Chemical Communication of Antibiotic Resistance by Highly Resistant Bacteria.

The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. I use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, I report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of PmB than the rest of the cells in the culture, and protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to PmB. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. I propose that putrescine and YceI resemble danger infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species. Putrescine protects from antibiotics through its ability to compete with PmB for surface binding and protection against antibiotic-induced oxidative stress. YceI proteins are conserved bacterial lipocalins or “bacteriocalins”. Bacteriocalins from different Gram-positive and Gram-negative bacteria are involved in the response to hydrophobic or amphiphilic antibiotics (PmB, rifampicin, norfloxacin and ceftazidime) but not hydrophilic ones (such as gentamicin). This effect is achieved by their preferential binding affinity to hydrophobic moieties. Together, my findings uncover a novel, non-genetic and cooperative mechanism of transient increase in resistance chemically communicated from more resistant members of heterogeneous populations to less resistant bacteria of the same or other species. This multifactorial mechanism of communication of antibiotic resistance offers novel targets for antimicrobial intervention

Antimicrobial Heteroresistance: an Emerging Field in Need of Clarity

“Heteroresistance” describes a phenomenon where subpopulations of seemingly isogenic bacteria exhibit a range of susceptibilities to a particular antibiotic. Unfortunately, a lack of standard methods to determine heteroresistance has led to inappropriate use of this term. Heteroresistance has been recognized since at least 1947 and occurs in Gram-positive and Gram-negative bacteria. Its clinical relevance may be considerable, since more resistant subpopulations may be selected during antimicrobial therapy. However, the use of nonstandard methods to define heteroresistance, which are costly and involve considerable labor and resources, precludes evaluating the clinical magnitude and severity of this phenomenon. We review the available literature on antibiotic heteroresistance and propose recommendations for definitions and determination criteria for heteroresistant bacteria. This will help in assessing the global clinical impact of heteroresistance and developing uniform guidelines for improved therapeutic outcomes

Detection of Campylobacter concisus and other Campylobacter species in colonic biopsies from adults with ulcerative colitis

Peer reviewedPublisher PD

Voltammetric studies of some azo compounds derived from 4-methyl-6,7-dihydroxy coumarin in microemulsion and aqueous media

The cyclic voltammetric(CV) behavior of some azo compounds based on coumarin derivatives  was investigated in microemulsion systems and in aqueous solutions. The obtained results indicated that these compounds undergo an irreversible 4-electron reduction step leading to cleavage of the N=N center with the formation of amine compounds in all media. The effect of medium on the CV parameters was discussed. The total number of electrons involved in the reduction process was determined by controlled potential coulometry. Also, The effect of substituents on the electrode reaction pathway and the kinetic parameters of the electrode process were calculated and discussed. Based on the data obtained the electroreduction mechanism was suggested and discussed

Genetic and Modifiable Risk Factors Contributing to Cisplatin-Induced Toxicities

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent that has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient’s quality of life, but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin induced ototoxicity, neurotoxicity and nephrotoxicity. Traditional genome-wide association studies have identified single nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities, and currently available means to prevent or treat their occurrence

Endovenous Laser Ablation, Radiofrequency Ablation and Flebogrif versus Conventional Surgery in Treatment of Primary Varicose Vein of the Lower Limb: Prospective Randomized Controlled Study

Background: Endovenous laser ablation (EVLA), radiofrequency ablation (RFA) and mechanochemical ablation (MOCA) of primary varicose vein are thought to minimise postoperative morbidity and reduce work loss compared with the conventional surgical procedure. Objective: To determine, whether endovenous ablation methods (radiofrequency, laser and mechanochemical) have any advantages or disadvantages in comparison with conventional surgery, in the treatment of primary varicose vein. Patients and Methods: This was a prospective randomized study, conducted on forty patients presented at Vascular Outpatient Clinic for management of chronic venous insufficiency. All patients underwent clinical examination and duplex ultrasonography. Ten (10) patients were treated with ligation and stripping of the great saphenous vein (GSV). Ten (10) patients were treated with radiofrequency ablation. Ten (10) patients were treated with endovenous laser ablation. Ten (10) patients were treated with Flebogrif. Results: Compared with conventional surgery, endovenous ablation methods reduced postoperative discomfort and pain, with a lower complication rate after treatment for avoidance of a groin incision and dissection at the saphenofemoral confluence. Cosmetic demands were also better satisfied. Non-controlled clinical trials have shown that the ablation rate of GSV after EVLA is over 90%. However, risks of EVLA, RFA and Flebogrif remain in terms of recanalization and neoreflux via junctional tributaries. Conclusion: RFA, EVLA, and Flebogrif are minimally invasive procedures. Their potential early benefits, by avoiding groin dissection and GSV stripping, have been confirmed by the findings from this trial. Current evidence based on randomized trials consistently demonstrates significant early benefits after RFA, EVLA and Flebogrif in suitable patients with varicose veins

Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori

Background & Aims:Helicobacter pylori is believed to predispose to gastric cancer by inducing gastric atrophy and hypochlorhydria. First-degree relatives of patients with gastric cancer have an increased risk of developing gastric cancer. The aim of this study was to determine the prevalence of atrophy and hypochlorhydria and their association with H. pylori infection in first-degree relatives of patients with gastric cancer. Methods:H. pylori status, gastric secretory function, and gastric histology were studied in 100 first-degree relatives of patients with noncardia gastric cancer and compared with those of controls with no family history of this cancer. Results: Compared with healthy controls, relatives of patients with gastric cancer had a higher prevalence of hypochlorhydria (27% vs. 3%) but a similar prevalence of H. pylori infection (63% vs. 64%). Relatives of cancer patients also had a higher prevalence of atrophy (34%) than patients with nonulcer dyspepsia (5%) matched for H. pylori prevalence. Among the relatives of cancer patients, the prevalence of atrophy and hypochlorhydria was increased only in those with evidence of H. pylori infection, was greater in relatives of patients with familial cancer than in relatives of sporadic cancer index patients, and increased with age. Eradication of H. pylori infection produced resolution of the gastric inflammation in each subject and resolution of hypochlorhydria and atrophy in 50% of the subjects. Conclusions: Relatives of patients with gastric cancer have an increased prevalence of precancerous gastric abnormalities, but this increase is confined to those with H. pylori infection. Consequently, prophylactic eradication of the infection should be offered to such subjects

Bioactive Cytotoxic Agents and Chemokine Production Inhibitors in LPS-Induced Raw264.7 Macrophage Cell Line from Flowers of Crepis Senecioides

Crepis senecioides is one of the endemic plant species found in Libya. The ethanol extract (E) of the flowers was partitioned on silica gel column with dichloromethane affording four compounds. Their structures were elucidated by the physicochemical and spectral data as germanicol acetate (1), 3`,3``butyl, 8`,8``carboxy) di-octyl phethalate (2), taraxasterol (3) and β-sitosterol (4). effect of the tested samples 1 and 2 on the viability of RAW macrophage 264.7 were studied. anti-cancer activity was tested on several human cell lines. Anti-inflammatory effect was also screened. Compound 1 had promising cellular cytotoxicity with IC50 60.26µg/mL on HepG2. Compound 2 had a talented cellular cytotoxicity with IC50 50.18 µg/mL on PC3. Both 1 and 2 exerted alike cytotoxicity with IC50 µg/mL 78.53, 78.14 on PC3 and MCF-7 carcinoma cell lines respectively. The treatment of LPS-stimulated macrophage with 2 led to a highly significant inhibition 45.05% in the nitrite concentration in LPS-stimulated macrophage. Compound 1 had a promising cellular cytotoxicity on HepG2, while 2 exhibited an inhibition on chemokine expression in LPS-induced RAW 264.7 macrophages and had talented cellular cytotoxicity on PC3. Keywords: Crepis senecioide;, Asteraceae; Anti-inflammatory; cytotoxic effect; terpenoids; phethalate derivative