Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer.

Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.

Exploration of the integration of microbiology and immunology emerging topics into undergraduate medical education.

PURPOSE: Medical school educators face challenges determining which new and emerging topics to incorporate into medical school curricula, and how to do so. A study was conducted to gain a better understanding of the integration of emerging topics related to microbiology and immunology in the undergraduate medical curriculum (UME). METHODS: An anonymous survey with 17 questions was emailed to medical school faculty who teach immunology and/or microbiology through the DR-Ed listserv, the American Society for Microbiology (ASM) Connect listserv, and attendees of the Association of Medical School Microbiology and Immunology Chairs (AMSMIC) Educational Strategies Workshop. Participants were asked about experiences, perceptions, and the decision-making process regarding integrating emerging topics into UME. RESULTS: The top emerging topics that were added to the curriculum or considered for addition in the last 10 years included COVID-19, Zika virus, mRNA vaccines, and Mpox (formerly known as monkeypox). Most respondents reported lectures and active learning as the major methods for topic delivery, with most faculty indicating that formative assessment was the best way to assess emerging topics. Content experts and course directors were the most cited individuals making these decisions. Top reasons for incorporating emerging topics into curricula included preparing students for clinical treatment of cases, followed by demonstrating the importance of basic science, and opportunities to integrate basic science into other disciplines. Challenges for incorporating these topics included making room in an already crowded curriculum, followed by content overload for students. CONCLUSIONS: This study describes the rationale for integrating emerging topics related to microbiology and immunology into UME, and identifies the current new and emerging topics, as well as the main methods of integration and assessment. These results may be used by medical educators to inform curricular decisions at their institutions. Future studies will include developing innovative learning modules that overcome barriers to integration.

Garcinia cambogia Extract Increased Hepatic Levels of Lipolysis-Stimulated Lipoprotein Receptor and Lipids in Mice on Normal Diet.

Garcinia cambogia extract (GCE) is a popular weight-loss supplement that also lowers plasma triglyceride (TG) levels. We hypothesized that GCE-mediated inhibition of ATP citrate lyase and thereby hepatic TG production could lead to compensatory mechanisms, including increased hepatic TG uptake via lipoprotein receptors. GCE (20 mg/day) administered 40 days orally to female C57BL/6Rj mice on a standard chow diet led to a decrease in both plasma fasting and post-prandial TG-rich lipoprotein levels, but with no significant change in body weight gain. Lipolysis stimulated lipoprotein receptor (LSR) protein levels, but not those of LDL-receptor, were increased as compared to controls. Mouse Hepa1-6 cells treated with the GCE active ingredient, hydroxycitrate, also led to increased LSR protein levels. Hepatic total cholesterol, TG, and muscle TG contents were higher in GCE-treated animals as compared to controls, whereas adipose TG levels were unchanged. LSR and LDL-receptor protein levels were correlated with liver total cholesterol, but only LDL-receptor was associated with liver TG. These results show that GCE treatment in mice on a standard chow diet led to significantly increased liver and muscle lipids, with no significant change in adipose tissue TG levels, which should be considered in the long-term use of GCE.

Nanosecond Laser Induced Surface Structuring of Cadmium after Ablation in Air and Propanol Ambient.

In the present study KrF Excimer laser has been employed to irradiate the Cadmium (Cd) targets for various number of laser pulses of 500, 1000, 1500 and 2000, at constant fluence of 3.6 J cm-2. Scanning Electron Microscopy (SEM) analysis was utilized to reveal the formation of laser induced nano/micro structures on the irradiated target (Cd) surfaces. SEM results show the generation of cavities, cracks, micro/nano wires/rods, wrinkles along with re-deposited particles during irradiation in air, whereas subsurface boiling, pores, cavities and Laser Induced Periodic Surface Structures (LIPSS) on the inner walls of cavities are revealed at the central ablated area after irradiation in propanol. The ablated volume and depth of ablated region on irradiated Cd targets are evaluated for various number of pulses and is higher in air as compared to propanol ambient. Fast Fourier Transform Infrared spectroscopy (FTIR), Energy Dispersive X-ray Spectroscopy (EDS) and X-ray Diffraction (XRD) analyses show the presence of oxides and hydro-oxides of Cd after irradiation in propanol, whereas the existence of oxides is observed after irradiation in air ambient. Nano-hardness tester was used to investigate mechanical modifications of ablated Cd. It reveals an increase in hardness after irradiation which is more pronounced in propanol as compared to air.

Lacticaseibacillus rhamnosus FM9 and Limosilactobacillus fermentum Y57 Are as Effective as Statins at Improving Blood Lipid Profile in High Cholesterol, High-Fat Diet Model in Male Wistar Rats.

Elevated serum cholesterol is a major risk factor for coronary heart diseases. Some Lactobacillus strains with cholesterol-lowering potential have been isolated from artisanal food products. The purpose of this study was to isolate probiotic Lactobacillus strains from traditional yoghurt (dahi) and yogurt milk (lassi) and investigate the impact of these strains on the blood lipid profile and anti-obesity effect in a high cholesterol high fat diet model in Wistar rats. Eight candidate probiotic strains were chosen based on in vitro probiotic features and cholesterol reduction ability. By 16S rDNA sequencing, these strains were identified as Limosilactibacillus fermentum FM6, L. fermentum FM16, L. fermentum FM12, Lacticaseibacillus rhamnosus FM9, L. fermentum Y55, L. fermentum Y57, L. rhamnosus Y59, and L. fermentum Y63. The safety of these strains was investigated by feeding 2 × 108 CFU/mL in saline water for 28 days in a Wistar rat model. No bacterial translocation or any other adverse effects were observed in animals after administration of strains in water, which indicates the safety of strains. The cholesterol-lowering profile of these probiotics was evaluated in male Wistar rats using a high-fat, high-cholesterol diet (HFCD) model. For 30 days, animals were fed probiotic strains in water with 2 × 108 CFU/mL/rat/day, in addition to a high fat, high cholesterol diet. The cholesterol-lowering effects of various probiotic strains were compared to those of statin. All strains showed improvement in total cholesterol, LDL, HDL, triglycerides, and weight gain. Serum cholesterol levels were reduced by 9% and 8% for L. rhamnosus FM9 and L. fermentum Y57, respectively, compared to 5% for the statin-treated group. HDL levels significantly improved by 46 and 44% for L. rhamnosus FM9 and L. fermentum Y57, respectively, compared to 46% for the statin-treated group. Compared to the statin-treated group, FM9 and Y57 significantly reduced LDL levels by almost twofold. These findings show that these strains can improve blood lipid profiles as effectively as statins in male Wistar rats. Furthermore, probiotic-fed groups helped weight control in animals on HFCD, indicating the possible anti-obesity potential of these strains. These strains can be used to develop food products and supplements to treat ischemic heart diseases and weight management. Clinical trials, however, are required to validate these findings.

Use of cubic structure with primitive nanochannels for fabrication of free standing 3D nanowire network of Pt withPm3msymmetry.

In this work, we developed a lipid mixture based on phytantriol / polyoxyethylene surfactant (Brij-56) that forms aIm3msymmetry bicontinuous cubic phase based on the Schwartz primitive surface (QIIP), from which we templated highly ordered 3D nanoporous platinum with a novel 'single primitive' morphology (Pm3msymmetry). TheQIIPtemplate phase is obtained by incorporation of 17.5% w/w Brij-56 (C16EO10) (a type-I surfactant) into phytantriol under excess hydration conditions. Phytantriol alone forms the double diamondQIID(Pn3m) phase, and in previous studies incorporating Brij-56 at different compositions the cubic phase maintained this morphology, but increased its lattice parameter; mesoporous metals templated from theseQIIDlipid templates all exhibited the 'single diamond' (Fd3m) morphology. In contrast, the current paper presents the availability of ourQIIPcubic phases to template nanoporous materials of single primitivePm3mmorphology via chemical and electrochemical methods. To explore the structure porosity and morphological features of the templated Pt material, x-ray scattering and transmission electron microscopy are used. The resulting 3D nanoporous Pt materials are found to exhibit a regular network of Pt nanowires of âˆ¼4 nm in diameter with a unit cell dimension of 14.8 ± 0.8 nm, reflecting the aqueous network within theQIIPtemplate.

Climate beast: a potential threat for repercussions of disease status in Pakistan.

Pakistan is amongst the developing countries, which have been strongly affected by several emerging and re-emerging disease outbreaks as a consequence of climate change. Various studies have clearly demonstrated the impact of climate change on human health in Pakistan. This has increased the rate of morbidity and mortality, related not only to vector-borne, water-borne and food-borne diseases but has also contributed to the prevalence of neurological, cardiovascular and respiratory disorders. It is therefore important to take adequate measurements for water management and improve sanitary conditions especially in case of natural disasters. In order to effectively control the emerging and re-emerging infections in the country, an early, more Rigorous response is required, by the national health department, to monitor and evaluate the spread of infections in future. Therefore, precise planning and management strategies should be defined in order to circumvent the damage caused by the natural disasters associated with climate changes. This mini-review gives an overview about the public health issues associated with environmental change with special reference to Pakistan. This will provide a baseline for policymakers to develop public health surveillance programs in Pakistan.

Lactoferrin as an antimicrobial against Salmonella enterica and Escherichia coli O157:H7 in raw milk.

Improper storage conditions or processing of milk leads to potential spoilage and illness, due in part to temperature abuse, allowing bacteria present to grow and spoil the product. However, certain proteins naturally found in raw milk, such as lactoferrin, have reported antibacterial properties. The levels of lactoferrin required to effectively inhibit growth of pathogens have not been investigated thoroughly. This study aimed to examine various concentrations of lactoferrin as a potential biopreservative and as an antimicrobial against the common dairy pathogens Salmonella enterica and Escherichia coli O157:H7. Minimum inhibitory concentration assays were conducted on raw bovine milk in which the bacteria were exposed to varying concentrations of lactoferrin. In the raw milk system, the growth of E. coli O157:H7 was significantly decreased at levels greater than 14.05 mg/mL lactoferrin based on the reduction of tetrazolium salts. For S. enterica, only lactoferrin concentrations at or above 112.5 mg/mL in the milk resulted in reduced growth. Taken together, these results indicate that lactoferrin may have biopreservative potential. To fully examine the practicality and effectiveness of lactoferrin as an antimicrobial additive, a similar study should be conducted using additional (gram-positive) pathogens, such as Bacillus cereus and Listeria monocytogenes. If effective, lactoferrin could prolong the shelf life of dairy products and help reduce the incidence of foodborne illnesses in developing countries with limited refrigeration capability.

Opportunistic physiology: inserting physiology and pathophysiology content into virtually delivered clinical rotations.

It is important to reinforce physiology and pathophysiology concepts during clinical rotations, which traditionally occur after the foundational sciences in the US medical school system. We took an opportunistic approach when the COVID-19 pandemic forced our content into virtual delivery mode, as clinical medical education required a shift to nonpatient contact. We describe our experience in building a 2-wk course that consisted of online small groups during week 1 and panels and cases during week 2. The physiology content involved faculty-vetted resources, along with both discrete and open-ended focus questions for each learning objective. The course also included mechanical ventilation, and the physiologist utilized discussion points and developed a formative quiz to emphasize the physiology correlates, in addition to the very clinical aspects of mechanical ventilation. There were pathophysiology opportunities with pneumonia, acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple-organ system dysfunction among the clinical correlates. Review and recall of the foundational sciences occurred, allowing links between the pre-clerkship and clerkship years that were previously undiscovered in our institution. This virtually delivered medical curriculum related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 is timely, carries high student interest, and can benefit medical students and the communities they serve.

Epistatic interaction of apolipoprotein E and lipolysis-stimulated lipoprotein receptor genetic variants is associated with Alzheimer's disease.

The ε4 allele of the apolipoprotein E (APOE) gene common polymorphism is the strongest genetic risk factor for Alzheimer's disease (AD). Human APOE gene is located on chromosome 19q13.1, a region linked to AD that also includes the LSR gene, which encodes the lipolysis-stimulated lipoprotein receptor (LSR). As an APOE receptor, LSR is involved in the regulation of lipid homeostasis in both periphery and brain. This study aimed to determine the potential interactions between 2 LSR genetic variants, rs34259399 and rs916147, and the APOE common polymorphism in 142 AD subjects (mean age: 73.16 ± 8.50 years) and 63 controls (mean age: 70.41 ± 8.49 years). A significant epistatic interaction was observed between APOE and both LSR variants, rs34259399 (beta = -0.95; p = 2 × 10-5) and rs916147 (beta = -0.83; p = 6.8 × 10-3). Interestingly, the interaction of LSR polymorphisms with APOE non-ε4 alleles increased AD risk. This indicates the existence of complex molecular interactions between these 2 neighboring genes involved in the pathogenesis of AD, which merits further investigation.

Ultrathin Uniform Platinum Nanowires via a Facile Route Using an Inverse Hexagonal Surfactant Phase Template.

We present an attractive method for the fabrication of long, straight, highly crystalline, ultrathin platinum nanowires. The fabrication is simply achieved using an inverse hexagonal (HII) lyotropic liquid crystal phase of the commercial surfactant phytantriol as a template. A platinum precursor dissolved within the cylindrical aqueous channels of the liquid crystal phase is chemically reduced by galvanic displacement using stainless steel. We demonstrate the production of nanowires using the HII phase in the phytantriol/water system which we obtain either by heating to 55 °C or at room temperature by the addition of a hydrophobic liquid, 9- cis-tricosene, to relieve packing frustration. The two sets of conditions produced high aspect nanowires with diameters of 2.5 and 1.7 nm, respectively, at least hundreds of nanometers in length, matching the size of the aqueous channels in which they grow. This versatile approach can be extended to produce highly uniform nanowires from a range of metals.

The future of telomere length in personalized medicine.

Telomere length has been subject of studies for many decades, aiming to elucidate its role in physiological processes, in process of aging and in diverse pathologies. Yet today, there is still no "big title" discovery that would lead to a practical use of telomeres as a reliable biomarker or target for a new drug. However, therapies for chronic disease patients are being tested and companies are already offering commercial tests for telomere length measurement. The strong genetic heritability of telomeres is opening the place for pharmacogenomics researches that could promote the personalized treatment of diverse diseases. In this article, we present the recent knowledge of telomeres genetic determination obtained by genome-wide association studies (GWAS), important biomarkers related to telomere length and review the possibilities of telomere's practical implementation in the medical treatment of diverse diseases and as a potential biomarker in personalized medicine. Furthermore, we summarise commercial offers of telomere length measurements available and we discuss the actions that should be taken to make steps forward into final application of the accumulated knowledge into practical use.

Phytantriol based smart nano-carriers for drug delivery applications.

From the last couple of decades, lyotropic liquid crystals have garnered enormous attentions in medical and pharmaceutical sciences. Non-toxic, chemically stable, and biocompatible properties of these liquid crystal systems are contributing to their applications for drug delivery. Among a large variety of liquid crystal phases, inverse bicontinuous cubic and inverse hexagonal mesophases have been extensively investigated for their ability to encapsulate and controlled release of bioactive molecules of various sizes and polarity. The concept of changing the drug release rate in situ by simply changing the mesophase structure is much more fascinating. The encapsulation of bioactive compounds in mesophase systems of desirable features in sub-micron sized particles such as hexosomes and cubosomes, at ambient and high temperature is bringing innovation in the development of new drug applications. This review article outlines unique structural features of cubosomes and hexosomes, their methods of productions, factors affecting their formations and their potential utilization as smart nano-carriers for biopharmaceuticals in drug delivery applications.

Expression profile of hepatic genes related to lipid homeostasis in LSR heterozygous mice contributes to their increased response to high-fat diet.

Perturbations of lipid homeostasis manifest as dyslipidemias and obesity, which are significant risk factors for atherosclerosis and diabetes. Lipoprotein receptors in the liver are key players in the regulation of lipid homeostasis, among which the hepatic lipolysis stimulated lipoprotein receptor, LSR, was recently shown to play an important role in the removal of lipoproteins from the circulation during the postprandial phase. Since heterozygous LSR+/- mice demonstrate moderate dyslipidemia and develop higher body weight gain in response to high-fat diet compared with littermate LSR+/+ controls, we questioned if LSR heterozygosity could affect genes related to hepatic lipid metabolism. A target-specific qPCR array for 84 genes related to lipid metabolism was performed on mRNA isolated from livers of 6 mo old female LSR+/- mice and LSR+/+ littermates following a 6 wk period on a standard (STD) or high-fat diet (60% kcal, HFD). Of the 84 genes studied, 32 were significantly downregulated in STD-LSR+/- mice compared with STD-LSR+/+, a majority of which were PPARα target genes involved in lipid metabolism and transport, and insulin and adipokine-signaling pathways. Of these 32 genes, 80% were also modified in HFD-LSR+/+, suggesting that STD-LSR+/- mice demonstrated a predisposition towards a "high-fat"-like profile, which could reflect dysregulation of liver lipid homeostasis. Since similar profiles of genes were affected by either LSR heterozygosity or by high-fat diet, this would suggest that LSR is a key receptor in regulating hepatic lipid homeostasis, and whose downregulation combined with a Western-type diet may increase predisposition to diet-induced obesity.

Multiple Plasmids Contribute to Antibiotic Resistance and Macrophage Survival In Vitro in CMY2-Bearing Salmonella enterica.

Multiple drug resistance (MDR) in bacteria represents a notable problem but if carried on plasmid their spread could become a significant threat to public health. Plasmids in members of the Enterobacteriaceae family and in particular Salmonella and Escherichia coli strains have been implicated in the spread of antibiotic resistance genes. However, the mechanisms involved in the transfer of plasmid-borne resistance genes are not fully understood. Here, we analyzed the ability of Salmonella enterica clinical isolates to transfer plasmid-borne MDR to E. coli. We also determined whether possession of an Inc A/C plasmid by a S. enterica isolate would confer increased fitness compared to an isolate not carrying the plasmid. Sixteen human and animal isolates of S. enterica were screened using a three-panel multiplex PCR assay, and simplex PCR for the blaCMY-2 gene. Using these data we selected a suitable strain as a plasmid donor for the construction of a new Salmonella strain with an Inc A/C plasmid. This allowed us to compare isogenic strains with and without the Inc A/C plasmid in multiple growth, fitness, and invasion assays. The results showed that possession of Inc A/C plasmid confers significant fitness advantage when tested in J774 macrophages as opposed to HEp-2 cells where no significant difference was found. In addition, stress assays performed in vitro showed that the possession of this large plasmid by Salmonella strains tested here does not appear to incur a significant fitness cost. Gaining a better understanding of molecular mechanisms of plasmid transfer between pathogenic bacteria will allow us to characterize the role of MDR in pathogenicity of bacteria and to identify methods to reduce the frequency of dissemination of multiple antibiotic resistance genes.

Experimental Evidence for Proposed Transformation Pathway from the Inverse Hexagonal to Inverse Diamond Cubic Phase from Oriented Lipid Samples.

A macroscopically oriented inverse hexagonal phase (HII) of the lipid phytantriol in water is converted to an oriented inverse double diamond bicontinuous cubic phase (QII(D)). The initial HII phase is uniaxially oriented about the long axis of a capillary with the cylinders parallel to the capillary axis. The HII phase is converted by cooling to a QII(D) phase which is also highly oriented, where the cylindrical axis of the former phase has been converted to a ⟨110⟩ axis in the latter, as demonstrated by small-angle X-ray scattering. This epitaxial relationship allows us to discriminate between two competing proposed geometric pathways to convert HII to QII(D). Our findings also suggest a new route to highly oriented cubic phase coatings, with applications as nanomaterial templates.

Inhibitory action of benzo[α]pyrene on hepatic lipoprotein receptors in vitro and on liver lipid homeostasis in mice.

BACKGROUND: Dyslipidemia associated with obesity often manifests as increased plasma LDL and triglyceride-rich lipoprotein levels suggesting changes in hepatic lipoprotein receptor status. Persistent organic pollutants have been recently postulated to contribute to the obesity etiology by increasing adipogenesis, but little information is available on their potential effect on hepatic lipoprotein metabolism. OBJECTIVE: The objective of this study was to investigate the effect of the common environmental pollutant, benzo[α]pyrene (B[α]P) on two lipoprotein receptors, the LDL-receptor and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP-binding cassette transporter A1 (ABCA1) using cell and animal models. RESULTS: LSR, LDL-receptor as well as ABCA1 protein levels were significantly decreased by 26-48% in Hepa1-6 cells incubated (<2 h) in the presence of B[α]P (≤1 µM). Real-time PCR analysis and lactacystin studies revealed that this effect was due primarily to increased proteasome, and not lysosomal-mediated degradation rather than decreased transcription. Furthermore, ligand blots revealed that lipoproteins exposed to 1 or 5 µM B[α]P displayed markedly decreased (42-86%) binding to LSR or LDL-receptor. B[α]P-treated (0.5 mg/kg/48 h, i.p. 15 days) C57BL/6J mice displayed higher weight gain, associated with significant increases in plasma cholesterol, triglycerides, and liver cholesterol content, and decreased hepatic LDL-receptor and ABCA1 levels. Furthermore, correlational analysis revealed that B[α]P abolished the positive association observed in control mice between the LSR and LDL-receptor. Interestingly, levels of other proteins involved in liver cholesterol metabolism, ATP-binding cassette transporter G1 and scavenger receptor-BI, were decreased, while those of acyl-CoA:cholesterol acyltransferase 1 and 2 were increased in B[α]P-treated mice. CONCLUSIONS: B[α]P demonstrates inhibitory action on LSR and LDL-R, as well as ABCA1, which we propose leads to modified lipid status in B[α]P-treated mice, thus providing new insight into mechanisms underlying the involvement of pollutants in the disruption of lipid homeostasis, potentially contributing to dyslipidemia associated with obesity.

Lactoferrin and its hydrolysate bind directly to the oleate-activated form of the lipolysis stimulated lipoprotein receptor.

The hepatic removal of triglyceride-rich chylomicrons during the postprandial phase represents an important step towards determining the bioavailability of dietary lipids amongst the peripheral tissues. Indeed, elevated postprandial lipemia is often associated with obesity and increased risk of coronary heart disease. The milk protein, lactoferrin, has been shown to inhibit hepatic chylomicron remnant removal by the liver, resulting in increased postprandial lipemia. Despite numerous studies on potential targets for lactoferrin, the molecular mechanisms underlying the effect of lactoferrin remain unclear. We recently demonstrated that the lipolysis stimulated lipoprotein receptor (LSR) contributes to the removal of triglyceride-rich lipoproteins during the postprandial phase. Here, we report that while lactoferrin does not have any significant effect on LSR protein levels in mouse Hepa1-6 cells, this protein colocalizes with LSR in cells but only in the presence of oleate, which is needed to obtain LSR in its active form as lipoprotein receptor. Ligand blotting using purified LSR revealed that lactoferrin binds directly to the receptor in the presence of oleate and prevents the binding of triglyceride-rich lipoproteins. Both C- and N-lobes of lactoferrin as well as a mixture of peptides derived from its hydrolysis retained the ability to bind LSR in its active form. We propose then that the elevated postprandial lipemia observed upon lactoferrin treatment in vivo is mediated in part by its direct interaction with free fatty acid activated LSR, thus preventing clearance of chylomicrons and their remnants through the LSR pathway.

Increased resistance to multiple antimicrobials and altered resistance gene expression in CMY-2-positive Salmonella enterica following a simulated patient treatment with ceftriaxone.

Salmonellosis is one of the most common causes of food-borne disease in the United States. Increasing antimicrobial resistance and corresponding increases in virulence present serious challenges. Currently, empirical therapy for invasive Salmonella enterica infection includes either ceftriaxone or ciprofloxacin (E. L. Hohmann, Clin. Infect. Dis. 32:263-269, 2001). The bla(CMY-2) gene confers resistance to ceftriaxone, the antimicrobial of choice for pediatric patients with invasive Salmonella enterica infections, making these infections especially dangerous (J. M. Whichard et al., Emerg. Infect. Dis. 11:1464-1466, 2005). We hypothesized that bla(CMY-2)-positive Salmonella enterica would exhibit increased MICs to multiple antimicrobial agents and increased resistance gene expression following exposure to ceftriaxone using a protocol that simulated a patient treatment in vitro. Seven Salmonella enterica strains survived a simulated patient treatment in vitro and, following treatment, exhibited a significantly increased ceftriaxone MIC. Not only would these isolates be less responsive to further ceftriaxone treatment, but because the bla(CMY-2) genes are commonly located on large, multidrug-resistant plasmids, increased expression of the bla(CMY-2) gene may be associated with increased expression of other drug resistance genes located on the plasmid (N. D. Hanson and C. C. Sanders, Curr. Pharm. Des. 5:881-894, 1999). The results of this study demonstrate that a simulated patient treatment with ceftriaxone can alter the expression of antimicrobial resistance genes, including bla(CMY-2) and floR in S. enterica serovar Typhimurium and S. enterica serovar Newport. Additionally, we have shown increased MICs following a simulated patient treatment with ceftriaxone for tetracycline, amikacin, ceftriaxone, and cefepime, all of which have resistance genes commonly located on CMY-2 plasmids. The increases in resistance observed are significant and may have a negative impact on both public health and antimicrobial resistance of Salmonella enterica.