Antibacterial and Antifungal Activities of Poloxamer Micelles Containing Ceragenin CSA-131 on Ciliated Tissues.

Ceragenins were designed as non-peptide mimics of endogenous antimicrobial peptides, and they display broad-spectrum antibacterial and antifungal activities, including the ability to eradicate established biofilms. These features of ceragenins make them attractive potential therapeutics for persistent infections in the lung, including those associated with cystic fibrosis. A characteristic of an optimal therapeutic for use in the lungs and trachea is the exertion of potent antimicrobial activities without damaging the cilia that play a critical role in these tissues. In previous work, potent antimicrobial activities of ceragenin CSA-131 have been reported; however, we found in ex vivo studies that this ceragenin, at concentrations necessary to eradicate established biofilms, also causes loss of cilia function. By formulating CSA-131 in poloxamer micelles, cilia damage was eliminated and antimicrobial activity was unaffected. The ability of CSA-131, formulated with a poloxamer, to reduce the populations of fungal pathogens in tracheal and lung tissue was also observed in ex vivo studies. These findings suggest that CSA-131, formulated in micelles, may act as a potential therapeutic for polymicrobial and biofilm-related infections in the lung and trachea.

Family Structure and Child Behavior Problems in Australia, the United Kingdom, and the United States.

A large body of literature suggests that children living with two married, biological parents on average have fewer behavior problems than those who do not. What is less clear is why this occurs. Competing theories suggest that resource deficiencies and parental selectivity play a part. We suggest that examining different contexts can help adjudicate among different theoretical explanations as to how family structure relates to child behavior problems. In this paper, we use data from the Growing Up in Australia: Longitudinal Study of Australian Children (LSAC), the UK Millennium Cohort Study (MCS), and the US Early Childhood Longitudinal Study (ECLS-K) to examine the relationship between family structure and child behavior problems. Specifically, we look at how living in several configurations of biological and social parents may relate to child behavior problems. Findings suggest both similarities and differences across the three settings, with explanations in the UK results favoring selectivity theories, US patterns suggesting that there is a unique quality to family structure that can explain outcomes, and the Australian results favoring resource theories.

Gamma-Irradiation Reduces Survivorship, Feeding Behavior, and Oviposition of Female Aedes aegypti.

Aedes aegypti is a prominent disease vector that is difficult to control through traditional integrated vector management due to its cryptic peridomestic immature-stage habitat and adult resting behavior, increasing resistance to pesticide formulations approved by the US Environmental Protection Agency, escalating deregistration of approved pesticides, and slow development of new effective chemical control measures. One novel method to control Ae. aegypti is the sterile insect technique (SIT) that leverages the mass release of irradiated (sterilized) males to overwhelm mate choice of natural populations of females. However, one potential liability of SIT is sex sorting errors prior to irradiation, resulting in accidental release of females. Our goal in this study was to test the extent to which irradiation affects female life-history parameters to assess the potential impacts of releasing irradiated females accidentally sorted with males. In this study, we determined that a radiation dose ≥30 Gy-a dose sufficient to sterilize males while preserving their mating competitiveness-may substantially impact longevity, bloodfeeding, oviposition, and egg hatch rate of female Ae. aegypti after being irradiated as pupae. These findings could reduce public concern for accidental release of females alongside irradiated males in an operational Ae. aegypti SIT control program.

Proteomic Analysis of Resistance of Gram-Negative Bacteria to Chlorhexidine and Impacts on Susceptibility to Colistin, Antimicrobial Peptides, and Ceragenins.

Use of chlorhexidine in clinical settings has led to concerns that repeated exposure of bacteria to sub-lethal doses of chlorhexidine might result in chlorhexidine resistance and cross resistance with other cationic antimicrobials including colistin, endogenous antimicrobial peptides (AMPs) and their mimics, ceragenins. We have previously shown that colistin-resistant Gram-negative bacteria remain susceptible to AMPs and ceragenins. Here, we investigated the potential for cross resistance between chlorhexidine, colistin, AMPs and ceragenins by serial exposure of standard strains of Gram-negative bacteria to chlorhexidine to generate resistant populations of organisms. Furthermore, we performed a proteomics study on the chlorhexidine-resistant strains and compared them to the wild-type strains to find the pathways by which bacteria develop resistance to chlorhexidine. Serial exposure of Gram-negative bacteria to chlorhexidine resulted in four- to eight-fold increases in minimum inhibitory concentrations (MICs). Chlorhexidine-resistant organisms showed decreased susceptibility to colistin (8- to 32-fold increases in MICs) despite not being exposed to colistin. In contrast, chlorhexidine-resistant organisms had the same MICs as the original strains when tested with representative AMPs (LL-37 and magainin I) and ceragenins (CSA-44 and CSA-131). These results imply that there may be a connection between the emergence of highly colistin-resistant Gram-negative pathogens and the prevalence of chlorhexidine usage. Yet, use of chlorhexidine may not impact innate immune defenses (e.g., AMPs) and their mimics (e.g., ceragenins). Here, we also show that chlorhexidine resistance is associated with upregulation of proteins involved in the assembly of LPS for outer membrane biogenesis and virulence factors in Pseudomonas aeruginosa. Additionally, resistance to chlorhexidine resulted in elevated expression levels of proteins associated with chaperones, efflux pumps, flagella and cell metabolism. This study provides a comprehensive overview of the evolutionary proteomic changes in P. aeruginosa following exposure to chlorhexidine and colistin. These results have important clinical implications considering the continuous application of chlorhexidine in hospitals that could influence the emergence of colistin-resistant strains.

Susceptibility of Multidrug-Resistant Bacteria, Isolated from Water and Plants in Nigeria, to Ceragenins.

The continuous emergence of multidrug resistant pathogens is a major global health concern. Although antimicrobial peptides (AMPs) have shown promise as a possible means of combatting multidrug resistant strains without readily engendering resistance, costs of production and targeting by proteases limit their utility. Ceragenins are non-peptide AMP mimics that overcome these shortcomings while retaining broad-spectrum antimicrobial activity. To further characterize the antibacterial activities of ceragenins, their activities against a collection of environmental isolates of bacteria were determined. These isolates were isolated in Nigeria from plants and water. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of selected ceragenins and currently available antimicrobials against these isolates were measured to determine resistance patterns. Using scanning electron microscopy (SEM), we examined the morphological changes in bacterial membranes following treatment with ceragenins. Finally, we investigated the effectiveness of ceragenins in inhibiting biofilm formation and destroying established biofilms. We found that, despite high resistance to many currently available antimicrobials, including colistin, environmental isolates in planktonic and biofilm forms remain susceptible to ceragenins. Additionally, SEM and confocal images of ceragenin-treated cells confirmed the effective antibacterial and antibiofilm activity of ceragenins.

Molecular detection of severe fever with thrombocytopenia syndrome and tick-borne encephalitis viruses in ixodid ticks collected from vegetation, Republic of Korea, 2014.

Ticks play an important role in transmission of arboviruses responsible for emerging infectious diseases, and have a significant impact on human, veterinary, and wildlife health. In the Republic of Korea (ROK), little is known about information regarding the presence of tick-borne viruses and their vectors. A total of 21,158 ticks belonging to 3 genera and 6 species collected at 6 provinces and 4 metropolitan areas in the ROK from March to October 2014 were assayed for selected tick-borne pathogens. Haemaphysalis longicornis (n=17,570) was the most numerously collected, followed by Haemaphysalis flava (n=3317), Ixodes nipponensis (n=249), Amblyomma testudinarium (n=11), Haemaphysalis phasiana (n=8), and Ixodes turdus (n=3). Ticks were pooled (adults 1-5, nymphs 1-30, and larvae 1-50) and tested by one-step reverse transcription polymerase chain reaction (RT-PCR) or nested RT-PCR for the detection of severe fever with thrombocytopenia virus (SFTSV), tick-borne encephalitis virus (TBEV), Powassan virus (POWV), Omsk hemorrhagic fever virus (OHFV), and Langat virus (LGTV). The overall maximum likelihood estimation (MLE) [estimated numbers of viral RNA positive ticks/1000 ticks] for SFTSV and TBEV was 0.95 and 0.43, respectively, while, all pools were negative for POWV, OHFV, and LGTV. The purpose of this study was to determine the prevalence of SFTSV, TBEV, POWV, OHFV, and LGTV in ixodid ticks collected from vegetation in the ROK to aid our understanding of the epidemiology of tick-borne viral diseases. Results from this study emphasize the need for continuous tick-based arbovirus surveillance to monitor the emergence of tick-borne diseases in the ROK.