Magnitude, distribution, risk factors and care-seeking behaviour of acute, self-reported gastrointestinal illness among US Army Soldiers: 2015.

Throughout history, acute gastrointestinal illness (AGI) has been a significant cause of morbidity and mortality among US service members. We estimated the magnitude, distribution, risk factors and care seeking behaviour of AGI among the active duty US Army service members using a web-based survey. The survey asked about sociodemographic characteristics, dining and food procurement history and any experience of diarrhoea in the past 30 days. If respondents reported diarrhoea, additional questions about concurrent symptoms, duration of illness, medical care seeking and stool sample submission were asked. Univariable and multivariable logistic regression were used to identify the factors associated with AGI and factors associated with seeking care and submitting a stool sample. The 30-day prevalence of AGI was 18.5% (95% CI 16.66-20.25), the incidence rate was 2.24 AGI episodes per person-year (95% CI 2.04-2.49). Risk factors included a region of residence, eating at the dining facility and eating at other on-post establishments. Individuals with AGI missed 2.7-3.7 days of work, which costs approximately $ 847 451 629 in paid wages. Results indicate there are more than 1 million cases of AGI per year among US Army Soldiers, which can have a major impact on readiness. We found that care-seeking behaviours for AGI are different among US Army Service Members than the general population. Army Service Members with AGI report seeking care and having a stool sample submitted less often, especially for severe (bloody) diarrhoea. Factors associated with seeking care included rank, experiencing respiratory symptoms (sore throat, cough), experiencing vomiting and missing work for their illness. Factors associated with submitting a stool sample including experiencing more than five loose stools in 24 h and not experiencing respiratory symptoms. US Army laboratory-based surveillance under-estimates service members with both bloody and non-bloody diarrhoea. To our knowledge, this is the first study to estimate the magnitude, distribution, risk factors and care-seeking behaviour of AGI among Army members. We determined Army service members care-seeking behaviours, AGI risk factors and stool sample submission rates are different than the general population, so when estimating burden of AGI caused by specific foodborne pathogens using methods like Scallan et al. (2011), unique multipliers must be used for this subset of the population. The study legitimises not only the importance of AGI in the active duty Army population but also highlights opportunities for public health leaders to engage in simple strategies to better capture AGI impact so more modern intervention strategies can be implemented to reduce burden and indirectly improve operational readiness across the Enterprise.

Estimate of the annual burden of foodborne illness in nondeployed active duty US Army Service Members: five major pathogens, 2010-2015.

In this study, we estimate the burden of foodborne illness (FBI) caused by five major pathogens among nondeployed US Army service members. The US Army is a unique population that is globally distributed, has its own food procurement system and a food protection system dedicated to the prevention of both unintentional and intentional contamination of food. To our knowledge, the burden of FBI caused by specific pathogens among the US Army population has not been determined. We used data from a 2015 US Army population survey, a 2015 US Army laboratory survey and data from FoodNet to create inputs for two model structures. Model type 1 scaled up case counts of Campylobacter jejuni, Shigella spp., Salmonella enterica non-typhoidal and STEC non-O157 ascertained from the Disease Reporting System internet database from 2010 to 2015. Model type 2 scaled down cases of self-reported acute gastrointestinal illness (AGI) to estimate the annual burden of Norovirus illness. We estimate that these five pathogens caused 45 600 (5%-95% range, 30 300-64 000) annual illnesses among nondeployed active duty US Army Service members. Of these pathogens, Norovirus, Campylobacter jejuni and Salmonella enterica non-typhoidal were responsible for the most illness. There is a tremendous burden of AGI and FBI caused by five major pathogens among US Army Soldiers, which can have a tremendous impact on readiness of the force. The US Army has a robust food protection program in place, but without a specific active FBI surveillance system across the Department of Defence, we will never have the ability to measure the effectiveness of modern, targeted, interventions aimed at the reduction of specific foodborne pathogens.

Murine models for evaluating antiretroviral therapy.

The pandemic of the acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus type 1 (HIV-1), requires rapid development of effective therapy and prevention. Analysis of candidate anti-HIV-1 drugs in animals is problematic since no ideal animal model for HIV-1 infection and disease exists. For many reasons, including small size, availability of inbred strains, immunological reagents, and lymphokines, murine systems have been used for in vivo analysis of antiretroviral agents. Here we review currently available murine models involving HIV-1 in transgenic mice and in chimeric mice reconstituted with human cells, as well as murine systems using retroviruses of the subfamily Oncovirinae rather than Lentivirinae. We report our results on various antiretroviral treatment strategies, including chemoprophylaxis after acute retroviral exposure, therapy of chronic viremia, quantitative analysis of combination therapy, and therapy during pregnancy and in the neonatal period aimed at preventing viremia in the offspring. Due to our highly effective postexposure treatment protocols with 3'-azido-3'-deoxythymidine (zidovudine) combined with recombinant human interferon-alpha A/D, retrovirus-inoculated mice developed immunity to the virus to which they were exposed, which will allow us to determine the nature of protective antiretroviral immunity in inbred mice.

Sir William Wilde and provision for the blind in nineteenth-century Ireland.

As Assistant Commissioner for the Census of Ireland Sir William Wilde worked as an early epidemiologist, providing information regarding the deaf-and-dumb and the blind in mid-nineteenth-century Ireland. As a social agitator he focussed the attention of the authorities to the plight of the blind and their inability to earn a living and support themselves. This paper highlights his contribution to the provision for the blind in Ireland.

Genetic interactions between naturally occurring alleles at quantitative trait loci and mutant alleles at candidate loci affecting bristle number in Drosophila melanogaster.

Previously, we mapped quantitative trait loci (QTL) affecting response to short-term selection for abdominal bristle number to seven suggestive regions that contain loci involved in bristle development and/or that have adult bristle number mutant phenotypes, and are thus candidates for bristle number QTL in natural populations. To test the hypothesis that the factors contributing to selection response genetically interact with these candidate loci, high and low chromosomes from selection lines were crossed to chromosomes containing wild-type or mutant alleles at the candidate loci, and the numbers of bristles were recorded in trans heterozygotes. Quantitative failure to complement, detected as a significant selection line*cross effect by analysis of variance, can be interpreted as evidence for allelism or epistasis between the factors on selected chromosomes and the candidate loci. Mutations at some candidate loci (bb, emc, h, Dl, Hairless) showed strong interactions with selected chromosomes, whereas others interacted weakly (ASC, abd, Scr) or not at all (N, mab, E(spl)). These results support the hypothesis that some candidate loci, initially identified through mutations of large effect on bristle number, either harbor or are close members in the same genetic pathway as variants that contribute to standing variation in bristle number.

High resolution mapping of genetic factors affecting abdominal bristle number in Drosophila melanogaster.

Factors responsible for selection response for abdominal bristle number and correlated responses in sternopleural bristle number were mapped to the X and third chromosome of Drosophila melanogaster. Lines divergent for high and low abdominal bristle number were created by 25 generations of artificial selection from a large base population, with an intensity of 25 individuals of each sex selected from 100 individuals of each sex scored per generation. Isogenic chromosome substitution lines in which the high (H) X or third chromosome were placed in an isogenic low (L) background were derived from the selection lines and from the 93 recombinant isogenic (RI) HL X and 67 RI chromosome 3 lines constructed from them. Highly polymorphic neutral roo transposable elements were hybridized in situ to the polytene chromosomes of the RI lines to create a set of cytogenetic markers. These techniques yielded a dense map with an average spacing of 4 cM between informative markers. Factors affecting bristle number, and relative viability of the chromosome 3 RI lines, were mapped using a multiple regression interval mapping approach, conditioning on all markers > or = 10 cM from the tested interval. Two factors with large effects on abdominal bristle number were mapped on the X chromosome and five factors on the third chromosome. One factor with a large effect on sternopleural bristle number was mapped to the X and two were mapped to the third chromosome; all factors with sternopleural effects corresponded to those with effects on abdominal bristle number. Two of the chromosome 3 factors with large effects on abdominal bristle number were also associated with reduced viability. Significant sex-specific effects and epistatic interactions between mapped factors of the same order of magnitude as the additive effects were observed. All factors mapped to the approximate positions of likely candidate loci (ASC, bb, emc, h, mab, Dl and E(spl), previously characterized by mutations with large effects on bristle number.

Charles Lucas and medical legislation in eighteenth century Ireland.

INTRODUCTION: Charles Lucas, apothecary, physician and MP, was instrumental in facilitating legislation in Ireland in 1765 that established a nationwide network of hospitals in Ireland. This legislation was unique in contemporary Europe, and by the end of the century, there was a hospital in every county in the country. MATERIALS AND METHODS: His work as an apothecary provided him with the knowledge to attempt to address the problems in the apothecaries' trade, and his 1741 pamphlet, Pharmacomastix, provided the framework for the 1761 Irish Apothecaries Act, which attempted to address these issues. It was, however, 1791 before nationwide regulation of the Irish apothecaries' trade was implemented following the establishment of the Apothecaries Hall, and this was 24 years before similar regulatory legislation was passed in Britain. Lucas sought enhanced regulation of the apothecaries' trade to provide better quality drugs and medicines for the general public, and he tried to ensure that untrained quacks did not practise as apothecaries, unbeknownst to their patients. He was aware that his proposals would meet with opposition, but he had the courage to pursue these without any element of personal gain. CONCLUSION: In medical terms, Charles Lucas was man ahead of his time.

Sir Patrick Dun and the Complete School of Physic in eighteenth-century Dublin.

INTRODUCTION: 2013 is the tercentenary of the death of Sir Patrick Dun. When Dun died in 1713, he left the proceeds of his estate to enhance medical education in Dublin by funding chairs in medicine. He showed remarkable innovation, but it took 95 years, five Acts of Parliament, two House of Commons enquiries and a House of Lords enquiry before Dun's wishes were brought to fruition and systematic clinical education was available for Dublin medical students. The passage of the final School of Physic Act in 1800 insured that a hospital would open in his name and regular clinical education was provided. The physician, Richard Steevens, who died 3 years earlier in 1710, left the proceeds of his estate to found a hospital, which opened, in his name, in 1733. MATERIALS AND METHODS: The contemporary primary sources have been analysed and material from relevant secondary sources has been included where appropriate. CONCLUSION: Dublin was the beneficiary of these bequests and if circumstances had been more favourable, and the proceeds had been used more efficiently at the start of the eighteenth-century, Dublin could well have rivalled Edinburgh as the seat of medical education in the eighteenth century. In the early nineteenth century, it would fulfil that role and equal Edinburgh as one of the primary centres of medical education in Europe.

In vivo analysis of castanospermine, a candidate antiretroviral agent.

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), an inhibitor of glycoprotein processing, has been shown to inhibit the human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured cells. In contrast to reverse transcriptase inhibitors, castanospermine targets host enzymes. We have analyzed castanospermine in murine systems, using cultured cells as well as live animals. Plaque formation by Rauscher murine leukemia virus (RLV) was inhibited with a median inhibitory concentration (IC50) of 2 micrograms/ml. RLV-exposed BALB/c mice treated with a 20 day course of castanospermine starting 4 h postinoculation showed a dose-dependent inhibition of splenomegaly. Oral castanospermine therapy given to chronically RLV-infected mice prolonged median survival from 36 to 94 days when compared to untreated controls (p = 0.007). Castanospermine was better tolerated orally than intraperitoneally at the same dose. Toxic effects included weight loss, lethargy, and dose-dependent thrombocytopenia. At the highest intraperitoneal dose, lymphoid depletion occurred in thymus, spleen, and lymph nodes. We conclude that castanospermine is an active antiviral agent in animals and that prolonged oral administration is tolerable; however, when compared to 3'-azido-3'-deoxythymidine in the same murine system, castanospermine was less active and more toxic.

Castanospermine vs. its 6-O-butanoyl analog: a comparison of toxicity and antiviral activity in vitro and in vivo.

Inhibitors of glycoprotein processing, such as castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), have been shown previously to inhibit human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured human cells. In prior experiments, we have tested the toxicity and antiviral efficacy of castanospermine in mice infected with the Rauscher murine leukemia virus (RLV). When compared with 3'-azido-3'-deoxythymidine (AZT, zidovudine), castanospermine was less effective and more toxic. Since the 6-O-butanoyl analog of castanospermine was previously found to have a more favorable activity profile than the parent compound against HIV-1 in cultured cells, we compared the antiviral efficacy of both compounds in parallel in vitro and in vivo in the RLV system. Plaque formation in the XC assay was inhibited with a 50% inhibitory concentration (IC50) of 2.4 microM for the 6-O-butanoyl analog of castanospermine, as compared to 9 microM for castanospermine. For both compounds, concentrations resulting in significant cytotoxicity were about ten times higher. Both compounds significantly decreased HIV-1 env-induced syncytium formation in a novel in vitro assay. In RLV-exposed mice, the 6-O-butanoyl analog showed no advantage over the parent compound: both curves for toxicity as well as antiviral efficacy were super-imposable. We conclude that the 6-O-butanoyl analog of castanospermine as well as castanospermine itself are active antiviral agents in mice and that prolonged oral administration is tolerable. However, in comparison to AZT, their antiviral activity profiles are less favorable.

Interferon-alpha and 3'-azido-3'-deoxythymidine are highly synergistic in mice and prevent viremia after acute retrovirus exposure.

This study was undertaken to calculate the in vivo drug interactions between recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) and 3'-azido-3'-deoxythymidine (AZT) in a quantitative model for retroviral viremia. When given as single agents, both AZT and rHuIFN-alpha A/D suppressed virus-induced splenomegaly in a dose-dependent fashion in mice inoculated with Rauscher murine leukemia virus (RLV). However, suppressive doses of single-agent AZT caused anemia after 20 days of therapy. Combining rHuIFN-alpha A/D with AZT allowed drastic dose reductions for each agent while maintaining greater than or equal to 93% inhibition of splenomegaly. No clinically significant toxicity was seen. Computer analysis with the isobologram technique and combination index method showed that these combination regimens were highly synergistic. A 20-day course of AZT + rHuIFN-alpha A/D started 4 h after virus exposure was protective against RLV viremia and disease. After cessation of therapy, the animals were resistant to rechallenge with fully infectious RLV. We conclude that prompt initiation of effective combination therapy after retroviral exposure prevented viremia and disease and led to protective immunity.

Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice.

Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3'-azido-3'-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.

What do American nephologists think about dialysis modality selection? .

In the United States, 87.3% of the patients with end-stage renal disease (ESRD) requiring dialysis are treated with hemodialysis (HD) and 12.7% with peritoneal dialysis (PD). This represents a greater use of HD than in many other nations. We mailed a survey questionnaire to members of the National Kidney Foundation Council on Dialysis to better understand the attitudes of American nephrologists toward dialysis modality decisions. We received responses from 240 of 507 nephrologists (47.3%). The respondents were heavily involved in clinical dialysis work. Results showed that decisions regarding modality selection were strongly based on patient preference (4.54 on a scale of 1 to 5), quality of life (4.18), morbidity (4.02), and mortality (3.90), whereas the least important factors reported were facility reimbursement (2.09) and physician reimbursement (1.98). When asked about the current use of modalities, hospital-based HD and full-care HD were believed to be overused (2.63 for each on a scale of 1 [vastly overused] to 5 [vastly underused]), whereas home HD (4.29), continuous ambulatory PD (3.71), and cycler PD (3.59) were underused. A hypothetical question about optimal modality distribution to maximize survival or cost-effectiveness showed that HD should constitute 71% or 66% of dialysis (with 11% or 14% in the form of home HD, respectively). PD use would increase between two- and threefold over current practices. Our results suggest that American nephrologists believe home therapies are underused. Because modality distribution is an important determinant of costs and possibly outcomes in patients with ESRD, there is an urgent need for further research in this area.

Monitoring cytomegalovirus retinitis prevalence in an HIV-seropositive cohort: the assessment of improvements observed following the introduction of highly active antiretroviral triple therapy.

This paper concerns the ophthalmic assessment of patients with acquired immunodeficiency syndrome (AIDS) for a number of eye conditions and in particular cytomegalovirus (CMV) retinitis. CMV has been the most common opportunistic infection associated with AIDS and the leading cause of blindness among AIDS patients. There have been early indications of a widespread fall in CMV prevalence internationally following the introduction of a new highly active antiretroviral triple (HAART) therapy. Our study sought to assess the position for Ireland. Our cohort was the entire population of stage IV AIDS patients attending the country's leading referral centre. The total number of patients examined was 167 and the period of examination was 1 May 1995 to 30 April 1997. HAART was introduced in March 1996, so the data permitted a 'before and after' comparison of various clinical findings. The incidence of new CMV cases was found to be 4 among the 102 patients examined in the first 12-month period and one among 107 patients examined in the second 12-month period. There were accompanying declines in HIV-related noninfectious retinal vasculopathy (HIVR), keratitis and other conditions. The findings are promising, but we argue that caution is needed in assessing long-term trends. In the paper we discuss a number of methodological issues in the collection and analysis of the clinical data and in the interpretation of results.

Protective cellular retroviral immunity requires both CD4+ and CD8+ immune T cells.

We have found previously that postexposure chemoprophylaxis with 3'-azido-3'-deoxythymidine (also known as zidovudine or AZT) in combination with recombinant human alpha A/D interferon fully protected mice exposed to a lethal dose of Rauscher murine leukemia virus (RLV) against viremia and disease. After cessation of therapy, over 90% of these mice were able to resist rechallenge with live RLV, thus demonstrating an acquired immunity. Adoptive cell transfer of 4 x 10(7) cells from immunized mice fully protected naive recipients from viremia and splenomegaly after RLV challenge. However, when these immune T cells were fractionated into CD4+ and CD8+ subpopulations, only partial protection was found when 4 x 10(7) T cells of either subset were given. Full protection against RLV challenge was seen again when the T-cell subsets from immunized mice were recombined and transferred at the same number into naive mice. We conclude that cellular immunity alone is protective and that both CD4+ and CD8+ cell types are required for conferring full protection against live virus challenge.

Vaccination with a live retrovirus: the nature of the protective immune response.

We tested 3'-azido-3'-deoxythymidine (zidovudine) combined with interferon alpha as chemoprophylaxis after exposing mice to Rauscher murine leukemia virus. Therapy started 4 hr after inoculation and administered for 20 days prevented viremia and disease in all 234 mice tested. When the animals were rechallenged with live virus after cessation of therapy, 96% were resistant. The nature of this protective immune response was analyzed: Passive serotherapy of naive mice challenged subsequently with Rauscher murine leukemia virus was only protective at a high dose of immune serum. Immune, but not naive, T cells alone were fully protective against virus challenge. We conclude that vaccination with a live retrovirus that cannot replicate because of pharmacological blockade induces a T-cell response capable of protecting against a lethal retrovirus-induced disease.

A Chinese hamster fibroblast mutant defective in thrombin-induced signaling has a low level of phospholipase C-beta 1.

A mutant fibroblast, 2A4b, was isolated from the Chinese hamster lung cell line CCL39 by a previously described selection (Rath, H. M., Doyle, G. A. R., and Silbert, D. F. (1989) J. Biol. Chem. 264, 13387-13390) for cells deficient in thrombin-induced signaling. Although the antiporter activation by thrombin in 2A4b is only approximately 60% that in CCL39, the stimulation by serum is not significantly impaired, indicating that the defect in 2A4b lies upstream of the antiporter in the signaling pathway. The addition of thrombin to serum-starved 2A4b cells causes blunted responses both in production of inositol phosphates and in the cytosolic [Ca2+] transient, particularly when no Ca2+ is added to the external medium. The in vitro inositol phospholipid-specific phospholipase C (PLC) activity of 2A4b cytosol plus membrane extracts exceeds that in CCL39. However, immunoblots with antibodies to PLC isozymes show that although the levels of PLC-delta 1, PLC-gamma 1, and PLC-beta 3 are at least as great as those in CCL39, the amount of PLC-beta 1 in 2A4b is markedly deficient (< or = 10%). PLC-beta 1 is found primarily in the nucleus and in non-nuclear membranes of CCL39 and is proportionately low in these subcellular locations of 2A4b. Thrombin activation of phospholipases D and A2 is impaired in 2A4b. We postulate that the deficiency in PLC-beta 1 causes defective targeting of protein kinase C-alpha to specific membrane sites, which may be required for activation of these downstream phospholipases.