Serum LPO was measured in blood samples collected at the same time. ATP values were higher in the DBcAMP group than in the control group. PCr was significantly higher in the DBcAMP group than in the control group. LPO levels in skeletal muscle tissue did not differ significantly between the DBcAMP and control groups. In contrast, serum LPO levels were significantly lower in the DBcAMP group than the control group. On morphologic analysis the control and DBcAMP groups showed normal vascular endothelial cells and absence of the 'no-reflow' phenomenon. These data confirm that in this reperfusion model the administration of DBcAMP enhances the viability of skeletal muscle cells. Moreover, mediated by an effect on vascular endothelial cells this agent is thought to be of help in mitigating the vascular endothelial cell injury occurring in acute ischemic injury. DBcAMP may be a useful agent in mitigating skeletal muscle ischemia-reperfusion injury.

Adenine Nucleotides↗

PubMed1983

Effects of experimental hyperadrenocorticism on the growth of the femur and tibia in normal and bipedal rats.

Daily subcutaneous injections of glucocorticoid preparations have been shown to produce clinical signs of hyperadrenocorticism which resulted in interference with the growth of rats, shown by measurements both of body weight and of the length of long bones. The purpose of this study was to see if increased, intermittent, compressive forces, produced by experimental bipedalism, would mitigate the negative effects of cortisone injections on long bone growth and if there would be a difference in reaction between male and female rats. Male and female Sprague-Dawley rats were used for control, cortisone-injected, and cortisone-injected plus bipedal groups. Experimental bipedalism was produced at 10 days of age; cortisone injections began at 30 days of age; all animals were sacrificed at 65 days of age. Tibial and femoral lengths were measured. The results do not support the hypothesis that bipedalism can be instrumental in mitigating the effects of hyperadrenocorticism on hindlimb long bone growth.

Adrenal Cortex Diseases↗

PubMed1993

Does obesity influence early target organ damage in hypertensive patients?

BACKGROUND: Various prospective studies have found that lean hypertensive patients have greater cardiovascular morbidity and mortality than obese hypertensive subjects. It was therefore hypothesized that hypertension is more benign when associated with obesity. In the present study, we evaluated effects of obesity on early target organ damage in patients with essential hypertension. METHODS AND RESULTS: In a total of 207 subjects, systemic and renal hemodynamics as well as left ventricular structure and function were assessed by measuring cardiac output (indocyanine green dye dilution), renal blood flow (clearance of 131I paraimmunohippuric acid), and mean arterial pressure (invasively) and by two-dimensionally guided M-mode echocardiographic findings. Systemic and renal vascular resistance, compliance of the large arteries evaluated by the stroke volume/pulse pressure index, and left ventricular mass served as parameters for early target organ damage. All individuals were categorized into four groups: lean and obese normotensive as well as lean and obese hypertensive subjects. In obese hypertensive patients, total peripheral resistance was significantly lower and stroke volume/pulse pressure index was higher than in the lean hypertensive group, almost reaching values of normotensive control subjects. No effect of obesity on the renal circulation was noted, whereas in hypertension, renal vascular resistance was elevated. The degree of left ventricular hypertrophy was more pronounced in the hypertensive groups than in their normotensive counterparts and progressively increased with obesity. Nevertheless, in obese hypertensive patients, left ventricular function, as measured by fractional fiber shortening and velocity of circumferential fiber shortening, was maintained despite the fact that the heart had been exposed to the double burden of an increased preload (obesity) and afterload (hypertension). CONCLUSIONS: Obesity had a disparate effect on target organs in hypertension. At rest, obesity seemed to mitigate cardiovascular changes in the systemic vascular bed caused by hypertension. However, no such mitigation was observed in the renal vasculature, and left ventricular hypertrophy was even exacerbated by the presence of obesity. Our findings in part negate the concept that obesity is able to exert a protective effect on early target organ damage in hypertensive patients and, in particular, on the heart.

Adult↗

PubMed1988

Adenosine in renin-dependent renovascular hypertension.

Our previous studies support the hypothesis that activation of the renin-angiotensin system by renal ischemia elevates adenosine levels and that adenosine acts in a negative feedback loop to limit renin release and to mitigate some of the hypertension-producing effects of angiotensin II. To further test this hypothesis, we compared the time course of caffeine-induced increases in plasma renin activity with the time course of changes in plasma levels of adenosine in two models of renin-dependent renovascular hypertension. Also, we compared the effects of caffeine on plasma renin activity and arterial blood pressure in renin-dependent versus renin-independent renovascular hypertension. In comparison to sham-operated rats, plasma levels of adenosine in the left and right renal veins and aorta were elevated severalfold in two-kidney, one clip rats (2K1C) 1 week after left renal artery clipping. However, adenosine levels declined during the second and third weeks after clipping. In 2K1C rats treated chronically with caffeine, plasma renin activity was markedly elevated during the first week after operation as compared to non-caffeine-treated 2K1C rats. However, during the second and third weeks after clipping, caffeine had lesser effects on plasma renin activity. A temporal relationship between plasma adenosine levels and caffeine-induced hyperreninemia was also observed in rats with aortic ligation. Caffeine accelerated hypertension in 2K1C rats and rats with aortic ligation (renin-dependent renovascular hypertension), but it had no effect on plasma renin activity or blood pressure in one-kidney, one clip rats (renin-independent renovascular hypertension). These results lend further support to the hypothesis that adenosine functions to mitigate the renin-angiotensin system in renin-dependent renovascular hypertension.

Adenosine↗

PubMed2000

Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats.

Several recent studies have shown that certain forms of genetic or acquired hypertension are associated with oxidative stress and that animals with those types of hypertension respond favorably to antioxidant therapy. We hypothesize that oxidative stress may cause hypertension via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion by means of the GSH synthase inhibitor buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for 2 weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. The BSO-treated group showed a 3-fold decrease in tissue GSH content, a marked elevation in blood pressure, and a significant reduction in the urinary excretion of the NO metabolite nitrate plus nitrite, which suggests depressed NO availability. These characteristics were associated with a significant accumulation in various tissues of nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species. Administration of vitamin E plus vitamin C ameliorated hypertension, improved urinary nitrate-plus-nitrite excretion, and mitigated nitrotyrosine accumulation (despite GSH depletion) in the BSO-treated animals but had no effect in the control group. In conclusion, GSH depletion resulted in perturbation of the NO system and severe hypertension in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, which supports the notion that oxidative stress was involved in the pathogenesis of hypertension in this model.

Animals↗

PubMed2005

Delayed preconditioning-mimetic actions of nitroglycerin in patients undergoing exercise tolerance tests.

BACKGROUND: Nitroglycerin (NTG) induces delayed preconditioning (PC)-mimetic effects in animal models and in humans during coronary angioplasty. We tested the hypothesis that NTG mitigates ischemia and enhances functional capacity during an exercise tolerance test (ETT) in patients with coronary artery disease. METHODS AND RESULTS: Twenty-eight patients with stable angina and ischemia documented by a stress test were randomized in a double-masked, crossover design to receive a titrated intravenous infusion of NTG or normal saline over 4 hours. At 24 to 28 hours after study medication infusion, each patient underwent 2 ETTs separated by a 1-week washout period. Compared with control patients, pretreatment with NTG was associated with a dose-dependent increase in exercise duration averaging 40 seconds (412+/-19 versus 372+/-24 seconds, P=0.014) and an improvement in ECG manifestations of ischemia, as shown by a decrease in maximal ST-segment depression (1.84+/-0.14 versus 1.63+/-0.13 mm, P=0.011), sum of ST-segment depressions in 12 leads (7.64+/-1.01 versus 6.61+/-0.83 mm, P=0.027), and time to resolution of ST-segment depression (229+/-30 versus 207+/-28 s, P=0.018). These benefits occurred despite an increase in myocardial workload after NTG, as indicated by a higher peak rate-pressure product (24 492+/-1054 versus 22 536+/-1019 mm Hg/min, P=0.015). CONCLUSIONS: NTG produces a late PC-mimetic effect that mitigates the ECG manifestations of ischemia during exercise and improves exercise capacity. To our knowledge, this is the first study to demonstrate that NTG can alleviate exercise-induced ischemia 24 hours after its administration, long after the hemodynamic effects have subsided. The finding that nitrate-induced late PC ameliorates a common manifestation of coronary artery disease has potentially significant implications for the management of this disorder and for the design of clinical trials.

Aged↗

PubMed1990

Influenza virus infection, ozone exposure, and fibrogenesis.

Oxidant exposure following chemically induced lung injury exacerbates the tendency to develop pulmonary fibrosis. Influenza virus pneumonitis causes severe acute lung damage that, upon resolution, is followed by a persistent alveolitis and parenchymal changes characterized by patchy interstitial pneumonia and collagen deposition in the affected areas. To determine whether oxidant exposure exacerbates the virus-induced alveolitis and residual lung damage, mice were infected by aerosol inhalation with influenza A virus and continuously exposed to 0.5 ppm ozone or ambient air. Noninfected control mice were exposed to either ambient air or ozone. On various days during the first month after infection, groups of mice were sacrificed and their lungs assessed for acute injury (lung lavage albumin, total and differential cell counts, wet/dry ratios, and morphometry). At 30, 60, 90, and 120 days after infection, groups of mice were sacrificed for total and differential lavage cell counts, lung hydroxyproline content, and morphometric analysis. Ozone exposure did not alter the proliferation of virus in the lungs as quantitated by infectious virus titers of lung homogenates at 1, 4, 7, 10, and 15 days after virus infection but mitigated the virus-induced acute lung injury by approximately 50%. After Day 30 a shift in the character of the pulmonary lesions was observed in that continuous exposure to ozone potentiated the postinfluenzal alveolitis and structural changes in the lung parenchyma. Additional studies suggest that the mechanism for the enhanced postinfluenzal lung damage may be related to the oxidant impairing the repair process of the acute influenzal lung damage. These data demonstrate that ozone exposure mitigates acute virus-induced lung injury and potentiates residual lung damage.

Air Pollutants↗

PubMed1989

Hepatocellular copper toxicity and its attenuation by zinc.

We studied the mechanisms by which excess copper exerts, and zinc mitigates, toxic effects on HepG2 cells. Survival and cell growth were reduced in media containing greater than 500 microM copper chloride for 48 h; LD50 was 750 microM. At 1,000 microM copper for 1 h, there was a general reduction of protein synthesis, and no recognizable changes in cellular ultrastructure. Incubation of cells with 200 microM zinc acetate before exposure to copper, raised the LD50 for confluent cells to 1,250 microM copper chloride, improved protein synthesis, and increased synthesis of a 10-kD protein, apparently metallothionein. The mitigation, by zinc, of copper's toxicity may in part be mediated through induction of this protein in the hepatocyte.

Adenosine Triphosphate↗

PubMed2003

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.

Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: alpha-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the alpha-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid-mediated activation of the stress-response gene sigB. Expression of the sigB-repressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes.

Animals↗

PubMed2024

Just a spoonful of metformin helps the medicine go down.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.

Humans↗