Repurposing medications for use in treating HIV infection: A focus on valproic acid as a latency-reversing agent.

WHAT IS KNOWN AND OBJECTIVE: Combined antiretroviral therapy (ART) reduces human immunodeficiency virus type 1 (HIV-1) RNA plasma levels below the limit of detection. However, HIV-1 persists in latently infected CD4+ T cells, which is currently the barrier to curing HIV-1. Novel mechanisms are being explored to target HIV-1 latent reservoirs. The purpose of this review was to critically evaluate the available literature on innovative use of valproic acid (VPA) for the agent's therapeutic effects on reversing latent human immunodeficiency virus (HIV) reservoirs. METHODS: A search of PubMed (1996-December 2017) and International Pharmaceutical Abstracts (1970-December 2017) was conducted using the MeSH terms HIV, valproic acid and latency. Free text searches included the terms latency-reversing agents, HIV therapy and valproic acid. RESULTS: Six clinical trials and one case report were critically evaluated on VPA's therapeutic effects on reversing HIV reservoirs. Only one study reported that VPA therapy has a significant effect on reversing HIV-1 latent reservoirs; all other studies reviewed and did not demonstrate an appreciable effect of VPA on reversing HIV latent reservoirs. WHAT IS NEW AND CONCLUSION: Current literature does not support the use of VPA as adjunctive therapy to reverse HIV-1 latent reservoirs. Sample sizes were small, and overall studies were not sufficiently powered. Further studies are needed to make informed conclusions on the use of VPA as an HIV-1 latency-reversing agent.

Perceptions of anonymised data use and awareness of the NHS data opt-out amongst patients, carers and healthcare staff.

BACKGROUND: England operates a National Data Opt-Out (NDOO) for the secondary use of confidential health data for research and planning. We hypothesised that public awareness and support for the secondary use of health data and the NDOO would vary by participant demography and healthcare experience. We explored patient/public awareness and perceptions of secondary data use, grouping potential researchers into National Health Service (NHS), academia or commercial. We assessed awareness of the NDOO system amongst patients, carers, healthcare staff and the public. We co-developed recommendations to consider when sharing unconsented health data for research. METHODS: A patient and public engagement program, co-created and including patient and public workshops, questionnaires and discussion groups regarding anonymised health data use. RESULTS: There were 350 participants in total. Central concerns for health data use included unauthorised data re-use, the potential for discrimination and data sharing without patient benefit. 94% of respondents were happy for their data to be used for NHS research, 85% for academic research and 68% by health companies, but less than 50% for non-healthcare companies and opinions varied with demography and participant group. Questionnaires showed that knowledge of the NDOO was low, with 32% of all respondents, 53% of all NHS staff and 29% of all patients aware of the NDOO. Recommendations to guide unconsented secondary health data use included that health data use should benefit patients; data sharing decisions should involve patients/public. That data should remain in close proximity to health services with the principles of data minimisation applied. Further, that there should be transparency in secondary health data use, including publicly available lists of projects, summaries and benefits. Finally, organisations involved in data access decisions should participate in programmes to increase knowledge of the NDOO, to ensure public members were making informed choices about their own data. CONCLUSION: The majority of participants in this study reported that the use of healthcare data for secondary purposes was acceptable when accessed by NHS. Academic and health-focused companies. However, awareness was limited, including of the NDOO. Further development of publicly-agreed recommendations for secondary health data use may improve both awareness and confidence in secondary health data use.

Health data from routine care can be pseudonymised (with a link remaining to the patient but identifying features removed) or anonymised (with identifying features removed and the link to the patient severed) and used for research and health planning; termed "secondary use". The National Health Service (NHS) is a single publicly-funded health service for the United Kingdom (UK). The NHS supports secondary data use with a National Data opt-out system. The potential benefits of data secondary use are clear but concerns have been raised. Although the Data Opt-Out is publicised, it is unclear how much public awareness there is of this scheme. We report a patient and publicly created and delivered series of activities including > 350 people; with young adults, patients, NHS staff and the public; to assess concerns, knowledge and acceptance of data sharing.Perceptions of and support for secondary health data use varied depending on who was asked (by age, gender) and their experience of health services (Staff member, patient, member of the public). Knowledge of schemes to limit secondary data use (such as the UK National Data Op-Out) was low, even among NHS staff. The main concerns of sharing health data included onward data use, the potential for discrimination and exploitation and commercial gain from data use with no benefit to patients. Despite this, most participants agreed with health data sharing with NHS, academic and commercial health-based entities. Agreed, co-created themes to increase the acceptability of health data secondary use included education about 'Opt-out' schemes, health service oversight of data use (as the most trusted partner), public and patient involvement in data sharing decisions and public transparency.

Potential for manipulation of the rumen fermentation through the use of recombinant DNA techniques.

Recombinant DNA techniques offer a new approach to the study and eventual genetic manipulation of rumen bacteria to modify the rate and extent of nutrient digestion within the rumen. The foreign genes cloned into a rumen bacterium undoubtedly will have to enhance its ability to compete; otherwise, the new trait will be lost from the highly competitive environment within the rumen. As a general rule, the types of metabolic activities amenable to gene cloning may be those that enhance substrate versatility or eliminate a dependence of a specific rumen bacteria on cross-feeding by other rumen microorganisms. Enhanced substrate diversity and bypassing cross-feeding probably will become more important as the use of highly refined feeds and waste materials from the food and other industries are used in greater quantities to meet the dietary needs of ruminants.

A review of ectoparasites and their effect on cattle production.

Losses in livestock production due to ectoparasite infestations exceed $2.26 billion annually. Over 50 species of ectoparasites infest cattle throughout the United States. The horn fly, Haematobia irritans (L.), is the most important and widespread of the five to six major pest species of pastured cattle in the southern region. Results from the examination of production traits from cattle under ectoparasite burdens have been variable, ranging from no effect to significant reductions in weight gains. Because of this inconsistency, specific physiological and nutritional responses in cattle infested or not infested with horn flies have been examined. Data have shown significant differences in nitrogen retention, blood cortisol concentrations, vital signs, water consumption, and urine production. Implications are that total energy balance is altered when an animal is exposed to ectoparasite infestations, thereby resulting in decreased productivity.

Comparing and assessing acid rain-sensitive ponds.

Changes in pH and temperature were monitored in two freshwater ponds in Southeastern Massachusetts from 1990 to 1993 using a remote-sensing system that collected data on a continuous basis. The sensing system included a combination electrode, pH meter and portable computer powered by a marine battery. Temperature and pH information from the pH meter were acquired every 10 min and stored in the computer. The two ponds, located within 2 km of one another, have a different average pH and sensitivity to acid precipitation. Maquan Pond has an average pH of 6.0 and an alkalinity of 7.4 mg/l, while Furnace Pond has an average pH of 6.9 and alkalinity of 14.9 mg/l. The pH of both ponds varied seasonally and showed diel changes due to the photosynthetic and respiratory activity of aquatic organisms. Precipitation events did not change the pH of Furnace Pond. Maquan Pond on the other hand, did exhibit changes in surface water pH due to specific acidic precipitation events. During certain rainstorms, the pH of Maquan surface waters dropped to values as low as pH 4. In addition to the transient changes in pH, the acid-sensitive pond also exhibited differences in planktonic distribution patterns.

Bioassay for detecting active site insensitivity in horn fly (Diptera: Muscidae) larvae.

A bioassay was used to detect active site insensitivity (knock-down resistance [kdr]) in pyrethroid resistant larvae of the horn fly, Haematobia irritans (L.). The larvae of the resistant population had KD50's 42.0-, 28.1- and 29.2-fold greater to permethrin, fenvalerate and lambda-cyhalothrin, respectively, compared with the susceptible population. In filter paper bioassays, resistant adult horn flies were 17 to 39.1 times less susceptible to the pyrethroids than susceptible adults at LC50. These results further document active site insensitivity as the major mechanism of pyrethroid resistance in the horn fly.

Permethrin metabolism in pyrethroid-resistant adults of the horn fly (Muscidae: Diptera).

The in vivo metabolism of topically applied 14C-permethrin was determined for adults of pyrethroid-resistant and -susceptible horn flies, Haematobia irritans (L.) at 1, 2, and 6 h after treatment. At 1 and 2 h after treatment, resistant horn flies had significantly higher internal levels of radioactivity (permethrin plus metabolites) compared with adults of the susceptible strain. Analysis of the internal extracts by thin-layer chromatography indicated no differences in the levels of permethrin. However, significantly higher levels of metabolites that co-chromatograph with 3-(2'- or 4'-hydroxyphenoxy)benzyl (1RS) cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate at 1 and 2 h after treatment and (1RS) cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid at 1 h after treatment. These results demonstrate that an enhanced penetration and metabolism are present during the early phases of permethrin intoxication. Enhanced metabolism may contribute to the ability of resistant horn flies to survive in the presence of pyrethroids.

Purification and characterization of a uracil-DNA glycosylase from the yeast. Saccharomyces cerevisiae.

An activity which releases free uracil from bacteriophage PBS1 DNA has been purified over 10,000 fold from extracts of Saccharomyces cerevisiae. The enzyme is active on both native and denatured PBS1 DNA and is active in the absence of divalent cation, and in the presence of 1 mM EDTA. The enzyme has a negative molecular weight of 27,800 as estimated by glycerol gradient centrifugation and gel filtration. Enzyme activity has been recovered after denaturation in SDS and electrophoresis in an SDS polyacrylamide gel. This analysis suggests that the enzyme consists of a single polypeptide chain of about 27,000 daltons. Normal levels of uracil-DNA glycosylase activity were found in partially purified extracts of the nitrous-acid sensitive rad18-2 mutant of yeast.

Characteristics of the endoglucanase encoded by a cel gene from Bacteroides succinogenes expressed in Escherichia coli.

A cel gene from Bacteroides succinogenes inserted into the vector pUC8 coded for an enzyme which exhibited high hydrolytic activity on carboxymethylcellulose, p-nitrophenylcellobioside, and lichenan and low activity on laminarin and xylan. The enzyme was not synthesized by the Escherichia coli host when cells were cultured in complex medium containing added glucose. In the absence of added glucose, the endoglucanase and cellobiosidase activities synthesized were partitioned into the periplasmic space during growth, and practically all enzyme was located in the periplasm when the stationary phase of growth was reached. The enzyme exhibited 17- and sixfold higher Km values for the hydrolysis of carboxymethylcellulose and lichenan, respectively, than did the extracellular endoglucanase complex from B. succinogenes. The Cel endoglucanase had a pH optimum similar to that of the B. succinogenes enzyme except that the range was narrower, and the Cel endoglucanase was more readily inactivated on exposure to high temperature, detergents, and certain metals. Its activity was stimulated by calcium and magnesium. Nondenaturing polyacrylamide gel electrophoresis at different acrylamide concentrations revealed the presence of three endoglucanase components, two with molecular weights of 43,000 and one with a molecular weight of 55,000.